The lysosomal integral membrane protein type-2 (LIMP-2) plays a pivotal role in the delivery of β-glucocerebrosidase (GC) to lysosomes. Mutations in GC result in Gaucher's disease (GD) and are the major genetic risk factor for the development of Parkinson's disease (PD). Variants in the LIMP-2 gene cause action myoclonus-renal failure syndrome and also have been linked to PD. Given the importance of GC and LIMP-2 in disease pathogenesis, we studied their interaction sites in more detail. Our previous data demonstrated that the crystal structure of LIMP-2 displays a hydrophobic three-helix bundle composed of helices 4, 5, and 7, of which helix 5 and 7 are important for ligand binding. Here, we identified a similar helical motif in GC through surface potential analysis. Coimmunoprecipitation and immunofluorescence studies revealed a triple-helical interface region within GC as critical for LIMP-2 binding and lysosomal transport. Based on these findings, we generated a LIMP-2 helix 5-derived peptide that precipitated and activated recombinant wild-type and GD-associated N370S mutant GC in vitro. The helix 5 peptide fused to a cell-penetrating peptide also activated endogenous lysosomal GC and reduced α-synuclein levels, suggesting that LIMP-2–derived peptides can be used to activate endogenous as well as recombinant wild-type or mutant GC efficiently. Our data also provide a structural model of the LIMP-2/GC complex that will facilitate the development of GC chaperones and activators as potential therapeutics for GD, PD, and related synucleinopathies.
The Modelica library TransiEnt is being developed within the research project TransiEnt.EE. After completion, the library will be freely available and will provide a framework to model coupled energy supply grids, i.e. electricity, district heating, and gas grids, including their corresponding producers, consumers and storage systems. This paper presents the current status of the library and outlines the library's structure and the modeling concept. The application possibilities of the library are presented in an exemplary simulation where the city of Hamburg is selected as the reference system. The impact of a high share of fluctuating renewable energy generation in the electric grid and the integration of excess electricity in the district heating network is presented.
Questions Roots represent a considerable proportion of biomass, primary production and litter input in arctic tundra, and plant allocation of biomass to above‐ or below‐ground tissue in response to climate change is a key factor in the future C balance of these ecosystems. According to optimality theory plants allocate C to the above‐ or below‐ground structure that captures the most limiting resource. We used an elevational gradient to test this theory and as a space‐for‐time substitution to inform on tundra carbon allocation patterns under a shifting climate, by exploring if increasing elevation was positively related to the root:shoot ratio, as well as a larger plant allocation to adsorptive over storage roots. Location Arctic tundra heath dominated by Empetrum hermaphroditum close to Abisko, Sweden. Methods We measured root:shoot and fine:coarse root ratios of the plant communities along an elevational gradient by sampling above‐ and below‐ground biomass, further separating root biomass into fine (<1 mm) and coarse roots. Results Plant biomass was higher at the lower elevations, but the root:shoot ratio did not vary with elevation. Resource allocation to fine relative to coarse roots increased with elevation, resulting in a fine:coarse root ratio that more than doubled with increasing elevation. Conclusions Contrary to previous works, the root:shoot ratio along this elevational gradient remained stable. However, communities along our study system were dominated by the same species at each elevation, which suggests that when changes in the root:shoot ratio occur with elevation these changes may be driven by differences in allocation patterns among species and thus turnover in plant community structure. Our results further reveal that the allocation of biomass to fine relative to coarse roots can differ between locations along an elevational gradient, even when overall above‐ vs below‐ground biomass allocation does not. Given the functionally different roles of fine vs coarse roots this could have large implications for below‐ground C cycling. Our results highlight the importance of direct effects vs indirect effects (such as changes in plant community composition and nutrient availability) of climate change for future C allocation above and below ground.
Abstract:Multi-carrier energy systems have been identified as a major concept for future energy supply. For their operation, model-based control methods are necessary whose design requires modular, multi-physical control-oriented models. In literature, there exists no control design model which combines the variables of the networks and system dynamics that go beyond ideal storage elements. Port-Hamiltonian systems represent a promising approach for the scalable modeling and control of multi-carrier energy systems. In this publication we present a case study which illustrates the port-Hamiltonian modeling of an exemplary coupled electricity and gas distribution system. Simulations indicate the plausibility of the presented model.
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