256 research outputs found
Runway exit designs for capacity improvement demonstrations. Phase 2: Computer model development
The development is described of a computer simulation/optimization model to: (1) estimate the optimal locations of existing and proposed runway turnoffs; and (2) estimate the geometric design requirements associated with newly developed high speed turnoffs. The model described, named REDIM 2.0, represents a stand alone application to be used by airport planners, designers, and researchers alike to estimate optimal turnoff locations. The main procedures are described in detail which are implemented in the software package and possible applications are illustrated when using 6 major runway scenarios. The main output of the computer program is the estimation of the weighted average runway occupancy time for a user defined aircraft population. Also, the location and geometric characteristics of each turnoff are provided to the user
Runway Exit Designs for Capacity Improvement Demonstrations. Phase 1: Algorithm Development
A description and results are presented of a study to locate and design rapid runway exits under realistic airport conditions. The study developed a PC-based computer simulation-optimization program called REDIM (runway exit design interactive model) to help future airport designers and planners to locate optimal exits under various airport conditions. The model addresses three sets of problems typically arising during runway exit design evaluations. These are the evaluations of existing runway configurations, addition of new rapid runway turnoffs, and the design of new runway facilities. The model is highly interactive and allows a quick estimation of the expected value of runway occupancy time. Aircraft populations and airport environmental conditions are among the multiple inputs to the model to execute a viable runway location and geometric design solution. The results presented suggest that possible reductions on runway occupancy time (ROT) can be achieved with the use of optimally tailored rapid runway designs for a given aircraft population. Reductions of up to 9 to 6 seconds are possible with the implementation of 30 m/sec variable geometry exits
Going the distance for procurement of donation after circulatory death livers for transplantation—Does reimbursement reflect reality?
Donation after circulatory death (DCD) liver transplantation (LT) has increased slowly over the past decade. Given that transplant surgeons generally determine liver offer acceptance, understanding surgeon incentives and disincentives is paramount. The purpose of this study was to assess aggregate travel distance per successful DCD versus deceased after brain death (DBD) liver procurement as a surrogate for surgeon time expenditure and opportunity cost. All consecutive liver offers made to Michigan Medicine from 2006 to 2017 were analyzed. Primary outcome was the summative travel distance (spent on all attempted procurements) per successful liver procurement that resulted in LT. Donation after circulatory death liver offer acceptance was lower than DBD liver offers, as was proportion of successful procurements among accepted offers. Overall, 10 275 miles were travelled for accepted DCD liver offers, resulting in 23 successful procurements (mean 447 miles per successful DCD liver procurement). For accepted DBD liver offers, 197 299 miles were travelled, resulting in 863 successful procurements (mean 229 miles per successful DBD liver procurement). On average, each successful DCD liver procurement required 218 more miles of travel than each successful DBD liver procurement. Current reimbursement policies poorly reflect increased surgeon travel (and time) expenditures between DCD and DBD liver offers.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154400/1/ctr13780_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154400/2/ctr13780.pd
Kidins220/ARMS binds to the B cell antigen receptor and regulates B cell development and activation
B cell antigen receptor (BCR) signaling is critical for B cell development and activation. Using mass spectrometry, we identified a protein kinase D\u2013interacting substrate of 220 kD (Kidins220)/ankyrin repeat\u2013rich membrane-spanning protein (ARMS) as a novel interaction partner of resting and stimulated BCR. Upon BCR stimulation, the interaction increases in a Src kinase\u2013independent manner. By knocking down Kidins220 in a B cell line and generating a conditional B cell\u2013specific Kidins220 knockout (B-KO) mouse strain, we show that Kidins220 couples the BCR to PLC\u3b32, Ca2+, and extracellular signal-regulated kinase (Erk) signaling. Consequently, BCR-mediated B cell activation was reduced in vitro and in vivo upon Kidins220 deletion. Furthermore, B cell development was impaired at stages where pre-BCR or BCR signaling is required. Most strikingly, \u3bb light chain\u2013positive B cells were reduced sixfold in the B-KO mice, genetically placing Kidins220 in the PLC\u3b32 pathway. Thus, our data indicate that Kidins220 positively regulates pre-BCR and BCR functionin
PROviding Better ACcess To ORgans: A comprehensive overview of organ‐access initiatives from the ASTS PROACTOR Task Force
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138905/1/ajt14441_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138905/2/ajt14441.pd
Towards system optimum: Finding optimal routing strategies in time dependent networks for large-scale evacuation problems
Disaster and evacuation planning crucially depend on good routing strategies. This article compares two different routing strategies in a multi-agent simulation of a large real world evacuation scenario. The first approach approximates a Nash equilibrium where every evacuee adopts an individually optimal routing strategy regardless of what this solution imposes on others. The second approach approximately minimizes the total travel time in the system, which requires to enforce cooperative behavior of the evacuees. Both approaches are analyzed in terms of the global evacuation dynamics and on a detailed geographic level
Influence of IFN-gamma and its receptors in human breast cancer
<p>Abstract</p> <p>Background</p> <p>Interferons are a group of proteins that trigger multiple responses including prevention of viral replication, inhibition of cell growth, and modulation of cell differentiation. In different mammary carcinoma cell lines IFNγ induces growth arrest at mid-G1. At the present there are no <it>in vivo </it>studies in human breast. The aim of this study was to investigate the expression patterns of IFNγ and its two receptors (IFNγ-Rα and IFNγ-Rβ) by Western blot and immunohistochemistry, in order to elucidate its role in the different types of human breast cancer (<it>in situ </it>and infiltrative).</p> <p>Methods</p> <p>Immunohistochemical and semiquantitative study of IFNγ, its receptors types (IFNγ-Rα and IFNγ-Rβ), cell proliferation (proliferating cell nuclear antigen, also named PCNA), and apoptosis (TUNEL method) was carried between the three breast groups (fibrocystic lesions, <it>in situ</it> tumors and infiltrating tumors).</p> <p>Results</p> <p>In the three groups of patients, IFNγ and IFNγ-Rα immunoreactions appeared in the cytoplasm while IFNγ-Rβ also was found in the nucleus. The optical density to IFNγ was higher in <it>in situ </it>carcinoma than in benign and infiltrating tumors. When we observed IFNγ-Rα, the optical density was lower in infiltrating carcinoma than in benign and <it>in situ </it>tumors (the higher density). To IFNγ-Rβ, the optical density was similar in the three group samples. In tumor samples PCNA and TUNEL index was significantly higher; than in benign diseases. PCNA index increased with the malignance. No significant differences were found between cancer types to TUNEL. IFNγ could be a potential therapeutic tool in breast cancer. However, tumor cells are able to escape from the control of this cytokine in the early tumor stages; this is probably due to a decreased expression of IFNγ, or also to an alteration of either its receptors or some transduction elements.</p> <p>Conclusion</p> <p>We conclude that the decrease in the % positive samples that expressed IFNγ and IFNγ-Rα together with the nuclear localization of IFNγ-Rβ, could be a tumoral cell response, although perhaps insufficient to inhibit the uncontrolled cell proliferation. Perhaps, IFNγ might be unable to activate p21 to stop the cell cycle, suggesting a possible participation in breast cancer development.</p
Cytotoxic response of ovarian cancer cell lines to IFN-γ is associated with sustained induction of IRF-1 and p21 mRNA
Results and harmonization guidelines from two large-scale international Elispot proficiency panels conducted by the Cancer Vaccine Consortium (CVC/SVI)
The Cancer Vaccine Consortium of the Sabin Vaccine Institute (CVC/SVI) is conducting an ongoing large-scale immune monitoring harmonization program through its members and affiliated associations. This effort was brought to life as an external validation program by conducting an international Elispot proficiency panel with 36 laboratories in 2005, and was followed by a second panel with 29 participating laboratories in 2006 allowing for application of learnings from the first panel. Critical protocol choices, as well as standardization and validation practices among laboratories were assessed through detailed surveys. Although panel participants had to follow general guidelines in order to allow comparison of results, each laboratory was able to use its own protocols, materials and reagents. The second panel recorded an overall significantly improved performance, as measured by the ability to detect all predefined responses correctly. Protocol choices and laboratory practices, which can have a dramatic effect on the overall assay outcome, were identified and lead to the following recommendations: (A) Establish a laboratory SOP for Elispot testing procedures including (A1) a counting method for apoptotic cells for determining adequate cell dilution for plating, and (A2) overnight rest of cells prior to plating and incubation, (B) Use only pre-tested serum optimized for low background: high signal ratio, (C) Establish a laboratory SOP for plate reading including (C1) human auditing during the reading process and (C2) adequate adjustments for technical artifacts, and (D) Only allow trained personnel, which is certified per laboratory SOPs to conduct assays. Recommendations described under (A) were found to make a statistically significant difference in assay performance, while the remaining recommendations are based on practical experiences confirmed by the panel results, which could not be statistically tested. These results provide initial harmonization guidelines to optimize Elispot assay performance to the immunotherapy community. Further optimization is in process with ongoing panels
A Model of a MAPK•Substrate Complex in an Active Conformation: A Computational and Experimental Approach
The mechanisms by which MAP kinases recognize and phosphorylate substrates are not completely understood. Efforts to understand the mechanisms have been compromised by the lack of MAPK-substrate structures. While MAPK-substrate docking is well established as a viable mechanism for bringing MAPKs and substrates into close proximity the molecular details of how such docking promotes phosphorylation is an unresolved issue. In the present study computer modeling approaches, with restraints derived from experimentally known interactions, were used to predict how the N-terminus of Ets-1 associates with ERK2. Interestingly, the N-terminus does not contain a consensus-docking site ((R/K)2-3-X2-6-ΦA-X-ΦB, where Φ is aliphatic hydrophobic) for ERK2. The modeling predicts that the N-terminus of Ets-1 makes important contributions to the stabilization of the complex, but remains largely disordered. The computer-generated model was used to guide mutagenesis experiments, which support the notion that Leu-11 and possibly Ile-13 and Ile-14 of Ets-1 1-138 (Ets) make contributions through binding to the hydrophobic groove of the ERK2 D-recruiting site (DRS). Based on the modeling, a consensus-docking site was introduced through the introduction of an arginine at residue 7, to give the consensus 7RK-X2-ΦA-X-ΦB13. This results in a 2-fold increase in kcat/Km for the phosphorylation of Ets by ERK2. Similarly, the substitution of the N-terminus for two different consensus docking sites derived from Elk-1 and MKK1 also improves kcat/Km by two-fold compared to Ets. Disruption of the N-terminal docking through deletion of residues 1-23 of Ets results in a 14-fold decrease in kcat/Km, with little apparent change in kcat. A peptide that binds to the DRS of ERK2 affects Km, but not kcat. Our kinetic analysis suggests that the unstructured N-terminus provides 10-fold uniform stabilization of the ground state ERK2•Ets•MgATP complex and intermediates of the enzymatic reaction
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