75 research outputs found
Akustische Aspekte des Sportunterrichts: leiser statt heiser
No full textWegener M, Wegener M, Kastrup V. Akustische Aspekte des Sportunterrichts: leiser statt heiser. Sportunterricht. 2012;61(9):258-264
New synthetic strategies towards psammaplin A, access to natural product analogues for biological evaluation
No full textNew synthetic routes towards the natural product psammaplin A were developed with the particular view to preparing diverse analogues for biological assessment. These routes utilize cheap and commercially available starting materials, and allowed access to psammaplin A analogues not accessible via currently reported methods. Preliminary biological studies revealed these compounds to be the most potent non peptidic inhibitors of the enzyme histone deacetylase 1 (HDAC1, class I) discovered so far. Interestingly, psammaplin A and our synthetic analogues show class I selectivity in vitro, an important feature for the design and synthesis of future isoform selective inhibitors
Highly ligand efficient and selectiveN-2-(thioethyl)picolinamide histone deacetylase inhibitors inspired by the natural product psammaplin A
No full textNovel picolinamide-based histone deacetylase (HDAC) inhibitors were developed, drawing inspiration from the natural product psammaplin?A. We found that the HDAC potency and isoform selectivity provided by the oxime unit of psammaplin?A could be reproduced by using carefully chosen heterocyclic frameworks. The resulting (hetero)aromatic amide based compounds displayed very high potency and isoform selectivity among the HDAC family, in addition to excellent ligand efficiency relative to previously reported HDAC inhibitors. In particular, the high HDAC1 isoform selectivity provided by the chloropyridine motif represents a valuable design criterion for the development of new lead compounds and chemical probes that target HDAC1
Thioester derivatives of the natural product psammaplin A as potent histone deacetylase inhibitors
No full textThere has been significant interest in the bioactivity of the natural product psammaplin A, most recently as a potent and isoform selective HDAC inhibitor. Here we report our preliminary studies on thioester HDAC inhibitors derived from the active monomeric (thiol) form of psammaplin A, as a means to improve compound delivery into cells. We have discovered that such compounds exhibit both potent cytotoxicity and enzymatic inhibitory activity against recombinant HDAC1. The latter effect is surprising since previous SAR suggested that modification of the thiol functionality should detrimentally affect HDAC potency. We therefore also report our preliminary studies on the mechanism of action of this observed effect
Online hate via social media platforms: challenges under legislation of the European Union
No full textThis thesis seeks to answer the following research question: do social media platforms appropriately balance the fundamental rights of the victims with the right to freedom of expression under laws regulating hate speech in the European Union? To achieve the goals of the thesis, the author uses legal dogmatic methodology and doctrinal legal research. The aim of the thesis is to develop a deeper understanding of the European Union legal framework applicable to social media platforms concerning tackling online hate speech, and victims’ perspectives in this regard. Within the scope of the thesis the author analyses the current legal environment, victims’ rights and an exercise of their rights, self-regulatory initiatives invented by social media platforms and new legislation from the European Union legislators -the Digital Service Act. In conclusion, the author argues that the applicable legislative acts demanding social media platforms to determine user-uploaded content as illegal and remove it without providing mandatory safeguards for freedom of expression, as well as the ruling on the major case regarding the freedom of expression on the internet and the obligations of the hosting service providers decided by the Court of Justice of the European Union, are balancing in favour of the complainants (victims) and against online speech. However, the Digital Service Act promises to improve the current legal framework from the freedom of expression perspective by establishing a transparency and accountability framework for online platforms into content moderation programs, practices and decisions and providing a single, uniform framework across the European Union
"Das Gewissen der Menschen bilden" Papst Benedikt XVI. und seine Sicht der Medien
No full textDer Papst als "Medienereignis" ist hinlänglich bekannt. Gezielt und doch anders weiß Benedikt XVI. die Klaviatur der Medien zu spielen, er inszeniert anders, vielleicht leiser als sein Vorgänger, aber mindestens genau so kennt er ihren Einfluss, Reichweiten, Quoten, kurzum Chancen und Risiken. Im ersten Pontifikatsjahr hat sich der Papst mehrfach zu Medienfragen geäußert, drei Aspekte sollen einer ersten Bestandsaufnahme nach "einem Jahr Benedikt" dienen. Wie bei den zahlreichen Pontifikatsbilanzen wird auch im Medienbereich gefragt werden müssen: Was war neues in den Botschaften, welche Akzente sind auszumachen, wo liegt die Perspektive? Nimmt man die Ansprache des Papstes an die Medienvertreter unmittelbar nach seiner Wahl, die erste Botschaft zum Welttag der sozialen Kommunikationsmittel und die Erläuterungen anlässtich einer Audienz für die Vertreter des Päpstlichen Medienrates, sind die genannten Fragen nicht leicht zu beantworten. (...
The Role of Flavin-Containing Monooxygenase in Intestinal Barrier Formation
No full textThe maintenance of a healthy intestine is critical for preserving overall health and preventing disease development. The intestinal barrier consists of specialized epithelial cells covered by a protective mucus bilayer. In the colon, this bilayer of mucus functions to prevent bacteria and harmful metabolites from invading the epithelium and increasing permeability. Intestinal barrier permeability is associated with various pathologies, including inflammatory bowel disease. However, the physiological and molecular stimuli driving intestinal barrier dysfunction and its relationship to gastrointestinal disease onset and progression remain poorly understood. This dissertation investigates mechanisms underlying the formation and maintenance of an intestinal barrier capable of resisting systemic and environmental stress.
Here, I demonstrate that an intestinal enzyme responsive to environmental stress in C. elegans contributes to maintaining intestinal barrier integrity in mice. Specifically, I identify the stress resistance and longevity gene, flavin-containing monooxygenase (FMO)-2, as a critical regulator of intestinal barrier integrity in C. elegans. I show that fmo-2 is upregulated following exposure to the barrier-damaging chemical, dextran sodium sulfate. Furthermore, I find that fmo-2 is required for the expression of a key actin protein essential for maintaining microvilli integrity, establishing its role in the structural maintenance of the C. elegans intestine.
FMOs are a highly conserved family of enzymes involved in xenobiotic and endogenous metabolism. To investigate whether mammalian FMOs play a similar role to fmo-2, I generated an intestinal epithelium-specific, conditional knockout model of the mammalian homolog, Fmo5. Extensive characterization of this mouse model revealed that acute loss of FMO5 in mice leads to rapid deterioration of crypt architecture in the colon. I further observed that FMO5 loss disrupts the localization of colonic goblet cells, which synthesize and secrete mucus, coinciding with a depletion of the mucosal barrier in mice. Interestingly, these effects are strongly sex-dependent, with dramatic phenotypes observed in female animals and only moderate changes in males. This finding suggests that FMO5 may interact with sex-dependent differences observed in human gastrointestinal diseases.
To elucidate the mechanism underlying the FMO5-mediated phenotype, I ruled out microbiota dysregulation as a primary cause and instead identified a role for FMO5 in maintaining endoplasmic reticulum (ER) homeostasis. Specifically, I observed a significant increase in mucin-related ER stress in female Fmo5IntKO mice. Supporting this mechanism, treatment of female Fmo5IntKO mice with an ER stress-resolving bile acid fully rescued defects in crypt architecture, goblet cell localization, and mucus barrier thickness. Together, these findings implicate FMO5 as a regulator of the intestinal epithelium and highlight its potential relevance to diseases affecting intestinal barrier integrity.
To conclude this project, I returned to the C. elegans model to investigate the role of fmo-2 in detecting microbial stimuli during exposure to the intestine-targeting pathogen Enterococcus faecalis. I identified neural signaling pathways to the intestine involved in this process and demonstrated that fmo-2 overexpression is sufficient to enhance survival following E. faecalis exposure.
The data presented here provide novel insights into goblet cell regulation and mucus barrier formation and maintenance. This work establishes a foundation for utilizing these models to explore gastrointestinal disease etiology and identify therapeutic strategies targeting FMOs to improve human health.PhDMolecular and Integrative PhysiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/197160/1/meschall_1.pd
Christliche Leichpredigt/ Aus dem Sprüchlein des Evangelisten S. Matthaei am 6. Cap. : ... Beym Begrebnis der ... Frawen Margarethen, Des ... Herrn Georgens von Freywaldt ... Hausfrawen ; Welche den 22. Septembr. Anno 1625 ... verschieden/ vnd den 25. Sept. ... bestattet worden / Gehalten durch Polycarpum Leisern D. Pfarrern vnd Professorn daselbst
No full textRegulation of Longevity by Flavin-Containing Monooxygenases
No full textAs the average age of the world’s population skews older, improving human healthspan and lifespan has become a priority. To that end, biogerontology focuses on identifying the genes and pathways that influence aging using model animals, such as mice and the nematode, Caenorhabditis elegans, with the ultimate goal of identifying therapeutic targets to extend lifespan and healthspan. Our previous work established C. elegans flavin-containing monooxygenase-2 (fmo-2) as 1) necessary and sufficient to increase lifespan downstream of dietary restriction and hypoxia-mediated longevity and 2) sufficient to increase resistance to many toxic stresses. fmo-2 encodes for a protein that is most likely an ER transmembrane protein, like mammalian FMOs, and shares ~88% of its catalytic residues with mammalian FMO5 and C. elegans FMO-1 and FMO- 4. Consequently, our central hypothesis is that the regulation of stress resistance and longevity is a conserved property of C. elegans and mammalian FMOs.
To that end, we initially hypothesized that overexpression of mouse FMOs in mammalian cell lines would also convey stress resistance. We find that mouse FMO overexpression conveys broad stress resistance against heavy metal, oxidative, ER, and UV stresses. We further find that FMO overexpression results in a shift from carbohydrate metabolism to mitochondrial metabolism and that FMOs regulate multiple endogenous metabolic pathways, including central carbon metabolism, essential amino acid metabolism, and energy metabolism. These data establish a conserved stress resistance role for FMOs.
Since mammalian FMO overexpression regulates cellular metabolism, we hypothesized that nematode fmo-2 overexpression would regulate endogenous metabolism and that one or more of these metabolic pathways would be required for fmo-2-mediated longevity. We find that fmo-2 interacts with one carbon metabolism to regulate longevity through modulations of the transmethylation pathway. We also find that fmo-2 interacts with tryptophan metabolism and the kynurenine pathway to regulate longevity as well. Last, due to one carbon metabolism and the kynurenine pathway regulating stress and longevity differently, we conclude that fmo-2 likely regulates longevity and stress resistance through separable pathways. Ultimately, we determine that fmo-2 regulates endogenous metabolism to affect stress resistance, like mammalian FMOs, and that these metabolic effects are also required for longevity.
C. elegans have two other fmos that encode for ER transmembrane proteins, fmo-1 and fmo-4. Since these are induced similarly to fmo-2 in multiple longevity pathways (e.g dietary restriction and hypoxia), we hypothesized that these fmos would also be necessary and sufficient to increase longevity downstream of these pathways. Interestingly, we find that both fmo-1 and fmo-4 are required multiple longevity pathways, including sDR, IF, and fmo-2 overexpression-mediated longevity. When overexpressed, fmo-1 and fmo-4 are sufficient to increase longevity, and fmo-4 is sufficient to increase oxidative stress resistance. Nematode fmos regulate multiple overlapping and distinct metabolic pathways with mammalian Fmos, such as glutathione metabolism, cysteine and methionine metabolism, and energy metabolism. We conclude that fmo-1 and fmo-4 function downstream of fmo-2 in regulation longevity and stress resistance, but the exact genetic and metabolic mechanisms of these pathways remain under investigation.
Collectively, these findings enhance our understanding of conserved FMO roles, including stress resistance and regulation of endogenous metabolic pathways. Further, these findings establish FMOs as regulators of C. elegans longevity with future work aiming to determine if this role also extends to mammalian FMOs with the long-term goal of identifying therapeutic targets that increase human healthspan and lifespan.PhDCellular & Molecular BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/174385/1/mhowingt_1.pd
Constructivism, epistemology and information processing
No full textThe author analyzes the main models of artificial intelligence which deal with the transition from one stage to another, a central problem in development. He describes the contributions of rule-based systems and connectionist systems to an explanation of this transition. He considers that Artificial Intelligence models, in spite of their limitations, establish fruitful points of contact with the constructivist position.El autor analiza los principales modelos de inteligencia artificial que dan cuenta del paso de la transición de un estudio a otro, problema central del desarrollo. Describe y señala las aportaciones de los sistemas basados en reglas así como de los sistemas conexionistas para explicar dicha transición. Considera que los modelos de inteligencia artificial, a pesar de sus limitaciones, permiten establecer puntos de contacto muy fructiferos con la posición constructivista
- …
