The identification of chemical compounds that decrease cellular levels of toxic Huntington's disease protein through a novel cell-based assay

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2006.Vita.Includes bibliographical references.Huntington's disease (HD) is a progressive degenerative neurological disorder. Individuals who inherit the IT15 gene with an expansion of the CAG repeat region inevitably succumb to increasingly sever motor, psychological, and cognitive symptoms. I sought to develop an assay system with the capability for identification of chemical compounds that selectively decrease the intracellular levels of disease-causing expanded polyglutamine huntingtin (Htt) protein without reducing the intracellular levels of the potentially protective normal Htt. To achieve this goal I designed a cell-based assay using the enzymatic activity of E. coli [beta]-galactosidase as a reporter for Htt protein levels. I expressed either expanded (97Q) or normal (23Q) Htt fused to the [beta]-galactosidase alpha-subunit ([alpha]) in an inducible fashion in PC12 cells which also expressed the [beta]-galactosidase delta-subunit ([delta]). Complementation between these expressed subunits allowed the formation of functional P-galactosidase. The level of [beta]-galactosidase activity in these [delta]-[alpha]97Q and [delta]-[alpha]23Q cells directly correlated with the amount of a 97Q and a 23Q fusion protein levels, indicating that [beta]-galactosidase activity could be used as a reporter in this system for Htt protein levels.(cont.) I implemented this cell-based assay as a secondary assay to characterize a group of compounds that had been initially identified in a High Throughput Screen because they reduced levels of expanded Htt-fragment fused to GFP. Of the 34 compounds characterized in the -galactosidase [delta]-[alpha]97Q assay, dose response curves and counter-screening with [delta]-[alpha]23Q cells revealed that seven compounds decrease [beta]-galactosidase activity only in [delta]-[alpha]97Q cells. Immunofluorescence demonstrated that two compounds decrease levels of expanded but not normal Htt proteins in the cells. Finally, tests of toxicity on HttQ103 PC12 cell lines, which show specific toxicity following expression of expanded Htt, revealed a significant correlation with the results from the [beta]-galactosidase assay and the identification of at least one compound which continued to meet the criteria for therapeutic intervention in HD. These results support the feasibility of the development of an HD therapeutic strategy based on small molecules which cause a specific reduction of intracellular expanded Htt protein levels and suggest a program of development for such molecules.by Myra Alfert Coufal.Ph.D

Alien Registration- Herttua, John Alfert (Litchfield, Kennebec County)

https://digitalmaine.com/alien_docs/17260/thumbnail.jp

Corporate venturing – a new way of creating a company’s future

Purpose – More and more companies are embarking on an experimental journey into an unpredictable future – a future that is characterised by uncertainty and new challenges. Corporate venturing enables established companies, so-called incumbents, to deal with new markets and business models in a highly flexible and innovative way, besides their existing business and well known, successful business models. A new innovator’s dilemma has emerged: not only established companies are required to be increasingly creative and to question existing thought patterns, but it is similar for start ups and new businesses. Research method – After conceptualising the paper and conducting literature bibliometry by VOSviewer, the research gap was identified. It is based on the three presented approaches: Causation, Effectuation and Bricolage as transformative approaches for strategic decision-making. Using a qualitative research by conducting 30 in-depth interviews, a transcription and a MaxQDA analysis, 5 identified corporate venturing tools were shown. Originality/value – The paper introduces a new approach of management which rapidly gains importance and which is crucial for companies in upcoming times to compete with flexible and disruptive start-up based business models.Thomas BAAKEN: [email protected] ALFERT: [email protected] KLIEWE: [email protected] BAAKEN, Professor - Managing Director of the Science-to-Business Marketing Research Centre, MünsterCarina ALFERT, MA - Academic Researcher, Science-to-Business Marketing Research Centre, Münster, Münster & VU Vrije Universiteit Amsterdam, The NetherlandsThorsten KLIEWE, Professor - Research Director of the Science-to-Business Marketing Research Centre, MünsterAlfert C., Bossink B., Baaken T., Kliewe T., 2019, Linking corporate venturing and effectuation in established organizations. 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Smith School of Business, University of Maryland, December.Dew N., Sarasvathy S.D., Rea S., Wiltbank R., 2008, Immortal firms in mortal markets?: An entrepreneurial perspective on the “innovator’s dilemma”, “European Journal of Innovation Management”, vol. 11(3), pp. 313-329, DOI: 10.1108/14601060810888982.Duymedjian R., Rüling C.-C., 2010, Towards a Foundation of Bricolage in Organization and Management Theory, “Organization Studies”, vol. 31(2), pp. 133-151, DOI: 10.1177/0170840609347051.van Eck N.J., Waltman L., 2017, Citation-based clustering of publications using CitNetExplorer and VOSviewer, “Scientometrics”, vol. 111(2), pp. 1053-1070, DOI: 10.1007/s11192-017-2300-7.Evald M.R., Senderovitz M., 2013, Exploring Internal Corporate Venturing in SMEs: Effectuation at Work in a New Context, “Journal of Enterprising Culture”, vol. 21(03), pp. 275-299, DOI: 10.1142/S021849581350012X.Fisher G., 2012, Effectuation, Causation, and Bricolage: A Behavioral Comparison of Emerging Theories in Entrepreneurship Research, “Entrepreneurship Theory and Practice”, vol. 36(5), pp. 1019-1051, DOI: 10.1111/j.1540-6520.2012.00537.x.Franco M., de Fátima Santos M., Ramalho I., Nunes C., 2014, An exploratory study of entrepreneurial marketing in SMEs: The role of the founder-entrepreneur, “Journal of Small Business and Enterprise Development”, vol. 21(2), pp. 265-283, DOI: 10.1108/JSBED-10-2012-0112.Futterer F., Schmidt J., Heidenreich S., 2018, Effectuation or Causation as the Key to Corporate Venture Success? Investigating Effects of Entrepreneurial Behaviors on Business Model Innovation and Venture Performance, „Long Range Planning”, vol. 51(1), pp. 64-81, DOI: 10.1016/j.lrp.2017.06.008.Garrett Jr. R.P., Neubaum D.O., 2013, Top management support and Initial strategic assets: A dependency model for internal corporate venture performance, “Journal of Product Innovation Management”, vol. 30(5), pp. 896-915, DOI: 10.1111/jpim.12036.Harms R., Schiele H., 2012, Antecedents and consequences of effectuation and causation in the international new venture creation process, “Journal of International Entrepreneurship”, vol. 10(2), pp. 95-116, DOI: 10.1007/s10843-012-0089-2.Hmieleski K.M., Corbett A.C., 2006, Proclivity for improvisation as a predictor of entrepreneurial intentions, “Journal of Small Business Management”, vol. 44(1), pp. 45-63, DOI: 10.1111/j.1540-627X.2006.00153.x.Faschingbauer M., Baierl R., Grichnik D., 2013, Effectuation: Gestalten statt Vorhersagen, [in:] Das unternehmerische Unternehmen: revitalisieren und gestalten der Zukunft mit Effectuation, Grichnik D., Gassmann O. (eds.), Springer-Gabler, Wiesbaden, pp. 3-21.Kliewe T., Alfert C., Baaken T., 2019, Corporate Venture Management und Entrepreneurial Marketing, [in:] Entrepreneurial Marketing, PraxisWISSEN Marketing, Rumler A., Stumpf M. 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Experiences in 3-Dimensional Visualization of Java Class Relations

Java software provides a vast amount of information about class and interface relations. Inheritance- or uses-relations of large software systems lay great demands on being able to overview the scene. Class browsers may help to master the information, although visualization is usually limited to two dimensions. We analyze the benefits of 3D presentation and discuss experiences with our sualization tool J3Browser. The tool realizes these benefits and some selected visualization techniques within the Java context. This paper leads a step towards a CAD-like design of Java software in 3D space

Vitruv: Specifying Temporal Aspects of Multimedia Presentations - A Transformational Approach based on Intervals

The development of large multimedia applications reveals similar problems to those of developing large software systems. This is not surprising, as multimedia applications are a special kind of software systems. Our experience within the Altenberg Cathedral Project showed, however, that during developing multimedia applications particular problems arise, which do not appear during traditional software development. This is the starting point of the research reported in this thesis. In this introduction, we start with a report on the Altenberg Cathedral Project (sec. 1.1), resulting in a problem statement and a list of requirements for possible solutions. After that we propose our solution named Vitruv (sec. 1.2 on page 11) and explain how it works in general (sec. 1.3 on page 12). It is followed by a discussion of key aspects of Vitruv and relations to other approaches (sec. 1.4 on page 14). The introduction closes with a brief outline of the thesis

Dense Cranial Electroacupuncture Stimulation for Major Depressive Disorder—A Single-Blind, Randomized, Controlled Study

BACKGROUND: Previous studies suggest that electroacupuncture possesses therapeutic benefits for depressive disorders. The purpose of this study was to determine whether dense cranial electroacupuncture stimulation (DCEAS) could enhance the antidepressant efficacy in the early phase of selective serotonin reuptake inhibitor (SSRI) treatment of major depressive disorder (MDD). METHODS: In this single-blind, randomized, controlled study, patients with MDD were randomly assigned to 9-session DCEAS or noninvasive electroacupuncture (n-EA) control procedure in combination with fluoxetine (FLX) for 3 weeks. Clinical outcomes were measured using the 17-item Hamilton Depression Rating Scale (HAMD-17), Clinical Global Impression-severity (CGI-S), and Self-rating Depression Scale (SDS) as well as the response and remission rates. RESULTS: Seventy-three patients were randomly assigned to n-EA (n = 35) and DCEAS (n = 38), of whom 34 in n-EA and 36 in DCEAS group were analyzed. DCEAS-treated patients displayed a significantly greater reduction from baseline in HAMD-17 scores at Day 3 through Day 21 and in SDS scores at Day 3 and Day 21 compared to patients receiving n-EA. DCEAS intervention also produced a higher rate of clinically significant response compared to n-EA procedure (19.4% (7/36) vs. 8.8% (3/34)). The incidence of adverse events was similar in the two groups. CONCLUSIONS: DCEAS is a safe and effective intervention that augments the antidepressant efficacy. It can be considered as an additional therapy in the early phase of SSRI treatment of depressed patients. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN88008690

Single-cell transcriptomics identifies potential cells of origin of MYC rhabdoid tumors

Rhabdoid tumors (RT) are rare and highly aggressive pediatric neoplasms. Their epigenetically-driven intertumoral heterogeneity is well described; however, the cellular origin of RT remains an enigma. Here, we establish and characterize different genetically engineered mouse models driven under the control of distinct promoters and being active in early progenitor cell types with diverse embryonic onsets. From all models only Sox2-positive progenitor cells give rise to murine RT. Using single-cell analyses, we identify distinct cells of origin for the SHH and MYC subgroups of RT, rooting in early stages of embryogenesis. Intra- and extracranial MYC tumors harbor common genetic programs and potentially originate from fetal primordial germ cells (PGCs). Using PGC specific Smarcb1 knockout mouse models we validate that MYC RT originate from these progenitor cells. We uncover an epigenetic imbalance in MYC tumors compared to PGCs being sustained by epigenetically-driven subpopulations. Importantly, treatments with the DNA demethylating agent decitabine successfully impair tumor growth in vitro and in vivo. In summary, our work sheds light on the origin of RT and supports the clinical relevance of DNA methyltransferase inhibitors against this disease

Electric power transfer in spin-pumping experiments

Spin pumping is becoming an established method to generate voltages from magnetic dynamics. The standard detection method of spin pumping is based on open circuit voltage measurement across ferromagnetic (FM) and non-magnetic (NM) bi-layers, where the inverse spin-Hall effect (ISHE) can convert spin currents into electrical charge accumulation. In this paper, we present that it is also possible to measure the associated electric charge current generated in FM/NM bi-layers, by using a macroscopic closed circuitry detection method. Using variable load resistors connected in series to the sample, we quantified charge currents and associated electric power dissipation as a function of the load resistance. By using basic circuit analysis, we are able to describe spin pumping cells as a non-ideal voltage source or equivalent current source with an internal resistor