The Role of MKK3 in Mediating Signals to the p38 MAP Kinase Pathway: A Dissertation

p38 mitogen-activated protein (MAP) kinases represent a subgroup of MAP kinases that respond to environmental stress and inflammatory cytokines. p38 MAPK is activated by two upstream kinases, MKK3 and MKK6, by dual phosphorylation on threonine and tyrosine in conserved kinase subdomain VII. Until recently the relative roles of MKK3 and MKK6 have remained unclear. I have undertaken two strategies in an effort to understand the importance of MKK3 as a p38 MAPK activator. First, I cloned and characterized the murine mkk3 gene and determined the structure of the 5\u27-terminus. Comparison of the murine and human mkk3 genes revealed that the mouse gene encodes a single MKK3 isoform, MKK3b, and the human gene encodes two isoforms, MKK3a and MKK3b. Comparison of the mouse and human mkk3 genes suggests that expression of MKK3a and MKK3b is regulated from different promotors. Analysis of the mkk3 promoter demonstrates that muscle specific expression of murine MKK3b is controlled, in part, by the transcription factors MEF2 and MyoD. Second, I have utilized a gene targeting strategy to disrupt the murine mkk3 gene and to examine the effect on p38 MAPK signaling. I found that there is a p38-specific signaling defect in MKK3 deficient primary mouse embryo fibroblasts (MEF) which correlates with deficits in interleukin (IL)-1 and IL-6 production in response to tumor necrosis factor-α (TNFα) stimulation. In addition there is a defect in TNFα mediated expression of TNFα and macrophage inflammatory proteins (MIP) 1α, MIP1β and MIP2. p38 MAPK-specific signaling defects were also observed in lipopolysaccharide (LPS) stimulated mkk3 (-/-) macrophages. Additionally, mkk3 (-/-) macrophages exhibit defects in LPS and CD40-ligand (CD40L) stimulated IL-12 biosynthesis. Similar data were obtained from CD40L-stimulated mkk3 (-/-) dendritic cells. I also observe that interferon (Ifn)-γ production is diminished during T-helper-1 (TH1) differentiation of CD4+ T-cells derived from mkk3 (-/-) mice. Taken together these data demonstrate a crucial role for p38 MAPK activation by MKK3 in response to the inflammatory cytokine, TNFα and during a TH1 inflammatory response

Faculty and Student Perceptions on Shared Teaching Materials for Advanced Manufacturing (STAM): Building Momentum Through Workshops

In this paper, we summarize the outcomes of the two workshops aimed at speeding up the transition of research-based advanced manufacturing knowledge into course curriculum for technology and engineering programs. Advanced manufacturing technologies have opened up the realm for new products that only a decade ago were considered unproducible. For example metals 3D Printing has almost no geometric limitations, which allows engineers to develop mesh–based products. Unfortunately, the educational system that serves to educate the majority of manufacturing technicians and engineers still utilizes many of the same curriculum resources for these emerging areas (textbooks, traditional lectures, etc.), frequently creating an unsuitable or inappropriate learning environment for state-of-the-science technician and engineering training. This is especially true for the development of manufacturing materials and laboratories to maintain currency in advanced manufacturing. With funding from NSF, two workshops were conducted that generated great enthusiasm for the concept of a teaching repository for advanced manufacturing technology. More than 50 advanced manufacturing instructors have attended the workshops, and a community of instructors has been created. Results from faculty and student perceptions on shared teaching materials for advanced manufacturing are also shared

Visibility from a Slice File for Rapid CNC Machining

A methodology for using CNC machining as a rapid prototyping process is being developed. The method involves cutting complex parts using layer-based machining operations from a plurality of orientations about one axis of rotation. A critical step is to determine the number of and location of those orientations. This paper presents an approach to mapping the visibility of a model about an axis of rotation using a set of model slices taken orthogonal to the axis of rotation

Economics of Sacrificial Fixturing for CNC Machining and Rapid Manufacturing

This paper presents a fixturing method for sacrificial fixturing machining using CNC equipment. The focus of the paper is not on the method itself, but on the economics of sacrificial fixturing CNC machining, which defines the domain of use for the results described in the paper. The paper presents an economic model of machining, and then analyzes the use of the method as a function of: the number of parts to be produced, the ratio of material removed to final part volume, the number of features on the part, and the basic part geometry. We conclude that sacrificial fixturing is a very practical method that should be seriously considered when machining small batches of parts, rapid prototyping with CNC machining and parts with some particular geometric characteristics

Determining Setup Orientations From the Visibility of Slice Geometry for Rapid Computer Numerically Controlled Machining

A method for rapid computer numerically controlled (CNC) machining is being developed in an effort to automatically create functional prototypes and parts in a wide array of materials. The method uses a plurality of simple two-and-a-half-dimensional (21/2-D) toolpaths from various orientations about an axis of rotation in order to machine the entire surface of a part without refixturing. It is our goal to automatically create these toolpaths for machining and eliminate the complex planning traditionally associated with CNC machining. In this paper, we consider a problem that arises in automating this process - visibility to the surface of a model that is rotated about a fourth axis. Our approach involves slicing the computer-aided design (CAD) model orthogonal to the axis of rotation. The slice geometry is used to calculate two-dimensional visibility maps for the set of polygons on each slice plane. The visibility data provides critical information for determining the minimum number and orientation of 21/2-D toolpaths required to machine the entire surface of a part

Advanced Manufacturing Using Linked Processes: Hybrid Manufacturing

Hybrid Manufacturing Processes (HMP) can significantly reduce time to customer, waste, and tooling costs per part, while increasing possible part geometric complexity for small batch parts. In the following chapter, HMP is defined by the production of parts produced first with a near-net shape process using methods including: additive manufacturing, casting, injection molding, etc., which is then coupled with multi-axis computer numerical control (CNC) subtractive machining or some other secondary material removal process. Creating process plans for such hybrid manufacturing processes typically takes weeks rather than hours or days. This chapter outlines several hybrid manufacturing processes and the intricacies required to develop process plans for these complex linked processes. A feature-based advanced hybrid manufacturing process planning system (FAH-PS) uses feature-specific geometric, tolerance, and material data inputs to generate automated process plans based on user-specified feature precedence for additive-subtractive hybrid manufacturing. Plans generated by FAH-PS can optimize process plans to minimize tool changes, orientation changes, etc., to improve process times. A case study of additive-subtractive methods for a patient-specific bone plate, demonstrates system capabilities and processing time reductions as compared to the current manual process planning for hybrid manufacturing methodologies. Using the generated FAH-PS process plan resulted in a 35% reduction in machining time from the current hybrid manufacturing strategy

Data Preservation: Final Step in the Life Cycle of a Mission

Many NASA Earth Observing System (EOS) have either already reached the end of their active life or are nearing it. Preservmissionsation of data products is a fairly well defined task for the NASA EOS Data Centers or DAACs.The Goddard Earth Sciences Data and Information Services Center (GES-DISC) has implemented a repository system, which is capable of long-term archive of documentation artifacts and other associated digital content. The existing GES-DISC Repository System is based on Fedora Commons, an open-source repository management software, for cost savings and flexibility.The first mission to utilize the GES-DISC Repository System was the High Resolution Dynamics Limb Sounder (HIRDLS) on the Aura spacecraft. Since then, the GES DISC has gathered documentation from the UARS and TOMS into the Repository. The Microwave Limb Sounder (MLS) team has begun delivering some early pre-launch documents to the GES-DISC Repository System as well. Other missions in planning or progress include AIRS, OMI, SORCE, SNPP Sounder, and TRMM

A Highway-Driving System Design Viewpoint using an Agent-based Modeling of an Affordance-based Finite State Automata

This paper presents an agent-based modeling framework for affordance-based driving behaviors during the exit maneuver of driver agents in human-integrated transportation problems. We start our discussion from one novel modeling framework based on the concept of affordance called the Affordance-based Finite State Automata (AFSA) model, which incorporates the human perception of resource availability and action capability. Then, the agent-based simulation illustrates the validity of the AFSA framework for the Highway-Lane-Driver System. Next, the comparative study between real driving data and agent-based simulation outputs is provided using the transition diagram. Finally, we perform a statistical analysis and a correlation study to analyze affordance-based driving behavior of driver agents. The simulation results show that the AFSA model well represents the perception-based human actions and drivers??? characteristics, which are essential for the design viewpoint of control framework of human driver modeling. This study is also expected to benefit a designed control for autonomous/self-driving car in the future