Alzheimer's Disease-Linked Mutations in Presenilin-1 Result in a Drastic Loss of Activity in Purified γ-Secretase Complexes

BACKGROUND: Mutations linked to early onset, familial forms of Alzheimer's disease (FAD) are found most frequently in PSEN1, the gene encoding presenilin-1 (PS1). Together with nicastrin (NCT), anterior pharynx-defective protein 1 (APH1), and presenilin enhancer 2 (PEN2), the catalytic subunit PS1 constitutes the core of the γ-secretase complex and contributes to the proteolysis of the amyloid precursor protein (APP) into amyloid-beta (Aβ) peptides. Although there is a growing consensus that FAD-linked PS1 mutations affect Aβ production by enhancing the Aβ1-42/Aβ1-40 ratio, it remains unclear whether and how they affect the generation of APP intracellular domain (AICD). Moreover, controversy exists as to how PS1 mutations exert their effects in different experimental systems, by either increasing Aβ1-42 production, decreasing Aβ1-40 production, or both. Because it could be explained by the heterogeneity in the composition of γ-secretase, we purified to homogeneity complexes made of human NCT, APH1aL, PEN2, and the pathogenic PS1 mutants L166P, ΔE9, or P436Q. METHODOLOGY/PRINCIPAL FINDINGS: We took advantage of a mouse embryonic fibroblast cell line lacking PS1 and PS2 to generate different stable cell lines overexpressing human γ-secretase complexes with different FAD-linked PS1 mutations. A multi-step affinity purification procedure was used to isolate semi-purified or highly purified γ-secretase complexes. The functional characterization of these complexes revealed that all PS1 FAD-linked mutations caused a loss of γ-secretase activity phenotype, in terms of Aβ1-40, Aβ1-42 and APP intracellular domain productions in vitro. CONCLUSION/SIGNIFICANCE: Our data support the view that PS1 mutations lead to a strong γ-secretase loss-of-function phenotype and an increased Aβ1-42/Aβ1-40 ratio, two mechanisms that are potentially involved in the pathogenesis of Alzheimer's disease

Ganzheitliche Logistikkonzepte Moeglichkeiten und Grenzen

SIGLEAvailable from TIB Hannover: T93B5384+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Forschung und Technologie (BMFT), Bonn (Germany)DEGerman

ZEEMAN EFFECT IN THE 2782 {\AA} BAND OF HCP

Author Institution: Department of Chemistry, University of IllinoisThe Zeeman effect in the 2782.22 {\AA} band of HCP has been observed and indicates the excited state is $^{3} \Delta_{1}$. A formula is derived for a $^{3} \Delta_{1}$ state, intermediate between case (a) and case (b), which expresses the Zeeman splitting as a function of J and the spin-orbit coupling constant. By applying this formula the spin-orbit coupling constant is found to be +22.3 or -$16.0 cm^{-1}$, depending on whether the $^{3} \Delta$ state is normal or inverted. The rotational constant and band origin for these two cases are also computed

Dynamisches Verhalten von Aerosolen aus semivolatilen Komponenten.

Aerosole aus semivolatilen organischen Komponenten (SVOC, semi volatile organic compounds) stellen eine großeHerausforderung für die exakte Probenahme am industriellen Arbeitsplatz dar, da sie in variierenden Anteilen gleichzeitig in Gas(Dampf)- und Partikelphase vorliegen können. Die Gas-Partikel-Fraktionierung von SVOC hängt erheblich von den Probenahmebedingungen ab. Daher wurde hier die SVOC-Verdampfung theoretisch und experimentell nachvollzogen und das Ausmaß möglicher Probenahmeverluste in einer Klimakammer untersucht. Aerosoltröpfchen wurden aus n-Alkanenunterschiedlicher Kettenlänge (n-Tetradecan bis n-Eicosan) in unterschiedlichen Partikelgrößen generiert, mit partikelfreiem Stickstoff verdünnt und nach einer Stabilisierungszeit vergleichend mit zwei Methoden untersucht: einem Filter kombiniert mit einem Adsorber (offline) und einem optischen Partikelanalysator kombiniert mit einem Flammenionisationsdetektor (online). Die Vergleichsmessungen zwischen beiden Methoden zeigten eine gute Übereinstimmung bei der Gesamtmassenkonzentration, jedoch offline einen systematisch niedrigeren Partikel- und höheren Gasphasenanteil. Dieser Effekt sollte bei der Risikobewertung am Arbeitsplatz berücksichtigt werden: Die SVOC-Probenahme mit Filtern allein kann die Arbeitsplatzkonzentration signifikant unterschätzen

ROMAP: Rosetta Magnetometer and Plasma Monitor

The scientific objectives, design and capabilities of the Rosetta Lander’s ROMAP instrument are presented. ROMAP’s main scientific goals are longterm magnetic field and plasma measurements of the surface of Comet 67P/Churyumov-Gerasimenko in order to study cometary activity as a function of heliocentric distance, and measurements during the Lander’s descent to investigate the structure of the comet’s remanent magnetisation. The ROMAP fluxgate magnetometer, electrostatic analyser and Faraday cup measure the magnetic field from 0 to 32 Hz, ions of up to 8000 keV and electrons of up to 4200 keV. Additional two types of pressure sensors – Penning and Minipirani – cover a pressure range from 108 to 101 mbar. ROMAP’s sensors and electronics are highly integrated, as required by a combined field/plasma instrument with less than 1 W power consumption and 1 kg mass

The DREAMS experiment onboard the Schiaparelli module of the ExoMars 2016 mission: Design, performances and expected results

The first of the two missions foreseen in the ExoMars program was successfully launched on 14th March 2016. It included the Trace Gas Orbiter and the Schiaparelli Entry descent and landing Demonstrator Module. Schiaparelli hosted the DREAMS instrument suite that was the only scientific payload designed to operate after the touchdown. DREAMS is a meteorological station with the capability of measuring the electric properties of the Martian atmosphere. It was a completely autonomous instrument, relying on its internal battery for the power supply. Even with low resources (mass, energy), DREAMS would be able to perform novel measurements on Mars (atmospheric electric field) and further our understanding of the Martian environment, including the dust cycle. DREAMS sensors were designed to operate in a very dusty environment, because the experiment was designed to operate on Mars during the dust storm season (October 2016 in Meridiani Planum). Unfortunately, the Schiaparelli module failed part of the descent and the landing and crashed onto the surface of Mars. Nevertheless, several seconds before the crash, the module central computer switched the DREAMS instrument on, and sent back housekeeping data indicating that the DREAMS sensors were performing nominally. This article describes the instrument in terms of scientific goals, design, working principle and performances, as well as the results of calibration and field tests. The spare model is mature and available to fly in a future mission