Regulation of cargo transfer between ESCRT-0 and ESCRT-I complexes by flotillin-1 during endosomal sorting of ubiquitinated cargo

Ubiquitin-dependent sorting of membrane proteins in endosomes directs them to lysosomal degradation. In the case of receptors such as the epidermal growth factor receptor (EGFR), lysosomal degradation is important for the regulation of downstream signalling. Ubiquitinated proteins are recognised in endosomes by the endosomal sorting complexes required for transport (ESCRT) complexes, which sequentially interact with the ubiquitinated cargo. Although the role of each ESCRT complex in sorting is well established, it is not clear how the cargo is passed on from one ESCRT to the next. We here show that flotillin-1 is required for EGFR degradation, and that it interacts with the subunits of ESCRT-0 and -I complexes (hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) and Tsg101). Flotillin-1 is required for cargo recognition and sorting by ESCRT-0/Hrs and for its interaction with Tsg101. In addition, flotillin-1 is also required for the sorting of human immunodeficiency virus 1 Gag polyprotein, which mimics ESCRT-0 complex during viral assembly. We propose that flotillin-1 functions in cargo transfer between ESCRT-0 and -I complexes

Application of the analytic hierarchy process in a comparative analysis of automated information systems

In a scientific study, we investigated decision-making methods, in particular, the methods of expert estimations to solve problems. Reflected the possibility of using the analytic hierarchy process for researching and selection of information systems in accordance with the requirements of the customer. Comparative analysis has been performed on the example of automated library information systems

Surface morphology of AlGaN/GaN heterostructures grown on bulk GaN by MBE

In this report the influence of the growth conditions on the surface morphology of AlGaN/GaN heterostructures grown on sapphire-based and bulk GaN substrates is nondestructively investigated with focus on the decoration of defects and the surface roughness. Under Ga-rich conditions specific types of dislocations are unintentionally decorated with shallow hillocks. In contrast, under Ga-lean conditions deep pits are inherently formed at these defect sites. The structural data show that the dislocation density of the substrate sets the limit for the density of dislocation-mediated surface structures after MBE overgrowth and no noticeable amount of surface defects is introduced during the MBE procedure. Moreover, the transfer of crystallographic information, e.g. the miscut of the substrate to the overgrown structure, is confirmed. The combination of our MBE overgrowth with the employed surface morphology analysis by atomic force microscopy (AFM) provides a unique possibility for a nondestructive, retrospective analysis of the original substrate defect density prior to device processing

Tensile strained InxGa1−xPIn_{x}Ga_{1-x}P membranes for cavity optomechanics

We investigate the optomechanical properties of tensile-strained ternary InGaP nanomembranes grown on GaAs. This material system combines the benefits of highly strained membranes based on stoichiometric silicon nitride, with the unique properties of thin-film semiconductor single crystals, as previously demonstrated with suspended GaAs. Here we employ lattice mismatch in epitaxial growth to impart an intrinsic tensile strain to a monocrystalline thin film (approximately 30 nm thick). These structures exhibit mechanical quality factors of 2*10^6 or beyond at room temperature and 17 K for eigenfrequencies up to 1 MHz, yielding Q*f products of 2*10^12 Hz for a tensile stress of ~170 MPa. Incorporating such membranes in a high finesse Fabry-Perot cavity, we extract an upper limit to the total optical loss (including both absorption and scatter) of 40 ppm at 1064 nm and room temperature. Further reductions of the In content of this alloy will enable tensile stress levels of 1 GPa, with the potential for a significant increase in the Q*f product, assuming no deterioration in the mechanical loss at this composition and strain level. This materials system is a promising candidate for the integration of strained semiconductor membrane structures with low-loss semiconductor mirrors and for realizing stacks of membranes for enhanced optomechanical coupling.Comment: 10 pages, 3 figure

Self-intersection local times of random walks: Exponential moments in subcritical dimensions

Fix $p>1$, not necessarily integer, with $p(d-2)<d$. We study the $p$-fold self-intersection local time of a simple random walk on the lattice $\Z^d$ up to time $t$. This is the $p$-norm of the vector of the walker's local times, $\ell_t$. We derive precise logarithmic asymptotics of the expectation of $\exp\{\theta_t \|\ell_t\|_p\}$ for scales $\theta_t>0$ that are bounded from above, possibly tending to zero. The speed is identified in terms of mixed powers of $t$ and $\theta_t$, and the precise rate is characterized in terms of a variational formula, which is in close connection to the {\it Gagliardo-Nirenberg inequality}. As a corollary, we obtain a large-deviation principle for $\|\ell_t\|_p/(t r_t)$ for deviation functions $r_t$ satisfying t r_t\gg\E[\|\ell_t\|_p]. Informally, it turns out that the random walk homogeneously squeezes in a $t$-dependent box with diameter of order $\ll t^{1/d}$ to produce the required amount of self-intersections. Our main tool is an upper bound for the joint density of the local times of the walk.Comment: 15 pages. To appear in Probability Theory and Related Fields. The final publication is available at springerlink.co

The long noncoding RNA neuroLNC regulates presynaptic activity by interacting with the neurodegeneration-associated protein TDP-43

The cellular and the molecular mechanisms by which long noncoding RNAs (lncRNAs) may regulate presynaptic function and neuronal activity are largely unexplored. Here, we established an integrated screening strategy to discover lncRNAs implicated in neurotransmitter and synaptic vesicle release. With this approach, we identified neuroLNC, a neuron-specific nuclear lncRNA conserved from rodents to humans. NeuroLNC is tuned by synaptic activity and influences several other essential aspects of neuronal development including calcium influx, neuritogenesis, and neuronal migration in vivo. We defined the molecular interactors of neuroLNC in detail using chromatin isolation by RNA purification, RNA interactome analysis, and protein mass spectrometry. We found that the effects of neuroLNC on synaptic vesicle release require interaction with the RNA-binding protein TDP-43 (TAR DNA binding protein-43) and the selective stabilization of mRNAs encoding for presynaptic proteins. These results provide the first proof of an lncRNA that orchestrates neuronal excitability by influencing presynaptic function

Using of polypropylene fibers for cleaning of industrial waste water from the fat-soluble organic pollutants

The paper shows the perspective of using methods of ion implantation and microwave irradiation for modifying polypropylene fiber by iron (II), lanthanum (II) and iron metal ions. It was shown that this method is very useful in order to obtain a material with a high photocatalytic activity for extracting liposoluble dyes from non-aqueous media under UV and visible light

How was it for you? Experiences of participatory design in the UK health service

Improving co-design methods implies that we need to understand those methods, paying attention to not only the effect of method choices on design outcomes, but also how methods affect the people involved in co-design. In this article, we explore participants' experiences from a year-long participatory health service design project to develop ‘Better Outpatient Services for Older People’. The project followed a defined method called experience-based design (EBD), which represented the state of the art in participatory service design within the UK National Health Service. A sample of participants in the project took part in semi-structured interviews reflecting on their involvement in and their feelings about the project. Our findings suggest that the EBD method that we employed was successful in establishing positive working relationships among the different groups of stakeholders (staff, patients, carers, advocates and design researchers), although conflicts remained throughout the project. Participants' experiences highlighted issues of wider relevance in such participatory design: cost versus benefit, sense of project momentum, locus of control, and assumptions about how change takes place in a complex environment. We propose tactics for dealing with these issues that inform the future development of techniques in user-centred healthcare design

Evolutionary trajectories in rugged fitness landscapes

We consider the evolutionary trajectories traced out by an infinite population undergoing mutation-selection dynamics in static, uncorrelated random fitness landscapes. Starting from the population that consists of a single genotype, the most populated genotype \textit{jumps} from a local fitness maximum to another and eventually reaches the global maximum. We use a strong selection limit, which reduces the dynamics beyond the first time step to the competition between independent mutant subpopulations, to study the dynamics of this model and of a simpler one-dimensional model which ignores the geometry of the sequence space. We find that the fit genotypes that appear along a trajectory are a subset of suitably defined fitness \textit{records}, and exploit several results from the record theory for non-identically distributed random variables. The genotypes that contribute to the trajectory are those records that are not \textit{bypassed} by superior records arising further away from the initial population. Several conjectures concerning the statistics of bypassing are extracted from numerical simulations. In particular, for the one-dimensional model, we propose a simple relation between the bypassing probability and the dynamic exponent which describes the scaling of the typical evolution time with genome size. The latter can be determined exactly in terms of the extremal properties of the fitness distribution.Comment: Figures in color; minor revisions in tex

Therapie der blanden Struma: Erfahrungen mit einer Kombination von 100 µg L-Thyroxin und 10 µg L-Trijodthyronin

Dtsch med Wochenschr 1981; 106: 579-583 DOI: 10.1055/s-2008-1070359 © Georg Thieme Verlag KG Stuttgart · New York Therapie der blanden Struma: Erfahrungen mit einer Kombination von 100 µg L-Thyroxin und 10 µg L-Trijodthyronin Treatment of non-toxic goitre: results of combined treatment with 100 µg L-thyroxine and 10 µg L-triiodothyronine C. R. Pickardt, R. Gärtner, J. Habermann, K. Horn, P. C. Scriba, F. A. Horster, H. Wagner, K. Hengst Medizinische Klinik Innenstadt der Universität München, Klinik für Innere Medizin, Medizinische Hochschule Lübeck, Medizinische Klinik C und Poliklinik der Universität Düsseldorf sowie Medizinische Klinik und Poliklinik der Universität Münster Zusammenfassung Bei 96 Patienten mit blander Struma wurde eine offene Prüfung mit einem neuen Schilddrüsenhormonpräparat durchgeführt, das 100 µg L-Thyroxin (T4) und 10 µg L-Trijodthyronin (T3) pro Tablette enthält. Als Parameter für die therapeutisch wirksame Tagesdosis wurde die Suppression des TRH-stimulierten Thyreotropinspiegels im Serum gewählt. Hierbei war eine Tagesdosis von 50 µg T4 und 5 µg T3 bei 16 Patienten unwirksam; 75 µg T4 und 7,5 µg T3waren bei nur 4 von 12 Patienten suppressiv wirksam, während 100 µg T4 und 10 µg T3 bei allen Düsseldorfer und Münsteraner Patienten, aber nur bei 17 von 31 Patienten in München den TRH-stimulierten TSH-Anstieg supprimierte. Während der gesamten Therapiedauer blieben Thyroxin- und Trijodthyroninspiegel im Serum im Normbereich; bei einigen Patienten erhöhte sich der Quotient aus Thyroxin und thyroxinbindendem Globulin über die Norm. Zeichen einer Überdosierung oder Unverträglichkeit wurden nicht beobachtet. In pharmakokinetischen Untersuchungen an acht freiwilligen schilddrüsengesunden Probanden erreichte der mittlere Thyroxin- und Trijodthyroninspiegel etwa 2 Stunden nach Applikation sein Maximum und näherte sich nach sechs Stunden wieder der Norm. Es zeigten sich deutliche individuelle Schwankungen in den ersten Stunden nach Applikation. Wir empfehlen deshalb, Schilddrüsenhormonspiegel erst 12 oder 24 Stunden nach Applikation eines Schilddrüsenhormonpräparates zu bestimmen; zu dieser Zeit sollte auch der TRH-Test durchgeführt werden. Die Untersuchungen bestätigen die Notwendigkeit, bei der Strumatherapie mit einem Schilddrüsenhormonpräparat die suppressiv wirksame Dosis individuell zu ermitteln; diese Dosis beträgt vorzugsweise 100 µg Thyroxin und 10 µg Trijodthyronin oder 150 µg Thyroxin oder 100 µg Thyroxin und 20 µg Trijodthyronin pro Tag.A new thyroid hormone preparation (100 µg L-thyroxine [T4] and 10 µg L-triiodothyronine [T3] per tablet) was given to 96 patients with non-toxic goitre. Suppression of the TRH-stimulated thyrotropin level in serum was chosen as a measure of therapeutic effectiveness. Daily dose of 50 µg T4 and 5 µg T3 was ineffective in 16 patients; 75 µg T4 and 7.5 µg T3 was effective in only four of twelve patients, while 100 µg T4and 10 µg T3 was effective in all patients from clinics in Düsseldorf and Münster, but in only 17 of 31 patients from Munich, in suppressing the TRH-stimulated TSH rise. During the entire period of treatment serum thyroxine and triiodothyronine levels remained normal. In some patients the ratio of thyroxine to thyroxine-binding globulin was above normal. Signs of overdosage or intolerance were not observed. Pharmacokinetic studies on eight volunteers with normal thyroid function demonstrated that the mean thyroxine and triiodothyronine levels reached maximum about two hours after administration, returning towards normal after six hours. There were marked individual variations in the first hours after administration. It is therefore recommended that the thyroid hormone level be determined no earlier than 12 or 24 hours after the thyroid hormone preparation has been administered; TRH test should also be performed at this time. These results indicate the need for determining individually the effective suppressive dose of a thyroid hormone preparation in the treatment of goitre. Preferably the dose should be 100 µg thyroxine and 10 µg triiodothyronine, or 150 µg thyroxine or 100 µg thyroxine and 20 µg triiodothyronine per day