The Biochemical and Genetic Odyssey to the Function of a Nicastrin-Like Protein

gamma-Secretase is a high-molecular-weight protein complex required for the proteolytic processing of various transmembrane proteins including the Alzheimer's disease-associated amyloid precursor protein and the signaling receptor Notch. One of the gamma-secretase complex components is the type I transmembrane protein nicastrin. Here we review the odyssey to a cyclopic fish, which at the end allowed the functional analysis of nicalin, a novel member of the nicastrin protein family. This 60-kDa protein is part of a previously unknown membrane protein complex unrelated to gamma-secretase and binds to Nomo (Nodal modulator, previously known as pM5), a novel 130-kDa transmembrane protein. Both proteins are highly conserved in metazoans and show almost identical tissue distribution in humans. Functional studies in zebrafish embryos and cultured human cells revealed that nicalin and Nomo collaborate to antagonize the Nodal/TGF beta signaling pathway. Thus, nicastrin and nicalin are both associated with protein complexes involved in cell fate decisions during early embryonic development. Copyright (C) 2004 S. Karger AG, Base

Cellular functions of gamma-secretase-related proteins

Amyloid-beta pepticle (A beta) is generated by gamma-secretase, a membrane protein complex with an unusual aspartyl protease activity consisting of the four components presenilin, nicastrin, APH-1 and PEN-2. Presenilin is considered the catalytic subunit of this complex since it represents the prototype of the new family of intramembrane-cleaving GxGD-type aspartyl proteases. Recently, five novel members of this family and a nicastrin-like protein were identified. Whereas one of the GxGD-type proteins was shown to be identical with signal pepticle peptidase (SPP), the function of the others, now called SPP-like proteins (SPPLs), is not known. We therefore analyzed SPPL2b and SPPL3 and demonstrated that they localize to different subcellular compartments suggesting nonredundant functions. This was supported by different phenotypes obtained in knockdown studies in zebrafish embryos. In addition, these phenotypes could be phenocopied by ectopic expression of putative active site mutants, providing strong evidence for a proteolytic function of SPPL2b and SPPL3. We also identified and characterized the nicastrin-like protein nicalin which, together with the 130-kDa protein NOMO (Nodal modulator), forms a membrane protein complex different from gamma-secretase. We found that during zebrafish embryogenesis this complex is involved in the patterning of the axial mesendoderm, a process controlled by the Nodal signaling pathway. Copyright (c) 2006 S. Karger AG, Basel

Functional Organo-Nano Particles by RAFT Copolymerisation

A significant impact of this work on the use of polymers is expected because the developed organo-nano particles (ONP) mixed into standard polymers will make them unique and traceable. The doping of polymers with non migrating ONP was demonstrated and applications for the recycling of plastics were discussed. Thus, perylene derivatives were linked to polymerisable vinyl groups and copolymerized under RAFT conditions (Reversible Addition Fragmentation chain Transfer) with styrene and methylmethacrylate, respectively, to obtain fluorescent ONP with sizes of 40 nm or even less and narrow distributions of molecular weight in most cases with polydispersities PD of 1.1 and lower

Nebenwirkungen von Sanktionen: Kulturelle Beziehungen mit Iran, Kuba, Russland und Belarus

Die vorliegende Studie untersucht, wie sich internationale Sanktionen als häufig angewandtes Mittel der Außenpolitik auf die kulturellen Beziehungen zwischen Deutschland und sanktionierten Staaten auswirken. Dazu werden in vier Fallstudien - Iran, Kuba, Russland und Belarus - Mittlerorganisationen und Kulturschaffende in den Blick genommen. Die Studie analysiert dabei (oftmals unbeabsichtigte) materielle Folgen und sogenannte mentale Effekte, die Sanktionen auf den Kulturaustausch haben können. Insgesamt erweist es sich als schwierig, die Effekte von Sanktionen auf kulturelle Beziehungen klar von innenpolitischen Entwicklungen sowie einer allgemeinen Verschlechterung der Beziehung zwischen Deutschland und dem jeweiligen Zielland zu trennen. Die Analyse zeigt nichtsdestotrotz, dass auch gezielte Sanktionen, die sich auf Entscheidungsträger oder bestimmte Wirtschaftsbereiche konzentrieren, von Kulturschaffenden und Wissenschaftlern1 als Einschnitt und Kooperationshemmnis wahrgenommen werden können. Oftmals steigt auch das Misstrauen der Behörden in den Zielländern gegenüber unabhängigen Kulturschaffenden. Zudem wirken sich die wirtschaftlichen Folgen von Sanktionen unbeabsichtigt auch auf Kulturprojekte aus. In allen vier Fallstudien versuchen die sanktionierten Regierungen zudem, externe Sanktionen als Legitimationsressource für sich und ihre Politik zu nutzen. Gleichzeitig sind jedoch auch verstärkte Bemühungen - von Kulturschaffenden sowohl in Deutschland als auch im Zielland - zu verzeichnen, einer Verringerung des Austauschs entgegenzuwirken. Trotz dieser Schwierigkeiten haben Kulturbeziehungen großes Potenzial, das Gespräch zwischen Gesellschaften angesichts eines politischen Konflikts aufrechtzuerhalten. Die Studie empfiehlt daher, im Fall von externen Sanktionierungen die Kulturbeziehungen mit dem jeweiligen Zielland verstärkt zu fördern und hier vor allem, so weit möglich, nichtstaatliche Akteure zu unterstützen

Vertical structure of a supernova-driven turbulent magnetized ISM

Stellar feedback drives the circulation of matter from the disk to the halo of galaxies. We perform three-dimensional magnetohydrodynamic simulations of a vertical column of the interstellar medium with initial conditions typical of the solar circle in which supernovae drive turbulence and determine the vertical stratification of the medium. The simulations were run using a stable, positivity-preserving scheme for ideal MHD implemented in the FLASH code. We find that the majority (\approx 90 %) of the mass is contained in thermally-stable temperature regimes of cold molecular and atomic gas at T < 200 K or warm atomic and ionized gas at 5000 K < T < 10^{4.2} K, with strong peaks in probability distribution functions of temperature in both the cold and warm regimes. The 200 - 10^{4.2} K gas fills 50-60 % of the volume near the plane, with hotter gas associated with supernova remnants (30-40 %) and cold clouds (< 10 %) embedded within. At |z| ~ 1-2 kpc, transition-temperature (10^5 K) gas accounts for most of the mass and volume, while hot gas dominates at |z| > 3 kpc. The magnetic field in our models has no significant impact on the scale heights of gas in each temperature regime; the magnetic tension force is approximately equal to and opposite the magnetic pressure, so the addition of the field does not significantly affect the vertical support of the gas. The addition of a magnetic field does reduce the fraction of gas in the cold (< 200 K) regime with a corresponding increase in the fraction of warm (~ 10^4 K) gas. However, our models lack rotational shear and thus have no large-scale dynamo, which reduces the role of the field in the models compared to reality. The supernovae drive oscillations in the vertical distribution of halo gas, with the period of the oscillations ranging from ~ 30 Myr in the T < 200 K gas to ~ 100 Myr in the 10^6 K gas, in line with predictions by Walters & Cox.Comment: Accepted for publication in ApJ. Replacement corrects an error in the observed CNM pressure distribution in Figure 15 and associated discussio

Bursa-Derived cells show a distinct mechano-response to physiological and pathological loading in vitro

The mechano-response of highly loaded tissues such as bones or tendons is well investigated, but knowledge regarding the mechano-responsiveness of adjacent tissues such as the subacromial bursa is missing. For a better understanding of the physiological role of the bursa as a friction-reducing structure in the joint, the study aimed to analyze whether and how bursa-derived cells respond to physiological and pathological mechanical loading. This might help to overcome some of the controversies in the field regarding the role of the bursa in the development and healing of shoulder pathologies. Cells of six donors seeded on collagen-coated silicon dishes were stimulated over 3 days for 1 or 4 h with 1, 5, or 10% strain. Orientation of the actin cytoskeleton, YAP nuclear translocation, and activation of non-muscle myosin II (NMM-II) were evaluated for 4 h stimulations to get a deeper insight into mechano-transduction processes. To investigate the potential of bursa-derived cells to adapt their matrix formation and remodeling according to mechanical loading, outcome measures included cell viability, gene expression of extracellular matrix and remodeling markers, and protein secretions. The orientation angle of the actin cytoskeleton increased toward a more perpendicular direction with increased loading and lowest variations for the 5% loading group. With 10% tension load, cells were visibly stressed, indicated by loss in actin density and slightly reduced cell viability. A significantly increased YAP nuclear translocation occurred for the 1% loading group with a similar trend for the 5% group. NMM-II activation was weak for all stimulation conditions. On the gene expression level, only the expression of TIMP2 was down-regulated in the 1 h group compared to control. On the protein level, collagen type I and MMP2 increased with higher/longer straining, respectively, whereas TIMP1 secretion was reduced, resulting in an MMP/TIMP imbalance. In conclusion, this study documents for the first time a clear mechano-responsiveness in bursa-derived cells with activation of mechano-transduction pathways and thus hint to a physiological function of mechanical loading in bursa-derived cells. This study represents the basis for further investigations, which might lead to improved treatment options of subacromial bursa-related pathologies in the future

NPHS2 mutation associated with recurrence of proteinuria after transplantation

Mutations in the NPHS2 gene encoding podocin are associated with steroid-resistant nephrotic syndrome (SRNS) in childhood. Patients usually present with focal segmental glomerulosclerosis (FSGS). It is unclear to what extent SRNS due to NPHS2 mutations predisposes to recurrence of proteinuria/FSGS after renal transplantation (RTx). A 4-year-old girl with infantile SRNS was started on peritoneal dialysis because of end-stage renal disease due to FSGS. Mutational screening of the patient and her parents revealed a novel single nucleotide deletion in exon 8 of the NHPS2 gene (948delT), for which the patient was homozygous and her parents confirmed heterozygous asymptomatic carriers. At the age of 4.5 years the patient received a renal graft from her mother. On day 7 after RTx, the patient developed progressive proteinuria (urine protein/creatinine ratio 2.4 g/g), which responded within 1 week to prednisone pulse therapy, an increased cyclosporin A dosage, and ramipril therapy. The patient has maintained stable graft function and no further recurrence of proteinuria has been observed. In conclusion, patients with SRNS due to NPHS2 mutations are not protected from recurrence of proteinuria after RTx. The quick response to increased immunosuppression in our patient suggests an immune-mediated pathomechanism for recurrence of proteinuria.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47824/1/467_2003_Article_1408.pd

Reduced Equalization Needs of 100 GHz Bandwidth Plasmonic Modulators

As bit rates of optical interconnects increase, a large amount of complicated signal conditioning is needed to compensate for the insufficient bandwidth of current modulators. In this paper, we evaluate the reduced equalization requirements of high-bandwidth plasmonic modulators in short-reach transmission experiments. It is shown that transmission of 100 Gbit/s nonreturn-to-zero (NRZ) and 112 Gbit/s pulse-amplitude modulation4 over 1 km and 2 km distance is possible without any receiver equalization. At higher bit-rates, such as 120 Gbit/s NRZ, data transmission is demonstrated over 500 m with reduced receiver equalization requirements. Transmission up to 200 Gbit/s over 1 km is also shown with more complex receiver equalization. The reduced complexity of the receiver digital signal processing is attributed to a flat frequency response of at least 108 GHz of the plasmonic modulators. All single wavelength transmissions have been performed at 1540 nm in standard single mode fiber