Signed & sealed : Agenda 21 and the role of the furniture designer-maker in developing a sustainable practice

The aim of this thesis has been to develop and document a research project that takes the form of a strategic response by a furniture designermaker (Philip Koomen Furniture) to the challenging ecological issues raised by the Earth Summit (Rio de Janeiro, 1992) and detailed in the document Agenda 21: Sustainable Development for the 21st Century. A Literature Review contextualises this research project in relation to issues around global resources and sustainable practices and considers various models of sustainable design in relation to the commercial mainstream but more particularly with regard to the role of the furniture designermaker in contemporary society. The thesis explores the rationale for what became termed the “Signed & Sealed” project and describes the development of an associated body of designs through the negotiation of the degraded state of the U.K.’s native woodlands and the location of three critical strands which together came to define the “Signed & Sealed” brand – strands identified by the terms semi-bespoke, local cycle and unique signature. These terms are illuminated in turn by discussion of the commissioning processes favoured by designer-makers and by consideration of the economic and aesthetic problems to be found in connection with the sourcing, development and use of local, noncommercial timbers. The thesis also describes the project’s formal presentation in the exhibition “Out of the Woods” (River & Rowing Museum, Henley-on-Thames, 17 September 2004 to 7 January 2005) and the two conferences “Our Woods in Your Hands” (River & Rowing Museum, Henley-on-Thames, 25 September 2004) and “Out of the Woods: Design for Sustainability” (River & Rowing Museum, Henley-on- Thames, 20 October 2004) and considers the peer reviews and responses which followed these events. Finally, the thesis offers a critical evaluation of the PhD research process which framed the project together with some discussion of further potential avenues of research and development.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Signed & Sealed: Agenda 21 and the Role of the Furniture

The aim of this thesis has been to develop and document a research project that takes the form of a strategic response by a furniture designermaker (Philip Koomen Furniture) to the challenging ecological issues raised by the Earth Summit (Rio de Janeiro, 1992) and detailed in the document Agenda 21: Sustainable Development for the 21st Century. A Literature Review contextualises this research project in relation to issues around global resources and sustainable practices and considers various models of sustainable design in relation to the commercial mainstream but more particularly with regard to the role of the furniture designermaker in contemporary society. The thesis explores the rationale for what became termed the “Signed & Sealed” project and describes the development of an associated body of designs through the negotiation of the degraded state of the U.K.’s native woodlands and the location of three critical strands which together came to define the “Signed & Sealed” brand – strands identified by the terms semi-bespoke, local cycle and unique signature. These terms are illuminated in turn by discussion of the commissioning processes favoured by designer-makers and by consideration of the economic and aesthetic problems to be found in connection with the sourcing, development and use of local, noncommercial timbers. The thesis also describes the project’s formal presentation in the exhibition “Out of the Woods” (River & Rowing Museum, Henley-on-Thames, 17 September 2004 to 7 January 2005) and the two conferences “Our Woods in Your Hands” (River & Rowing Museum, Henley-on-Thames, 25 September 2004) and “Out of the Woods: Design for Sustainability” (River & Rowing Museum, Henley-on- Thames, 20 October 2004) and considers the peer reviews and responses which followed these events. Finally, the thesis offers a critical evaluation of the PhD research process which framed the project together with some discussion of further potential avenues of research and development

Parametric Power Spectral Density Analysis of Noise from Instrumentation in MALDI TOF Mass Spectrometry

Noise in mass spectrometry can interfere with identification of the biochemical substances in the sample. For example, the electric motors and circuits inside the mass spectrometer or in nearby equipment generate random noise that may distort the true shape of mass spectra. This paper presents a stochastic signal processing approach to analyzing noise from electrical noise sources (i.e., noise from instrumentation) in MALDI TOF mass spectrometry. Noise from instrumentation was hypothesized to be a mixture of thermal noise, 1/f noise, and electric or magnetic interference in the instrument. Parametric power spectral density estimation was conducted to derive the power distribution of noise from instrumentation with respect to frequencies. As expected, the experimental results show that noise from instrumentation contains 1/f noise and prominent periodic components in addition to thermal noise. These periodic components imply that the mass spectrometers used in this study may not be completely shielded from the internal or external electrical noise sources. However, according to a simulation study of human plasma mass spectra, noise from instrumentation does not seem to affect mass spectra significantly. In conclusion, analysis of noise from instrumentation using stochastic signal processing here provides an intuitive perspective on how to quantify noise in mass spectrometry through spectral modeling

The Mitochondrial Deoxyguanosine Kinase is Required for Cancer Cell Stemness in Lung Adenocarcinoma

The mitochondrial deoxynucleotide triphosphate (dNTP) is maintained by the mitochondrial deoxynucleoside salvage pathway and dedicated for the mtDNA homeostasis, and the mitochondrial deoxyguanosine kinase (DGUOK) is a rate-limiting enzyme in this pathway. Here, we investigated the role of the DGUOK in the self-renewal of lung cancer stem-like cells (CSC). Our data support that DGUOK overexpression strongly correlates with cancer progression and patient survival. The depletion of DGUOK robustly inhibited lung adenocarcinoma tumor growth, metastasis, and CSC self-renewal. Mechanistically, DGUOK is required for the biogenesis of respiratory complex I and mitochondrial OXPHOS, which in turn regulates CSC self-renewal through AMPK-YAP1 signaling. The restoration of mitochondrial OXPHOS in DGUOK KO lung cancer cells using NDI1 was able to prevent AMPK-mediated phosphorylation of YAP and to rescue CSC stemness. Genetic targeting of DGUOK using doxycycline-inducible CRISPR/Cas9 was able to markedly induce tumor regression. Our findings reveal a novel role for mitochondrial dNTP metabolism in lung cancer tumor growth and progression, and implicate that the mitochondrial deoxynucleotide salvage pathway could be potentially targeted to prevent CSC-mediated therapy resistance and metastatic recurrence

GSK3β inhibition blocks melanoma cell/host interactions by downregulating N-cadherin expression and decreasing FAK phosphorylation.

This study addresses the role of glycogen synthase kinase (GSK)-3β signaling in the tumorigenic behavior of melanoma. Immunohistochemical staining revealed GSK3β to be focally expressed in the invasive portions of 12 and 33% of primary and metastatic melanomas, respectively. GSK3 inhibitors and small interfering RNA (siRNA) knockdown of GSK3β were found to inhibit the motile behavior of melanoma cells in scratch wound, three-dimensional collagen-implanted spheroid, and modified Boyden chamber assays. Functionally, inhibition of GSK3β signaling was found to suppress N-cadherin expression at the messenger RNA and protein levels, and was associated with decreased expression of the transcription factor Slug. Pharmacological and genetic ablation of GSK3β signaling inhibited the adhesion of melanoma cells to both endothelial cells and fibroblasts and prevented transendothelial migration, an effect rescued by the forced overexpression of N-cadherin. A further role for GSK3β signaling in invasion was suggested by the ability of GSK3β inhibitors and siRNA knockdown to block phosphorylation of focal adhesion kinase (FAK) and increase the size of focal adhesions. In summary, we have, to our knowledge, demonstrated a previously unreported role for GSK3β in modulating the motile and invasive behavior of melanoma cells through N-cadherin and FAK. These studies suggest the potential therapeutic utility of inhibiting GSK3β in defined subsets of melanoma

SePaCS—a web-based application for classification of seroreactivity profiles

Immunogenic antigen sets possess high potential for minimally invasive disease detection and monitoring. For various diseases, including cancer, appropriate antigen sets have already been detected in blood sera of patients. Typically, a large number of sera from diseased and unaffected persons is screened for the antigens of interest. Sophisticated statistical learning approaches are trained on the resulting data set to classify sera as either tumor or normal sera. We developed a web-based application, called ‘Seroreactivity Profile Classification Service’ (SePaCS) that enables clinical groups to carry out analyzes of training sets and predictions of unclassified seroreactivity profiles with minimal effort. SePaCS provides a broad range of classification methods: four versions of a Naïve Bayes Classifier, Support Vector Machines with a radial basis function kernel, Linear Discriminant Analysis, and Diagonal Discriminant Analysis. The computed results are summarized in a PDF file. We demonstrate the functionality of SePaCS exemplarily for meningioma, a generally benign intracranial tumor. As a second example, we evaluated SePaCS on glioma, a malignant brain tumor. SePaCS is freely available at http://www.bioinf.uni-sb.de/sepacs

Individual atrasentan exposure is associated with long-term kidney and heart failure outcomes in patients with type 2 diabetes and chronic kidney disease

Atrasentan, an endothelin receptor antagonist, showed clinically significant albuminuria reduction with minimal signs of fluid retention in phase 2 trials. We evaluated whether plasma exposure was associated with long-term outcomes for kidney protection and heart failure in the phase 3 SONAR trial (n=3668) in type 2 diabetics with chronic kidney disease. A population pharmacokinetic model was used to estimate plasma exposure of atrasentan 0.75 mg/day. Parametric time-to-event models were used to quantify the association between plasma exposure and long-term outcomes. Mean atrasentan plasma exposure was 41.4 ng.h/mL (2.5th to 97.5th P: 14.2 to 139.9). Compared to placebo, a mean atrasentan exposure translated in a hazard ratio of 0.76 (95% CI: 0.28-0.85) for kidney events and 1.13 (95% CI: 1.03-2.20) for heart failure events. At the mean atrasentan exposure the kidney protective effect was larger than the increase in heart failure supporting the atrasentan 0.75 mg/day dose in this population