Aging has long been considered as the main risk factor for several neurodegenerative disorders including a large group of diseases known as tauopathies. Even though neurofibrillary tangles (NFTs) ...have been examined as the main histopathological hallmark, they do not seem to play a role as the toxic entities leading to disease. Recent studies suggest that an intermediate form of tau, prior to NFT formation, the tau oligomer, is the true toxic species. However, the mechanisms by which tau oligomers trigger neurodegeneration remain unknown. This review summarizes recent findings regarding the role of tau oligomers in disease, including release from cells, propagation from affected to unaffected brain regions, uptake into cells, and toxicity via mitochondrial dysfunction. A greater understanding of tauopathies may lead to future advancements in regards to prevention and treatment.
In this study, we use the Algebraic Flame Surface Wrinkling (AFSW) model to conduct numerical simulations of the PSI (Paul Scherrer Institute) high pressure, turbulent premixed Bunsen flame ...experiments. The AFSW model was implemented in the open-source computational fluid dynamics solver OpenFOAM, and the numerical simulations were performed using a two-dimensional axial-symmetric model with the standard k–ɛ turbulence model with wall functions. The numerical simulations were performed for two different fuel/air mixtures, namely, 100% CH4 volumetric ratio and 60% CH4 + 40% H2 volumetric ratio. The thermophysical and transport properties of the mixture were calculated as a function of temperature using the library Cantera (an open-source suite of tools for problems involving chemical kinetics, thermodynamics, and transport processes), together with the GRI-Mech 3.0 chemical mechanism. It was found that the outcome of the AFSW model implemented in OpenFOAM was in good agreement with the experimental results, quantitatively and qualitatively. Further assessment of the results showed that, as much as the chemistry, the turbulence model and turbulent boundary/initial conditions significantly impact the flame shape and height.
This research addresses the extent to which economic freedom, understood as market economy-oriented institutions and policies, matters for opportunity entrepreneurship and necessity entrepreneurship. ...To this end, we carry out a panel data dynamic analysis in the OECD countries during the period 2001–2012 by using the system Generalized Method of Moments estimator. We examine the relationship between the Fraser Institute's economic freedom index and its five areas, and both indicators from the Global Entrepreneurship Monitor on opportunity entrepreneurship and necessity entrepreneurship. We find that economic liberalization tends to encourage opportunity entrepreneurship and to discourage necessity entrepreneurship. In particular, opportunity entrepreneurship seems to benefit from improvements in legal structure and security of property rights and in regulation of credit, labor, and business, while both aspects and more freedom to trade internationally seem to damage necessity entrepreneurship.
Several studies have proposed that fibrillary aggregates of tau and other amyloidogenic proteins are neurotoxic and result in numerous neurodegenerative diseases. However, these studies usually ...involve sonication or extrusion through needles before experimentation. As a consequence, these methods may fragment large aggregates producing a mixture of aggregated species rather than intact fibrils. Therefore, the results of these experiments may be reflective of other amyloidogenic species, such as oligomers and/or protofibrils/short fibrils. To investigate the effects of sonication on the aggregation of tau and other amyloidogenic proteins, fibrils were prepared and well characterized, then sonicated and evaluated by various biochemical and biophysical methods to identify the aggregated species present. We found that indeed a mixture of aggregated species was present along with short fibrils indicating that sonication leads to impure fibril samples and should be analyzed with caution. Our results corroborate the previous studies showing that sonication of prion and Aβ fibrils leads to the formation of toxic, soluble aggregates. We also show that the oligomeric forms are the most toxic species although it is unclear how sonication causes oligomer formation. Recent results suggest that these small toxic oligomers produced by sonication, rather than the stable fibrillar structures, are prion‐like in nature displaying seeding and cross‐seeding behavior.
Abiotic factors, substrate chemistry and decomposers community composition are primary drivers of leaf litter decomposition. In soil, much of the variation in litter decomposition is explained by ...climate and substrate chemistry, but with a significant contribution of the specialisation of decomposer communities to degrade specific substrates (home-field advantage, HFA). In streams, however, HFA effects on litter decomposition have not been explicitly tested. We evaluated responses of microbial decomposition and β-glucosidase activity to abiotic factors, substrate and decomposer assemblages, using a reciprocal litter transplant experiment: ‘ecosystem type’ (mountain vs lowland streams) × ‘litter chemistry’ (alder vs reed). Temperature, pH and ionic concentration were higher in lowland streams. Decomposition for both species was faster in lowland streams. Decomposition of reed was more accelerated in lowland compared with mountain streams than that of alder, suggesting higher temperature sensitivity of decomposition in reed. Q10 (5°C–15°C) values of β-glucosidase activity were over 2. The alkaline pH and high ionic concentration of lowland streams depleted enzyme activity. We found similar relationships of decomposition or enzyme activity with abiotic factors for both species, suggesting limited support to the HFA hypothesis. Overall, our results suggest a prime role of temperature interacting with substrate chemistry on litter decomposition.
Water temperature and leaf litter quality are majors factors affecting microbial decomposition and cellulolitic activity in headwater streams.
Tau aggregation is a pathological hallmark of Alzheimer's disease, Parkinson's disease, and many other neurodegenerative disorders known as tauopathies. Tau aggregates take on many forms, and their ...formation is a multistage process with intermediate stages. Recently, tau oligomers have emerged as the pathogenic species in tauopathies and a possible mediator of amyloid-β toxicity in Alzheimer's disease. Here, we use a novel, physiologically relevant method (oligomer cross-seeding) to prepare homogeneous populations of tau oligomers and characterize these oligomers in vitro. We show that both Aβ and α-synuclein oligomers induce tau aggregation and the formation of β-sheet-rich neurotoxic tau oligomers.
Identification of patient selection criteria and understanding of the potential mechanisms involved in the development of resistance are crucial for an appropriate and successful design of clinical ...trials with anti-insulin-like growth factor (IGF)-1R therapies. Few Ewing's sarcomas are highly sensitive to IGF-1R targeting and understanding the reason why, may hold the secret to improve successful treatments. In this paper, we show that a major mechanism of resistance to highly specific inhibitors of IGF-1R, either antibodies or tyrosine kinase inhibitors may involve enhanced insulin receptor (IR)-A homodimer formation and IGF-2 production. Resistant cells are able to switch from IGF-1/IGF-1R to IGF-2/IR-A dependency to maintain sustained activation of AKT and ERK1/2, proliferation, migration and metastasis. These cells also showed higher proliferative response to insulin, in keeping with a switch towards insulin pathways sustaining proliferation and malignancy, rather than metabolism. Our findings demonstrate a role for IR-A in eliciting intrinsic and adaptive resistance to anti-IGF-1R therapies. Thus, we indicate that tumors with low IGF-1R:IR ratio are unlikely to greatly benefit from anti-IGF-1R therapies and that the efficacy of anti-IGF-1R therapies should be evaluated in relationship to the IR-A:IGF-1R ratio in cancer cells. Moreover, we provide evidences supporting IR-A as an important target in sarcoma therapy.
Modular generation system, which consists of modular power conditioning converters, is an effective solution to integrate renewable energy sources with conventional utility grid to improve ...reliability and efficiency, especially for photovoltaic generation. A distributed control strategy based on improved dc bus signaling is proposed for a modular photovoltaic (PV) generation system with battery energy storage elements. In this paper, the modular PV generation system is composed of three modular dc/dc converters for PV arrays, two grid-connected dc/ac converters, and one dc/dc converter for battery charging/discharging and local loads, which is available of either grid-connected operation or islanding operation. By using the proposed control strategy, the operations of a modular PV generation system are categorized into four modes: islanding with battery discharging, grid-connected rectification, grid-connected inversion, and islanding with constant voltage (CV) generation. The power balance of the system under extreme conditions such as the islanding operation with a full-charged battery is taken into account in this control strategy. The dc bus voltage level is employed as an information carrier to distinguish different modes and determine mode switching. Control methods of modular dc/dc converters, battery converter, and grid-connected converter are addressed. An autonomous control method for modular dc/dc converters is proposed to realize smooth switching between CV operation and maximum power point tracking operation, which enables the dc bus voltage regulation capability of modular dc/dc converters. Seamless switching of a battery converter between charging and discharging and that of a grid-connected converter between rectification and inversion are ensured by the proposed control methods. Experiments verify the practical feasibility and the effectiveness of the proposed control strategies.
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