Reclaiming The Kingdom of God Metaphor for the Twenty-First-Century Church

In this dissertation I will argue that an egocentric eschatology (preoccupation with what happens to the individual at the moment of death) has unwittingly trumped the importance of incarnating the Kingdom of God in this present world. It is my assertion that a better understanding of Kingdom of God theology and the promotion of its priority will inspire Christian discipleship leading to reformation and renewal in the church. For this to happen, we must fundamentally renovate our definition and articulate the meaning of “Kingdom of God” as His sovereign reign and rule over a people He has called out, set apart, and sent forth to carry out His mission in the world. This Kingdom is both a present reality and a future hope. It exists already, but it is not yet fully realized. The supreme and sovereign reign of Christ has been established through His sinless life, sacrificial death, and bodily resurrection. All authority in Heaven and on earth is His. His reign was victoriously inaugurated, and it will be finally consummated when He returns at the end of this age. Christ’s Kingly influence has continued to expand from the time of His ascension to the present day and it will progress until the Second Advent. During this age, God is drawing to Himself a people from every nation, tribe, and language. We call this gathering of people the Church, and its members are citizens, ambassadors, and witnesses of His Kingdom on earth. A problem I have observed in a rural Wesleyan context is that an inaccurate and inadequate theology of the Kingdom has inadvertently undermined the priority of spiritual formation and gospel ministry. An inordinate emphasis on “going to heaven when I die” has subjugated the primacy of the Kingdom of God. The question for our consideration then is, how might redeeming and redefining a biblical Kingdom of God metaphor revitalize spiritual passion in rural Wesleyan churches? Myles Munro summarizes this conflict very well: “One of God’s biggest challenges in getting His message of the Kingdom to the world is the fact that we who are His witnesses on earth are so slow to understand the message. Dreams of golden streets and heavenly bliss have blinded us to our responsibilities on earth.” 1 In this dissertation I will argue the case that improving our understanding of Kingdom citizenship (its privileges and responsibilities) will help the church refocus her attention on the task of reproducing Christ-like disciples; ambassadors and witnesses of the Kingdom of God in the present age

1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) inhibitors

We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors

The Effect of LXR Activators on AP-1 Proteins in Keratinocytes

Oxysterols, via activation of liver X receptor (LXR), regulate keratinocyte differentiation by stimulating transglutaminase cross-linking of several constituent proteins leading to the formation of the cornified envelope. We previously reported that oxysterols increase the expression of one of these cross-linked proteins, involucrin, and that this effect can be abolished by mutations of the distal activator protein (AP)-1 response element in the involucrin promoter. Furthermore, oxysterols increase AP-1 binding in an electrophoretic gel mobility shift assay and increase the expression of an AP-1 reporter. In this study, we describe the individual components of the AP-1 complex that are involved in the oxysterol-mediated AP-1 activation and stimulation of keratinocyte differentiation. We identified Fra-1 within the AP-1 DNA binding complex by supershift analysis of nuclear extracts from oxysterol-treated, cultured keratinocytes and confirmed that oxysterol treatment increased the levels of Fra-1 by western blot analysis. Additionally, on Western and Northern analysis, oxysterol treatment increased two other AP-1 proteins, Jun-D and c-Fos, whereas Fra-2, Jun-B, and c-Jun were not changed. Similar alterations in AP-1 proteins occurred when 25-OH-cholesterol or non-steroidal LXR agonists (GW3965, TO-901317) were used. These results indicate that oxysterols induce specific AP-1 proteins, thereby activating involucrin, one of the genes required for epidermal differentiation

Coupling angle variability in healthy and patellofemoral pain runners

Background Patellofemoral pain is hypothesized to result in less joint coordination variability. The ability to relate coordination variability to patellofemoral pain pathology could have many clinical uses; however, evidence to support its clinical application is lacking. The aim was to determine if vector coding's coupling angle variability, as a measure of joint coordination variability, was less for runners with patellofemoral pain than healthy controls as is commonly postulated. Methods Nineteen female recreational runners with patellofemoral pain and eleven healthy controls performed a treadmill acclimation protocol then ran at a self-selected pace for 15 min. 3-D kinematics, force plate kinetics, knee pain and rating of perceived exertion were recorded each minute. Data were selected for the: pain group at the highest pain reached (pain � 3/10) in a non-exerted state (exertion < 14/20), and; non-exerted healthy group from the eleventh minute. Coupling angle variability was calculated over several portions of the stride for six knee-ankle combinations during five non-consecutive strides. Findings 46 of 48 coupling angle variability measures were greater for the pain group, with 7 significantly greater (P <.05). Interpretation These findings oppose the theory that less coupling angle variability is indicative of a pathological coordinate state during running. Greater coupling angle variability may be characteristic of patellofemoral pain in female treadmill running when a larger threshold of pain is reached than previously observed. A predictable and directional response of coupling angle variability measures in relation to knee pathology is not yet clear and requires further investigation prior to considerations for clinical utility. © 2013 Elsevier Ltd

Crystal structure of the PXR–T1317 complex provides a scaffold to examine the potential for receptor antagonism

The human pregnane X receptor (PXR) recognizes a range of structurally- and chemically-distinct ligands and plays a key role in regulating the expression of protective gene products involved in the metabolism and excretion of potentially harmful compounds. The identification and development of PXR antagonists is desirable as a potential way to control the up-regulation of drug metabolism pathways during the therapeutic treatment of disease. We present the 2.8 Å resolution crystal structure of the PXR ligand binding domain (LBD) in complex with T0901317 (T1317), which is also an agonist of another member of the orphan class of the nuclear receptor superfamily, the liver X receptor (LXR). In spite of differences in the size and shape of the receptors' ligand binding pockets, key interactions with this ligand are conserved between human PXR and human LXR. Based on the PXR-T1317 structure, analogues of T1317 were generated with the goal of designing an PXR antagonist effective via the receptor's ligand binding pocket. We find that selectivity in activating PXR vs. LXR was achieved; such compounds may be useful in addressing neurodegenerative diseases like Niemann-Pick C. We were not successful, however, in producing a PXR antagonist. Based on these observations, we conclude that the generation of PXR antagonists targeted to the ligand binding pocket may be difficult due to the promiscuity and structural conformability of this xenobiotic sensor

Characterization of a non-chemically amplified resist for photomask fabrication using a 257-nm optical pattern generator

optical pattern generato