Characterization of the protein phosphatase 1E (PPM1E) - Localisation and truncation in brain tissue and effects on neuronal morphology in primary neuronal culture

Die Alzheimer sche Erkrankung (Alzheimer s disease, AD) ist eine progressive, neurodegenerative Krankheit, die durch frühe Defizite im Lernen und Gedächtnis, mit letztendlichem Verlust von höheren kognitiven Funktionen, charakterisiert ist. Obwohl erhebliche Fortschritte im Verstehen der histologischen Veränderungen während der Krankheit gemacht wurden, sind alle heute zur Verfügung stehenden Therapien symptomatisch und die Mechanismen, die dem initialen Entstehen von AD zu Grunde liegen sind immer noch unklar. In einem Screen von humanem Gehirngewebe aus verschiedenen AD Stadien, wie repräsentiert durch die Braak Einstufung, ist die gehirnspezifische Proteinphosphatase 1E (PPM1E) durch ihre starke Hochregulation in frühen AD-Stadien aufgefallen. PPM1E wurde nie zuvor mit neurologischen Erkrankungen oder Demenz in Verbindung gebracht, allerdings war es bekannt, dass PPM1E die Ca2+/calmodulin-abhängigen Kinasen (CaMK) IV und II und die p21-aktivierte Kinase (PAK) 1 negativ reguliert. Diese Kinasen sind wichtige Regulatoren des Aktinzytoskeletts in dendritischen Spines und neuronalen Dendriten. Der Verlust an dendritischen Spines und Dystrophie von Dendriten kann im AD-beeinträchtigten Gehirn beobachtet werden. Eine negative Regulation der CaMKII, CaMKIV und PAK1 Kinasen könnte potentiell mit diesen frühen Veränderungen zusammenhängen. Die vorliegende Studie hat den Einfluss von PPM1E auf neuronale Morphologie in primärer Neuronenkultur evaluiert und versucht die zuvor wenig verstandene Phosphatase ausführlicher zu charakterisieren. Die vorliegende Studie zeigte, dass die Erhöhung der PPM1E mRNA Level in humanen Gehirngewebeproben in frühen Stadien der Alzheimer schen Erkrankung sich auch auf der Proteinebene widerspiegelte. PPM1E zeigte konservierte subzelluläre, prädominant zytoplasmatische Lokalisation und Proteintrunkierung in humanem Gehirngewebe in verschiedenen Braak Stadien, in Rattengehirngeweben und in maturierter, dissoziierter Rattenprimärkultur. Die subzelluläre Lokalisation von PPM1E veränderte sich graduell während der Maturierung der dissoziierten Primärkultur, von einer hauptsächlich kernbasierten Lokalisation in Richtung einer zytoplasmatischen Lokalisation in weiter maturierter Primärkultur. Außerdem war PPM1E angereichert an Stellen mit hoher Mitochondriendichte in den Dendriten der maturierten, dissoziierten hippocampalen Kultur. Obwohl vorgeschlagen worden war, dass CaMKIIα, CaMKIV and PAK1 durch PPM1E dephosphoryliert werden, hat die vorliegende Studie gefunden, dass erhöhte PPM1E Level keinen signifikanten Effekt auf den Phosphorylierungszustand der Kinase in maturierten dissoziierten Primärneuronen haben, während sie die Gesamtexpression der CaMKIV signifikant beeinflussen. Ferner hatten erhöhte Werte von PPM1E einen degenerativen Effekt auf die Anzahl von dendritischen, pilzförmigen Spines in maturierter Neuronenkultur, während Herunterregulation von PPM1E zu einer Erhöhung der Zahl von stummeligen Spines führte. Die Anzahl der Primärdendriten wurde sowohl von einer Herunter- als auch von einer Hochregulation von PPM1E in diesen dissoziierten Kulturen negativ beeinflusst. Folglich könnte eine frühe Dysregulation von PPM1E in der Alzheimer schen Erkrankung die Dendritenmorphogenese und die Morphogenese von dendritischen Spines oder deren Homöostase negativ beeinflussen. Eine Inhibition von PPM1E in früheren Alzheimer Stadien könnte den fortschreitenden kognitiven Abbau verzögern oder bestenfalls sogar stoppen. PPM1E könnte daher ein vielversprechendes neues Drug-Target für neurodegenerative Erkrankungen und besonders für AD sein

Reconfiguring welfare landscapes: A spatial typology

[EN] The post-war Danish social housing estates were a cornerstone in the construction of the Danish welfare society. Green open spaces played a central role in creating a framework for “the good life” in the many new social housing estates, which is why we propose to call them welfare landscapes. Today, these welfare landscapes are facing new challenges such as social segregation, extreme rainfall caused by climate change and changing uses. Therefore, they are increasingly being transformed, yet often with little or no interest for their existing spatial qualities. The welfare landscapes are insufficiently researched and knowledge about their spatial characteristics needs to be developed and communicated to preserve their inherited spatial qualities and to use these qualities as a resource for developing contemporary welfare landscapes. This paper aims to contribute to understanding the spatial characteristics and qualities of Danish welfare landscapes in order to create a better basis for their reconfiguration. Based on typo-morphological case studies of three social housing areas in the metropolitan area of Copenhagen this paper proposes a preliminary spatial typology of welfare landscapes from the small scale of the individual green space to the territorial scale. This typology will provide a basis to explore possible future development scenarios for Danish welfare landscapes through research-by-design.The studies carried out as part of this paper relates to A. Jessen’s ongoing PhD project titled Materialising Welfare Landscapes. The PhD is part of the larger research project Reconfiguring Welfare Landscapes at the University of Copenhagen, Section for Landscape Architecture and Planning, funded by the Danish Council for Independent Research. More about the Reconfiguring Welfare Landscapes research project: http://ign.ku.dk/english/research/landscapearchitecture-planning/landscape-architectureurbanism/research-project-1/Jessen, A.; Tietjen, A. (2018). Reconfiguring welfare landscapes: A spatial typology. En 24th ISUF International Conference. Book of Papers. Editorial Universitat Politècnica de València. 1673-1683. https://doi.org/10.4995/ISUF2017.2017.5963OCS1673168

Kragelundovnen

The Kragelund kiln By Anne Birgitte Jessen In 1984 a kiln was excavated in the village of Kragelund near Silkeborg. The kiln contained a flue and a kiln chamber placed horizontally in relation to each other, which classes it as a double-chambered horizontal kiln. The floor of the kiln was covered with clay. The kiln chamber contained a tongue-shaped platform, which was probably totally covered with clay. On each side of the platform was a rising flue. It is unknown whether the flue was as long as the kiln chamber or whether the flue rose to the level of the platform. The kiln was covered with a clay dome built up without any kind of osiers. It is likely that the back of the kiln had a loading aperture because it would have eased access to the kiln chamber, but the kiln was too badly preserved to determine whether an opening existed. Neither repairs nor rebuilding was observed during the excavation. There was no sign of other kilns in the area. The presence of only one kiln with one kiln phase this indicates that the pottery in Kragelund only existed for a short period of time. The ceramics found together with the kiln points towards a dating in the 14th century. This dating is supported by C-14 analysis

Gene array profiling of large hypothalamic CNS regions in lactating and randomly cycling virgin mice

A dramatic example of neuronal and physiological plasticity in adult mammals occurs during the transition from a non-maternal to a maternal, lactating state. In this study we compared gene expression within a large continuous region of the CNS involved in maternal behaviors (hypothalamus, preoptic regions, and nucleus accumbens) between lactating (L) (postpartum Day 7) and randomly cycling virgin (V) outbred mice. Using high density oligonucleotide arrays representing 11,904 genes, two statistical algorithms were used to identify significant differences in gene expression: robust multi array (p \u3c 0.001) (n = 92 genes) and significance analysis of microarrays using a 10% false discover rate (n = 114 genes). 27 common genes were identified as significant using both techniques. A subset of genes (n = 5) were selected and examined by real-time PCR. Our findings were consistent with previous published work. For example, neuropeptide Y (NPY) and proenkephalin were elevated in L mice, whereas POMC was decreased. Increased levels of NPY Y2 receptor and polo-like kinase and decreased levels of endothelin receptor type b in L mice are examples of novel gene expression changes not previously identified. Expression differences occurred in broad classes. Together, our findings provide possible new material on gene expression changes that may support maternal behaviors. The advantages and drawbacks of sampling large CNS regions using arrays are discussed

Rethinking architectural education - the new EU directive and the role of live projects

The symposium was held as part of the 2nd Annual AAE Conference 2014 - Living and Learning - at the University of Sheffield and encouraged the participants to discuss the teaching method of Live Projects as part of the typical 5 year architectural education in the UK. Within the context of the new EU directive and the potential for a rethinking of the “3+2 years” (+ 2 years in practice) usual architectural education in the UK, Live Projects play an important role, adding practical experience to a shorter “5+0 years” model (without the year in practice). The information and knowledge delivered in the symposium could play a demonstrative and exemplary role in future architectural educational reform. At the Cass. School of Architecture, several studios at Undergraduate and Diploma level choose to work on Live Projects with their students as the year-long programme. These Live Projects play an important role within the students’ architectural education and increasingly will do so also in the future, as Live Projects add practical experience to a potentially reduced architectural education to 5 years without a year out. The studios at the Cass do not only teach students about the professional side of architectural practice (e.g. real clients), but also contribute to research in architecture. Three studios presented their work and methodologies as a base for discussion at the beginning of the Symposium, this was followed by a short Q+A session, involving the audience and other institutions to discuss: • What makes a project live? • What support is needed for Live Projects? • What is the role of the architect within the Live Project

Point of care susceptibility testing in primary care:does it lead to a more appropriate prescription of antibiotics in patients with uncomplicated urinary tract infections? Protocol for a randomized controlled trial

BACKGROUND: Urinary tract infection (UTI) is a common infection in primary care and is the second leading reason for prescription of antibiotics in Denmark. The diagnosis is often based on symptoms and urine dip-stick, which has limited validity, causing the risk of unnecessary antibiotic prescription. Additionally, with increasing antibiotic resistance, the risk of choosing an antibiotic to which an infecting pathogen is resistant is rising. Combined point-of-care-tests (POCT) for urine culture and susceptibility testing have been developed and validated for primary care, and performing such a test in all patients with suspected UTI in primary care seems rational in order to reduce the use of inappropriate antibiotics. However, the clinical effect of the culture and susceptibility test has not yet been investigated. This study aims to investigate whether POCT urine culture and susceptibility testing decreases the inappropriate use of antibiotics and leads to faster patient recovery. METHODS/DESIGN: Randomized controlled open label trial of two diagnostic approaches. 750 patients with symptoms of uncomplicated UTI, consecutively contacting their general practitioner (GP), randomized to either POCT urine culture and susceptibility testing and targeted treatment or POCT urine culture without susceptibility testing and empirical treatment. Treatment is started when the POCT is read. The two groups are compared with regard to appropriate choice of antibiotics, clinical remission, and microbiological cure rates. DISCUSSION: The results of this study may provide important evidence to recommend POCT culture and susceptibility testing in all patients with suspected uncomplicated UTI. This could become an additional strategy to fight antibiotic resistance. TRIAL REGISTRATION: ClinicalTrials.gov NCT02323087

Exploring the feasibility and synergistic value of the One Health approach in clinical research:protocol for a prospective observational study of diagnostic pathways in human and canine patients with suspected urinary tract infection

BACKGROUND: The One Health approach is emerging in response to the development of bacterial resistance. To the best of our knowledge, the possibility to use this approach in a clinical context has not yet been explored. Thus, in this paper, we report the procedures to implement a prospective observational study of diagnostic pathways in human and canine patients with suspected urinary tract infection as a means to assess the feasibility and synergistic value of setting up One Health clinical research projects and interventions. METHODS/DESIGN: A prospective observational study will compare different diagnostic pathways (i.e., 16 possible combinations of diagnostic tools) to gold standard in human and veterinary primary care practice in Denmark. Fifty primary care practices and 100 veterinary clinics will each consecutively include 20 human patients or 8–10 dogs, respectively. Data will be collected at practice and patient level comprising (a) information about the organization of the practice and access to different diagnostic tools, (b) information about clinical history, diagnostic path and treatment during the index consultation, (c) information about severity of symptoms during the 7–10 days following inclusion, and (d) urine culture (type of microorganism and susceptibility test). The feasibility and synergistic value of conducting future research, and/or designing common interventions, will be assessed by evaluating the comparability of human primary care and veterinary primary care with respect to study implementation and study results. DISCUSSION: Results from this study will give an insight into the feasibility and synergistic value of setting-up One Health research projects in a clinical context. This is crucial if we are to embrace the One Health approach, as a legitimate strategy to implement common interventions aimed at influencing the diagnostic process in human and canine patients in order to decrease inappropriate use of antibiotics. TRIAL REGISTRATION: The study in humans has been registered in ClinicalTrials.gov NCT02249273. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40814-015-0036-9) contains supplementary material, which is available to authorized users

Optical Lattices for Atom Based Quantum Microscopy

We describe new techniques in the construction of optical lattices to realize a coherent atom-based microscope, comprised of two atomic species used as target and probe atoms, each in an independently controlled optical lattice. Precise and dynamic translation of the lattices allows atoms to be brought into spatial overlap to induce atomic interactions. For this purpose, we have fabricated two highly stable, hexagonal optical lattices, with widely separted wavelengths but identical lattice constants using diffractive optics. The relative translational stability of 12nm permits controlled interactions and even entanglement operations with high fidelity. Translation of the lattices is realized through a monolithic electro-optic modulator array, capable of moving the lattice smoothly over one lattice site in 11 microseconds, or rapidly on the order of 100 nanoseconds.Comment: 7 pages, 9 figure