Identification of cis-acting determinants mediating the unconventional secretion of tau.

The deposition of tau aggregates throughout the brain is a pathological characteristic within a group of neurodegenerative diseases collectively termed tauopathies, which includes Alzheimer's disease. While recent findings suggest the involvement of unconventional secretory pathways driving tau into the extracellular space and mediating the propagation of the disease-associated pathology, many of the mechanistic details governing this process remain elusive. In the current study, we provide an in-depth characterization of the unconventional secretory pathway of tau and identify novel molecular determinants that are required for this process. Here, using Drosophila models of tauopathy, we correlate the hyperphosphorylation and aggregation state of tau with the disease-related neurotoxicity. These newly established systems recapitulate all the previously identified hallmarks of tau secretion, including the contribution of tau hyperphosphorylation as well as the requirement for PI(4,5)P2 triggering the direct translocation of tau. Using a series of cellular assays, we demonstrate that both the sulfated proteoglycans on the cell surface and the correct orientation of the protein at the inner plasma membrane leaflet are critical determinants of this process. Finally, we identify two cysteine residues within the microtubule binding repeat domain as novel cis-elements that are important for both unconventional secretion and trans-cellular propagation of tau

Wegbereiter der Nachhaltigkeitsforschung

Das Bild der „Großen Transformation“ greift Kritikpositionen und Fragestellungen auf, die spätestens in den 1970er Jahren unter dem Stichwort „Ökologische Krise“ auf die wissenschaftliche und gesellschaftliche Agenda gesetzt wurden. Zahlreiche unabhängige Forschungsinstitute arbeiten seitdem an der Lösung dieser Fragestellungen

Verstehen - bewerten - gestalten : transdisziplinäres Wissen für eine nachhaltige Gesellschaft ; Memorandum zur Weiterentwicklung der sozial-ökologischen Forschung in Deutschland

Die Lösung globaler Probleme wie Klimawandel, Umweltzerstörung oder Ernährungssicherung erfordert grundlegende Transformationen unserer Gesellschaft. Um diese neuartigen und existenziellen Herausforderungen bewältigen zu können, brauchen wir neues Wissen – über die Entstehung der Probleme, über anzustrebende Lösungsansätze und über Wege zu deren Umsetzung. Mit dem Ziel, dieses Wissen zu schaffen, hat sich die transdisziplinäre sozial-ökologische Forschung entwickelt – eine innovative, praxisnahe Forschung entlang der zentralen Motive Verstehen – Bewerten – Gestalten: Komplexe Probleme zu verstehen, die erarbeitete Wissensbasis zu bewerten und Handlungsoptionen zu gestalten greifen bei diesem Forschungstypus ineinander. Die sozialökologische Forschung hat eine Pionierfunktion für die Umwelt- und Nachhaltigkeitsforschung in Deutschland übernommen und wegweisende Arbeiten etwa zur Energie-, Mobilitäts- oder Ernährungswende vorgelegt. Im Förderschwerpunkt Sozial-ökologische Forschung (SÖF) hat das Bundesministerium für Bildung und Forschung (BMBF) im Jahr 2000 erstmals ein Programm zur Förderung dieses spezifischen Forschungszugangs aufgelegt. Bis zum Jahr 2012 wurden darin Verbünde und Einzelvorhaben unterstützt, etwa zu Themen wie Umwelt - Ernährung - Gesundheit: Langfriststrategien für einen nachhaltigen Konsum oder Soziale Dimensionen von Klimaschutz und Klimawandel. Mit Erfolg: Forschungsvorhaben zur Transformation stehen inzwischen prominent auf der Tagesordnung von Politik und Gesellschaft. Und auch die Wissenschaft selbst öffnet sich immer mehr für die Fragen und Methoden der sozial-ökologischen Forschung. Dieses Memorandum setzt sich dafür ein, die Basis der sozial-ökologischen Forschung in den kommenden Jahren konsequent zu vertiefen und zu verbreitern – inhaltlich, organisatorisch und institutionell. Dazu gibt das Memorandum Empfehlungen zur Förderung von Themenfeldern und von Maßnahmen der Strukturentwicklung

A subgroup of plant aquaporins facilitate the bi-directional diffusion of As(OH)3 and Sb(OH)3 across membranes

<p>Abstract</p> <p>Background</p> <p>Arsenic is a toxic and highly abundant metalloid that endangers human health through drinking water and the food chain. The most common forms of arsenic in the environment are arsenate (As(V)) and arsenite (As(III)). As(V) is a non-functional phosphate analog that enters the food chain via plant phosphate transporters. Inside cells, As(V) becomes reduced to As(III) for subsequent extrusion or compartmentation. Although much is known about As(III) transport and handling in microbes and mammals, the transport systems for As(III) have not yet been characterized in plants.</p> <p>Results</p> <p>Here we show that the Nodulin26-like Intrinsic Proteins (NIPs) AtNIP5;1 and AtNIP6;1 from <it>Arabidopsis thaliana</it>, OsNIP2;1 and OsNIP3;2 from <it>Oryza sativa</it>, and LjNIP5;1 and LjNIP6;1 from <it>Lotus japonicus </it>are bi-directional As(III) channels. Expression of these NIPs sensitized yeast cells to As(III) and antimonite (Sb(III)), and direct transport assays confirmed their ability to facilitate As(III) transport across cell membranes. On medium containing As(V), expression of the same NIPs improved yeast growth, probably due to increased As(III) efflux. Our data furthermore provide evidence that NIPs can discriminate between highly similar substrates and that they may have differential preferences in the direction of transport. A subgroup of As(III) permeable channels that group together in a phylogenetic tree required N-terminal truncation for functional expression in yeast.</p> <p>Conclusion</p> <p>This is the first molecular identification of plant As(III) transport systems and we propose that metalloid transport through NIPs is a conserved and ancient feature. Our observations are potentially of great importance for improved remediation and tolerance of plants, and may provide a key to the development of low arsenic crops for food production.</p

Quasi-free Compton Scattering and the Polarizabilities of the Neutron

Differential cross sections for quasi-free Compton scattering from the proton and neutron bound in the deuteron have been measured using the Glasgow/Mainz tagging spectrometer at the Mainz MAMI accelerator together with the Mainz 48 cm $\oslash$ $\times$ 64 cm NaI(Tl) photon detector and the G\"ottingen SENECA recoil detector. The data cover photon energies ranging from 200 MeV to 400 MeV at $\theta^{LAB}_\gamma=136.2^\circ$. Liquid deuterium and hydrogen targets allowed direct comparison of free and quasi-free scattering from the proton. The neutron detection efficiency of the SENECA detector was measured via the reaction $p(\gamma,\pi^+ n)$. The "free" proton Compton scattering cross sections extracted from the bound proton data are in reasonable agreement with those for the free proton which gives confidence in the method to extract the differential cross section for free scattering from quasi-free data. Differential cross sections on the free neutron have been extracted and the difference of the electromagnetic polarizabilities of the neutron have been obtained to be $\alpha-\beta= 9.8\pm 3.6(stat){}^{2.1}_1.1(syst)\pm 2.2(model)$ in units $10^{-4}fm^3$. In combination with the polarizability sum $\alpha +\beta=15.2\pm 0.5$ deduced from photoabsorption data, the neutron electric and magnetic polarizabilities, $\alpha_n=12.5\pm 1.8(stat){}^{+1.1}_{-0.6}\pm 1.1(model)$ and $\beta_n=2.7\mp 1.8(stat){}^{+0.6}_{-1.1}(syst)\mp 1.1(model)$ are obtained. The backward spin polarizability of the neutron was determined to be $\gamma^{(n)}_\pi=(58.6\pm 4.0)\times 10^{-4}fm^4$

Hemangioma of the prostate - an unusual cause of lower urinary tract symptoms: Case report

<p>Abstract</p> <p>Background</p> <p>Hemangioma of the prostate gland is extremely rare and only a few cases have been reported. There have been several cases of hemangioma of posterior urethra, urinary bladder and periprostatic plexus in the literature, all presenting with hematuria or hematospermia. Diagnosis of prostatic hemangioma is difficult due to its rarity and unspecific symptoms such as hematuria, hematospermia or lower urinary tract symptoms. It cannot be detected by conventional examinations such as cystoscopy or standard rectal ultrasonography.</p> <p>Case presentation</p> <p>We present a case of prostatic hemangioma in an 84-year old male presenting with lower urinary tract symptoms. Bleeding has not been a feature in our case and diagnosis was not made until after operation. The patient was treated as a case of bladder neck outflow obstruction with transurethral resection of prostate gland and simultaneous bladder neck incisions. A period of self-catheterization was instituted due to postoperative urinary retention as the result of detrusor insufficiency.</p> <p>Conclusion</p> <p>Hemangioma of prostate gland is extremely rare and symptomatic prostatic hemangioma should be treated either by transurethral resection of prostate or laser evaporation.</p

Molecular Aspects of Secretory Granule Exocytosis by Neurons and Endocrine Cells

Neuronal communication and endocrine signaling are fundamental for integrating the function of tissues and cells in the body. Hormones released by endocrine cells are transported to the target cells through the circulation. By contrast, transmitter release from neurons occurs at specialized intercellular junctions, the synapses. Nevertheless, the mechanisms by which signal molecules are synthesized, stored, and eventually secreted by neurons and endocrine cells are very similar. Neurons and endocrine cells have in common two different types of secretory organelles, indicating the presence of two distinct secretory pathways. The synaptic vesicles of neurons contain excitatory or inhibitory neurotransmitters, whereas the secretory granules (also referred to as dense core vesicles, because of their electron dense content) are filled with neuropeptides and amines. In endocrine cells, peptide hormones and amines predominate in secretory granules. The function and content of vesicles, which share antigens with synaptic vesicles, are unknown for most endocrine cells. However, in B cells of the pancreatic islet, these vesicles contain GABA, which may be involved in intrainsular signaling.' Exocytosis of both synaptic vesicles and secretory granules is controlled by cytoplasmic calcium. However, the precise mechanisms of the subsequent steps, such as docking of vesicles and fusion of their membranes with the plasma membrane, are still incompletely understood. This contribution summarizes recent observations that elucidate components in neurons and endocrine cells involved in exocytosis. Emphasis is put on the intracellular aspects of the release of secretory granules that recently have been analyzed in detail

Neutron polarizabilities investigated by quasi-free Compton scattering from the deuteron

Measuring Compton scattered photons and recoil neutrons in coincidence, quasi-free Compton scattering by the neutron has been investigated at MAMI (Mainz) at $theta^{lab}_\gamma=136^o$ in an energy range from 200 to 400 MeV. From the data a polarizability difference of $\alpha_n - \beta_n = 9.8 \pm 3.6(stat)^{+2.1}_{-1.1}(syst)\pm 2.2(model)$ in units of $10^{-4}fm^3$ has been determined. In combination with the polarizability sum $\alpha_n+\beta_n= 15.2\pm 0.5$ deduced from photo absorption data, the neutron electric and magnetic polarizabilities, $\alpha_n=12.5\pm 1.8(stat)^{+1.1}_{-0.6}(syst)\pm 1.1(model)$ and $\beta_n = 2.7\mp 1.8(stat)^{+0.6}_{-1.1}(syst)\mp 1.1(model)$, are obtained

Quasi-free π0\pi^0 Photoproduction from the Bound Nucleon

Differential cross-sections for quasi-free $\pi^0$ photoproduction from the proton and neutron bound in the deuteron have been measured for $E_\gamma= 200 - 400$ MeV at $\theta^{\rm lab}_\gamma = 136.2^\circ$ usind the Glasgow photon tagger at MAMI, the Mainz 48 cm $\varnothing$ $\times$ 64 cm NaI(Tl) photon detector and the G\"ottingen SENECA recoil detector. For the proton measurements made with both liquid deuterium and liquid hydrogen targets allow direct comparison of "free" $\pi^0$ photoproduction cross-sections as extracted from the bound proton data with experimental free cross sections which are found to be in reasonable agreement below 320 MeV. At higher energies the "free" cross sections extracted from quasifree data are significantly smaller than the experimental free cross sections and theoretical predictions based on multipole analysis. For the first time, "free" neutron cross sections have been extracted in the $\Delta$-region. They are also in agreement with the predictions from multipole analysis up to 320 MeV and significantly smaller at higher photon energies