8,216 research outputs found
Performance of a micro-engineered ultrasonic particle manipulator
No full textAn ultrasonic microfluidic particle manipulator has been modeled and its experimentally measured separation performance has been compared with the modeled results for 1 µm latex particles, and yeast particles in water
10-05 "The Macroeconomics of Development without Throughput Growth"
No full textSerious discussion has begun of policies to promote the goal of increasing well-being without material growth. Moving towards this goal requires a profound reorientation of macroeconomic theory. Importantly, the call by ecological economists to move away from traditional growth-oriented models comes at a moment when standard macroeconomics is in considerable turmoil. The financial crisis of 2008/2009 seriously undermined the basis for mainstream macroeconomics and brought renewed attention to various forms of Keynesian analysis and policy previously regarded as outdated. There is a close complementarity between new Keynesian and ecological perspectives. While older Keynesian analysis was oriented towards promoting growth, a true Keynesian analysis of the relationship between investment and consumption does not depend on a growth orientation. What this analysis has in common with an ecological perspective is the rejection of market optimality assumed in classical models. Moving away from the neoclassical goal of inter-temporal utility maximization allows for different, pluralistic economic goals: full employment, provision of basic needs, social and infrastructure investment, and income equity. These goals are compatible with environmental preservation and resource sustainability, whereas indefinite growth is not. But they require a revitalization of the sphere of social investment, seriously neglected (indeed often omitted completely) in standard models. Reintroducing this perspective allows the development of an economic theory suitable for the transition to a stable-population, low-carbon, resource-conserving global economy. The barriers to this transition are primarily political and institutional, not economic. Specifically, an eco-Keynesian perspective emphasizes new macroeconomic categories including: * human-capital-intensive services * investment in energy-conserving capital * investment in natural and human capital The expansion of these categories provides a basis for growth in wellbeing without growth in throughput, while preserving full employment and economic stability. This paper explores some of the implications of this altered macroeconomic perspective for development in both the global "North" and "South". It is suggested that the problems following the global financial crisis cannot be resolved by a return to traditional growth patterns, and will require large-scale practical policies based on eco-Keynesianism.
The Contribution of Different Androgen Receptor Domains to Receptor Dimerization and Signaling
No full textThe androgen receptor (AR) is a ligand-activated transcription factor of the nuclear receptor superfamily that plays a critical role in male physiology and pathology. Activated by binding of the native androgens testosterone and 5{alpha}-dihydrotestosterone, the AR regulates transcription of genes involved in the development and maintenance of male phenotype and male reproductive function as well as other tissues such as bone and muscle. Deregulation of AR signaling can cause a diverse range of clinical conditions, including the X-linked androgen insensitivity syndrome, a form of motor neuron disease known as Kennedy’s disease, and male infertility. In addition, there is now compelling evidence that the AR is involved in all stages of prostate tumorigenesis including initiation, progression, and treatment resistance. To better understand the role of AR signaling in the pathogenesis of these conditions, it is important to have a comprehensive understanding of the key determinants of AR structure and function. Binding of androgens to the AR induces receptor dimerization, facilitating DNA binding and the recruitment of cofactors and transcriptional machinery to regulate expression of target genes. Various models of dimerization have been described for the AR, the most well characterized interaction being DNA-binding domain- mediated dimerization, which is essential for the AR to bind DNA and regulate transcription. Additional AR interactions with potential to contribute to receptor dimerization include the intermolecular interaction between the AR amino terminal domain and ligand-binding domain known as the N-terminal/C-terminal interaction, and ligand-binding domain dimerization. In this review, we discuss each form of dimerization utilized by the AR to achieve transcriptional competence and highlight that dimerization through multiple domains is necessary for optimal AR signaling.Margaret M. Centenera, Jonathan M. Harris, Wayne D. Tilley and Lisa M. Butle
Global Institutions and ecological crisis. by Jonathan M. Harris
No full textThe concepts of growth management and sustainable development have emerged as responses to the environmental crisis
Book Review: M. HESLOP, Medieval Greece: encounters between Latins, Greeks and others in the Dodecanese and the Mani [ser. Variorum Collected Studies]; foreword by Jonathan HARRIS [xvi-xviii] (London & New York: Routledge-Francis & Taylor Group, 2021)
No full textM. Heslop, Medieval Greece: encounters between Latins, Greeks and others in the Dodecanese and the Mani [ser. Variorum Collected Studies]; foreword by Jonathan HARRIS [xvi-xviii] (London & New York: Routledge-Francis & Taylor Group, 2021
Mutation of the androgen receptor causes oncogenic transformation of the prostate
No full textRecent evidence demonstrates that the androgen receptor (AR) continues to influence prostate cancer growth despite medical therapies that reduce circulating androgen ligands to castrate levels and/or block ligand binding. Whereas the mutation, amplification, overexpression of AR, or cross-talk between AR and other growth factor pathways may explain the failure of androgen ablation therapies in some cases, there is little evidence supporting a causal role between AR and prostate cancer. In this study, we functionally and directly address the role whereby AR contributes to spontaneous cancer progression by generating transgenic mice expressing (i) AR-WT to recapitulate increased AR levels and ligand sensitivity, (ii) AR-T857A to represent a promiscuous AR ligand response, and (iii) AR-E231G to model altered AR function. Whereas transgenes encoding either AR-WT or AR-T857A did not cause prostate cancer when expressed at equivalent levels, expression of AR-E231G, which carries a mutation in the most highly conserved signature motif of the NH2-terminal domain that also influences interactions with cellular coregulators, caused rapid development of prostatic intraepithelial neoplasia that progressed to invasive and metastatic disease in 100% of mice examined. Taken together, our data now demonstrate the oncogenic potential of steroid receptors and implicate altered AR function and receptor coregulator interaction as critical determinants of prostate cancer initiation, invasion, and metastasis.Guangzhou Han, Grant Buchanan, Michael Ittmann, Jonathan M. Harris, Xiaoqing Yu, Francesco J. DeMayo, Wayne Tilley and Norman M. Greenber
Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer
No full textCopyright © 2007 by The Federation of American Societies for Experimental BiologyThere is now considerable evidence that using a combination of synthetic progestins and estrogens in hormone replacement therapy (HRT) increases the risk of breast cancer compared with estrogen alone. Furthermore, the World Health Organization has recently cited combination contraceptives, which contain synthetic progestins, as potentially carcinogenic to humans, particularly for increased breast cancer risk. Given the above observations and the current trend toward progestin-only contraception, it is important that we have a comprehensive understanding of how progestins act in the millions of women worldwide who regularly take these medications. While synthetic progestins, such as medroxyprogesterone acetate (MPA), which are currently used in both HRT and oral contraceptives were designed to act exclusively through the progesterone receptor, it is clear from both clinical and experimental settings that their effects may be mediated, in part, by binding to the androgen receptor (AR). Disruption of androgen action by synthetic progestins may have serious deleterious side effects in the breast, where the balance between estrogen signaling and androgen signaling plays a critical role in breast homeostasis. Here, we review the role of androgen signaling in the normal breast and in breast cancer and present new data demonstrating that androgen receptor function can be perturbed by low doses of MPA, similar to doses achieved in serum of women taking HRT. We propose that the observed excess of breast malignancies associated with combined HRT may be explained, in part, by synthetic progestins such as MPA acting as endocrine disruptors to negate the protective effects of androgen signaling in the breast. Understanding the role of androgen signaling in the breast and how this is modulated by synthetic progestins is necessary to determine how combined HRT alters breast cancer risk, and to inform the development of optimal preventive and treatment strategies for this disease.Stephen N. Birrell, Lisa M. Butler, Jonathan M. Harris, Grant Buchanan and Wayne D. Tille
Natural and engineered plasmin inhibitors : applications and design strategies
No full textPlasmin is the primary enzyme responsible for dissolution of fibrin in the circulatory system. Plasminogen, the zymogen of plasmin is expressed ubiquitously in the human body [1], with the predominant source being the liver [2, 3]. Plasminogen is produced as an 810 amino acid protein with a 19 amino acid leader peptide, which is cleaved during secretion to produce the mature 791 amino acid one-chain zymogen. This is converted to plasmin by cleavage of the Arg561 - Val562 scissile bond [4], resulting in an active protease consisting of two disulfide linked chains. The amino-terminal heavy chain (residues Glu1-Arg561) is comprised of a plasminogen/apple/nematode (PAN) domain [5] and five kringle domains of approximately equal size [6] while the light chain (residues Val562-Asn791) contains a serine protease domain homologous to trypsin with a catalytic triad comprising His603, Asp646 and Ser741 [7]. Both plasmin and plasminogen occur in two forms, full length and a Lys77-Lys78 activated variant produced through self catalysis (Figure 1). The former exists in a tight conformation through binding of Lys50 and/or Lys62 to kringle domain 5 [8, 9] while Lys78-plasminogen assumes a more relaxed conformation rendering it more susceptible to plasmin conversion [10, 11]
'Giving honour to the Spirit' : a critical analysis and evaluation of the doctrine of pneumatological union in the Trinitarian theology of Jonathan Edwards in dialogue with Karl Barth
No full textThe extent to which the 'honour' of the Spirit influenced the theology of
Jonathan Edwards is a hitherto underdeveloped theme. Against a backdrop of
Patristic thought and in dialogue with the theology of Karl Barth, evaluation is
made of pneumatological union in Edwards' Trinitarian theology as this centres
on the nature and inter-relatedness of the 'three unions' that characterize his
theology: the union of the three Persons of the Trinity, the union of the saints
with God, and the union of the divine and human natures of Christ.
Edwards' seeks to honour the Spirit as the mutual love of the Father for the Son
within his Augustinian, Lockean model of the immanent Trinity, and as 'Person'
in the economy. The challenges of doing so within the limits of this
psychological model of the Trinity are evaluated in dialogue with the
Cappadocian Fathers and Barth.
In a manner patterned after union in the Trinity, Edwards gave prominence to the
concept of the pneumatological union of the saints with God in Christ, in
fulfilment of the self-glorifying purpose of God in creation and redemption.
Edwards' experiential theology of conversion, and his elevation of subjective
sanctification by the Spirit over objective justification in Christ, for assurance, is
contrasted with Barth's greater emphases on the Christological union of God
with humanity and objective justification in Christ. Barth's more contemplative
approach is contrasted with the overly introspective spirituality of Edwards.
Edwards' view of the role of the Spirit in the hypostatic union of God with
humanity in Christ, which is reflective of the other unions, is also evaluated in
light of Patristic, Reformed-Puritan and Barthian thought on the nature of the
humanity Christ assumed, and the doctrine of the vicarious humanity of Christ. A
more emphatic incarnational emphasis may have saved Edwards' Spirit-
honouring spirituality from an anthropocentricity which is ironical given that the
glory of God is his ontic doxological concern
- …
