Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity

Assemblies of huntingtin (HTT) fragments with expanded polyglutamine (polyQ) tracts are a pathological hallmark of Huntington's disease (HD). The molecular mechanisms by which these structures are formed and cause neuronal dysfunction and toxicity are poorly understood. Here, we utilized available gene expression data sets of selected brain regions of HD patients and controls for systematic interaction network filtering in order to predict disease-relevant, brain region-specific HTT interaction partners. Starting from a large protein-protein interaction (PPI) data set, a step-by-step computational filtering strategy facilitated the generation of a focused PPI network that directly or indirectly connects 13 proteins potentially dysregulated in HD with the disease protein HTT. This network enabled the discovery of the neuron-specific protein CRMP1 that targets aggregation-prone, N-terminal HTT fragments and suppresses their spontaneous self-assembly into proteotoxic structures in various models of HD. Experimental validation indicates that our network filtering procedure provides a simple but powerful strategy to identify disease-relevant proteins that influence misfolding and aggregation of polyQ disease proteins.DFG [SFB740, 740/2-11, SFB618, 618/3-09, SFB/TRR43 A7]; BMBF(NGFN-Plus) [01GS08169-73, 01GS08150, 01GS08108]; HDSA Coalition for the Cure; EU (EuroSpin) [Health-F2-2009-241498, HEALTH-F2-2009-242167]; Helmholtz Association (MSBN, HelMA) [HA-215]; FCT [IF/00881/2013]info:eu-repo/semantics/publishedVersio

Small-molecule conversion of toxic oligomers to nontoxic β-sheet-rich amyloid fibrils

Several lines of evidence indicate that prefibrillar assemblies of amyloid-{beta} (A{beta}) polypeptides, such as soluble oligomers or protofibrils, rather than mature, end-stage amyloid fibrils cause neuronal dysfunction and memory impairment in Alzheimer's disease. These findings suggest that reducing the prevalence of transient intermediates by small molecule-mediated stimulation of amyloid polymerization might decrease toxicity. Here we demonstrate the acceleration of A{beta} fibrillogenesis through the action of the orcein-related small molecule O4, which directly binds to hydrophobic amino acid residues in A{beta} peptides and stabilizes the self-assembly of seeding-competent, {beta}-sheet-rich protofibrils and fibrils. Notably, the O4-mediated acceleration of amyloid fibril formation efficiently decreases the concentration of small, toxic A{beta} oligomers in complex, heterogeneous aggregation reactions. In addition, O4 treatment suppresses inhibition of long-term potentiation by A{beta} oligomers in hippocampal brain slices. These results support the hypothesis that small, diffusible prefibrillar amyloid species rather than mature fibrillar aggregates are toxic for mammalian cells

Predictive pressure control of a water distribution network

W artykule zaprezentowano wyniki badań dotyczących sterowania predykcyjnego ciśnieniem w sieci wodociągowej o wielu zasilaniach. Przedmiotem sterowania była optymalizacja parametrów pracy sieci, mająca na celu obniżenie ciśnienia w porze nocnej, w miejscach sieci, gdzie ze względu na ich położenie ponad poziomem morza występuje maksymalne ciśnienie, przy jednoczesnym zapewnieniu minimalnego wymaganego ciśnienia w pozostałych punktach sieci. Rezultat ten uzyskano przez manipulowanie ciśnieniami na zasilaniach, które daje pożądany przebieg linii ciśnień dla danej strefy. W budowie regulatora zastosowano algorytm Generalized Predictive Control (GPC), w którym model obiektu sterowanego zidentyfikowano w oparciu o dane otrzymane w wyniku eksperymentu numerycznego. Sprawdzenie poprawności rozwiązania przeprowadzono w środowisku Matlab® korzystając z przybornika Model Predictive Control™. Weryfikację działania metody oparto o dane i strukturę obiektu zidentyfikowane w ramach projektu prowadzonego we współpracy z PWiK Rybnik Sp. z. o. o. Otrzymane wyniki potwierdzają poprawność działania metody dla tak postawionego problemu eksploatacji sieci wodociągowych.The paper presents results of research on predictive control of a water distribution network with multiple supplies. The object of study was optimization of work parameters of a water distribution network in order to decrease the level of pressure at night for the places with the highest pressure values. This was achieved by manipulating the supply pressures to obtain the desired level of the pressure lines for a given area. The considered water distribution networks are shown in Figs. 1 and 2, whereas description of the network characteristic points is given in Tab. 1. The detailed discussion of selected water networks is contained in [1, 2, 3]. The authors made a deep literature review [4] and, as a result, selected the Generalized Predictive Control algorithm (see Fig. 4) as a framework for the predictive control. The schema of the predictive control for an exemplary water distribution network is shown in Fig. 5. The con-trolled plant was identified from a numerical experiment made on a network simulation model. An exemplary result of model identification is shown in Fig. 3. The solution was verified in the Matlab® environment with use of the Model Predictive Control™ toolbox. The results shown in Figs. 6-10 confirm that the method is a proper solution to this water distribution network maintenance problem. Implementation of the predictive control in a real water distribution network needs some costs to be incurred. However, it is expected that the costs will be returned soon, thanks to significant decrease in the number of malfunctions in the network caused by excessive hydraulic loads of the water network elements. In addition, it is possible to use the predictive control as a solution to the problem of undetected leakages whose level may be reduced with this method of control

Oprogramowanie do tworzenia i prowadzenia misji grupy robotów

The need of a software used for a mission control and maintenance of a group of robots increases with the expansion of mobile robotics applications. This paper discusses requirements for a software dedicated for semiautonomous mission planning, execution and monitoring. The authors present a working solution proposal which meets the majority of requirements stated before. The designed software contains path planning and trajectory generating algorithms necessary for the navigation of robots. The solution is equipped with an additional tool used to create surroundings for the mission in the simulation environment. The software is an universal tool which allows its application with different types of robots and missions. The applications of the system confirm the demand for mission control software and the results obtained from tests of the project prove its design propriety.Wraz z rozwojem zastosowań robotyki mobilnej rośnie zapotrzebowanie na oprogramowania stosowane do prowadzenia misji grupy robotów. Artykuł przedstawia główne wymagania stawiane oprogramowaniu dedykowanemu półautonomicznemu planowaniu, przeprowadzaniu i nadzorowaniu misji. Autorzy prezentują propozycje aplikacji spełniającej większość wymagań. Utworzone oprogramowanie zawiera algorytmy planowania ścieżki i generowania trajektorii niezbędne do nawigowania robotami. Rozwiązanie wyposażono w dodatkowe narzędzie tworzenia otoczenia misji w środowisku symulacyjnym. Oprogramowanie jest uniwersalnym narzędziem do sterowania różnymi typami robotów mobilnych w misjach o różnym charakterze. Obecne zastosowania i dalsze prace rozwojowe potwierdzają popyt na aplikacje dla sterowania misją, zaś wyniki otrzymane w ramach testów programu potwierdzają poprawność jego działania

Design solutions for multi-purpose mobile robots using advanced technologies

Niniejszy artykuł prezentuje wyniki prac dotyczących grupy wielozadaniowych robotów mobilnych wykorzystujących zaawansowane technologie. W artykule zaprezentowane zostały rozwiązania konstrukcyjne wspólnej platformy nośnej robota transportowego i robota eksploracyjnego oraz małego robota monitorującego. W artykule dodatkowo opisano układy wykonawcze dla robota transportowego oraz eksploracyjnego: manipulator oraz układ szybkiej wymiany czujników.The paper presents results of the research concerning a group of mobile robots using advanced technologies. There were presented design solutions of a carrier platform being a base for both the transport and exploring robots, as well as design of a small monitoring robot. Moreover, actuators of the transport and exploring robots such as a manipulator and a system for rapid sensors' replacement were presented

Aggregation-induced changes in the chemical exchange saturation transfer (CEST) signals of proteins

Chemical exchange saturation transfer (CEST) is an MRI technique that allows mapping of biomolecules (small metabolites, proteins) with nearly the sensitivity of conventional water proton MRI. In living organisms, several tissue-specific CEST effects have been observed and successfully applied to diagnostic imaging. In these studies, particularly the signals of proteins showed a distinct correlation with pathological changes. However, as CEST effects depend on various properties that determine and affect the chemical exchange processes, the origins of the observed signal changes remain to be understood. In this study, protein aggregation was identified as an additional process that is encoded in the CEST signals of proteins. Investigation of distinct proteins that are involved in pathological disorders, namely amyloid beta and huntingtin, revealed a significant decrease of all protein CEST signals upon controlled aggregation. This finding is of particular interest with regard to diagnostic imaging of patients with neurodegenerative diseases that involve amyloidogenesis, such as Alzheimer's or Huntington's disease. To investigate whether the observed CEST signal decrease also occurs in heterogeneous mixtures of aggregated cellular proteins, and thus prospectively in tissue, heat-shocked yeast cell lysates were employed. Additionally, investigation of different cell compartments verified the assignment of the protein CEST signals to the soluble part of the proteome. The results of in vitro experiments demonstrate that aggregation affects the CEST signals of proteins. This observation can enable hypotheses for CEST imaging as a non-invasive diagnostic tool for monitoring pathological alterations of the proteome in vivo

Project of a group of multi-purpose mobile robots using advanced technologies

Niniejszy artykuł prezentuje wyniki prac dotyczących grupy wielozadaniowych robotów mobilnych wykorzystujących zaawansowane technologie. Opracowane roboty pozwalają wspomagać człowieka w realizacji zadań w środowisku mogącym stwarzać zagrożenie. Grupa składa się ze zdalnie sterowanych robotów: robota transportowego, robota eksploracyjnego oraz małych robotów monitorujących. Grupa robotów umożliwia m.in. monitorowanie oraz dokonywanie pomiarów wybranych wielkości fizycznych na terenie dowolnego obiektu, a następnie zdalne przesyłanie danych do użytkownika.The paper presents results of the research concerning a group of multitasking mobile robots that use advanced technologies. The developed robots allow aiding humans in accomplishing tasks in an environment that may be dangerous. The group consists of remote controlled robots: a transporting robot, an exploring robot, and small monitoring robots. The group of robots is capable of monitoring and carrying out measurements of selected physical quantities, that can occur within the territory of any object, and then remote transmission of data to the user

The Anti-amyloid Compound DO1 Decreases Plaque Pathology and Neuroinflammation-Related Expression Changes in 5xFAD Transgenic Mice

Self-propagating amyloid-β (Aβ) aggregates or seeds possibly drive pathogenesis of Alzheimer's disease (AD). Small molecules targeting such structures might act therapeutically in vivo. Here, a fluorescence polarization assay was established that enables the detection of compound effects on both seeded and spontaneous Aβ42 aggregation. In a focused screen of anti-amyloid compounds, we identified Disperse Orange 1 (DO1) ([4-((4-nitrophenyl)diazenyl)-N-phenylaniline]), a small molecule that potently delays both seeded and non-seeded Aβ42 polymerization at substoichiometric concentrations. Mechanistic studies revealed that DO1 disrupts preformed fibrillar assemblies of synthetic Aβ42 peptides and decreases the seeding activity of Aβ aggregates from brain extracts of AD transgenic mice. DO1 also reduced the size and abundance of diffuse Aβ plaques and decreased neuroinflammation-related gene expression changes in brains of 5xFAD transgenic mice. Finally, improved nesting behavior was observed upon treatment with the compound. Together, our evidence supports targeting of self-propagating Aβ structures with small molecules as a valid therapeutic strategy