Insulin-degrading enzyme (IDE) selectively degrades peptides, such as insulin, amylin, and amyloid β (Aβ) that form toxic aggregates, to maintain proteostasis. IDE defects are linked to the ...development of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). Structural and biochemical analyses revealed the molecular basis for IDE-mediated destruction of amyloidogenic peptides and this information has been exploited to develop promising inhibitors of IDE to improve glucose homeostasis. However, the inhibition of IDE can also lead to glucose intolerance. In this review, I focus on recent advances regarding our understanding of the structure and function of IDE and the discovery of IDE inhibitors, as well as challenges in developing IDE-based therapy for human diseases, particularly T2DM.
With more distributed energy resources penetrated into the residential community, nanogrid based peer-to-peer (P2P) energy market has rapidly emerged over recent years. Due to the complexities on the ...decision-making process of each market participant, an efficient, fair and beneficial oriented bidding strategy is thus necessary. In this article, a two-stage bidding strategy for P2P trading of nanogrid is proposed. To overcome the limitations of traditional methods, in the first stage, a supply-demand relationship considered two-step price predictor, which aims to promote the usage of local renewable energy, is formulated to provide the guidance on transaction adjustment. In the second stage, trading preference based simultaneous game-theoretic approach is fully introduced, which can optimize the market equilibrium and then increase the social welfare of the P2P market. Additionally, to mitigate the possible failure of price matching, value-at-risk is implemented through the trading process as a risk hedging tool. To verify the effectiveness of the proposed strategy, usages of local renewable energy, economic benefits and success rates of transaction is compared against the traditional method for various cases.
With the emerging of prosumers in residential level, peer-to-peer (P2P) energy trading provides a novel way to prompt the localized management of distributed energy resources (DERs). However, the ...work of designing an appropriate market framework, with the fair and flexible pricing strategy for each participant, is still very challenging. This article proposes a two-settlement P2P energy market framework for the joint scheduling and trading of prosumers in community microgrid. To provide price certainty and increase the localized transaction volume of DERs, a risk-implemented simultaneous game approach is adopted into the hour-ahead market. For mitigating the supply uncertainties in local, meanwhile optimizing the overall financial benefits for the entire microgrid, a BRP-based reserve services mechanism, with an auction-based pricing strategy, is implemented to a real-time market. The various case-based simulation results are presented to verify the effectiveness of the proposed two-settlement trading scheme for financial benefits enhancing and DERs consumption increasing in the P2P energy market.
As power distribution systems become increasingly interconnected and concentrated with distributed energy resources (DER) and high potential equipment, effectively avoiding the medium-low voltage ...caused safety risk, drawing more attention. Therefore, the accurate, fast, and reliable preemptive arc detection and location method is essential to be developed. However, due to the issues such as low sensitivity, delayed detection, complex structure, and susceptible to interference by other sources, the traditional approaches are not up to the detection and location job, for weak system source and high arcing resistance featured medium-low voltage arc flash. To overcome the limitations, this article explores a novel arc flash preemptive detection and location mechanism. With the application of geometric distribution analysis on magnetic density flux and current density, mathematical modeling incorporated magnetohydrodynamic approach is developed. With a series of actual cases incorporated simulations were performed, the criterion of arc initiation and concisely numerical model on arc fault location estimation is derived, which shows a good ability to catch the transient dynamics of arcing current in the early initiating stage, and also proves the reliability and accuracy on fast detection and location uses. These results offered valuable information for medium-low arc fault mitigation and hazard prevention.
The gradually increased proportion of power electronic devices and the distributed energy resource (DER), in the distribution network, induced more harmonic and pulse signals to be injected into the ...grid. Arc faults, as the critical and common faults in the distribution system, are the potential reasons for the safety of the personnel and equipment. Furthermore, intensely chaotic characteristics of the arc current and the harmonic generated from the power electronic devices pollute the fault signature, which may cause misjudgment or malfunctions of arc detection devices. Therefore, to identify the arc fault rapidly and accurately, this article starts with the mechanism of the arc formation. It analyzes the fault signature with resistive, inductive, and capacitive loads to reduce the detection of blind spots. Then, the time-frequency is utilized to analyze the fault current of each load type to capture the common feature in the frequency domain. Comparing multiple tests shows that the proposed approach can accurately and robustly identify the arc fault in different operation conditions.
The occurrence of electric arcs poses a huge threat to personal and equipment safety. As one of the effective ways to actively protect personnel and equipment away from serious arcing incidents, the ...signature recognition based arcing identification method has drawn much attention. However, since the strong nonlinear dynamics of the arcs, merely based on a specific time-domain or frequency-domain feature to develop the identification criteria may not be applicable in practice. To overcome the limitations, this article proposes a novel arc fault identification approach, which evaluated both the transient and steady dynamic states of arcing faults by time-frequency analysis. The complete ensemble empirical mode decomposition with adaptive noise, incorporated with Hilbert transform, has been designed to realize the rapid and reliable signatures extraction from arc fault profiles. Moreover, for dimension reduction purposes, correlation coefficient and partial least square regression based time-series dominant features selection method was developed. For ensuring the accuracy and robustness of the identification algorithm, a multiscenario based long short-term memory was also proposed. With the series of actual arc fault cases under different configurations, the effectiveness of the proposed method has.
Accurate equivalent model can be efficient to analyze the dynamic properties of active distribution network (ADN) as well as assess their impacts on stabilities of interconnected power system. ...However, due to the stochastic nature of renewable resources and time-varying configurations of load conditions, traditional ADN equivalent model may not be robust enough to different operation conditions. To overcome the limitations, this article proposed a robustness-improved method for dynamic equivalent modeling of ADN. To sketch out the most representative operation conditions of ADN, two-step clustering method with fisher discriminant analysis are used for grouping of operation conditions featured characteristic data sets. With the key parameter based identification technique applied, the multiple solution issue in parameter identification process could be effectively avoided. To further enhance the robustness of equivalent model, long short-term memory neural network is adopted to generalize the identified parameters. The performance of proposed modeling method is comprehensively evaluated by an actual ADN based verification cases.
Insulin-degrading enzyme (IDE), a Zn2+-metalloprotease, is involved in the clearance of insulin and amyloid- (refs 1-3). Loss-of-function mutations of IDE in rodents cause glucose intolerance and ...cerebral accumulation of amyloid- , whereas enhanced IDE activity effectively reduces brain amyloid- (refs 4-7). Here we report structures of human IDE in complex with four substrates (insulin B chain, amyloid- peptide (1-40), amylin and glucagon). The amino- and carboxy-terminal domains of IDE (IDE-N and IDE-C, respectively) form an enclosed cage just large enough to encapsulate insulin. Extensive contacts between IDE-N and IDE-C keep the degradation chamber of IDE inaccessible to substrates. Repositioning of the IDE domains enables substrate access to the catalytic cavity. IDE uses size and charge distribution of the substrate-binding cavity selectively to entrap structurally diverse polypeptides. The enclosed substrate undergoes conformational changes to form -sheets with two discrete regions of IDE for its degradation. Consistent with this model, mutations disrupting the contacts between IDE-N and IDE-C increase IDE catalytic activity 40-fold. The molecular basis for substrate recognition and allosteric regulation of IDE could aid in designing IDE-based therapies to control cerebral amyloid- and blood sugar concentrations.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genotype I (GI) virus has replaced genotype III (GIII) virus as the dominant Japanese encephalitis virus (JEV) in the epidemic area of Asia. The mechanism underlying the genotype replacement remains ...unclear. Therefore, we focused our current study on investigating the roles of mosquito vector and amplifying host(s) in JEV genotype replacement by comparing the replication ability of GI and GIII viruses. GI and GIII viruses had similar infection rates and replicated to similar viral titers after blood meal feedings in Culex tritaeniorhynchus. However, GI virus yielded a higher viral titer in amplifying host-derived cells, especially at an elevated temperature, and produced an earlier and higher viremia in experimentally inoculated pigs, ducklings, and young chickens. Subsequently we identified the amplification advantage of viral genetic determinants from GI viruses by utilizing chimeric and recombinant JEVs (rJEVs). Compared to the recombinant GIII virus (rGIII virus), we observed that both the recombinant GI virus and the chimeric rJEVs encoding GI virus-derived NS1-3 genes supported higher replication ability in amplifying hosts. The replication advantage of the chimeric rJEVs was lost after introduction of a single substitution from a GIII viral mutation (NS2B-L99V, NS3-S78A, or NS3-D177E). In addition, the gain-of-function assay further elucidated that rGIII virus encoding GI virus NS2B-V99L/NS3-A78S/E177E substitutions re-gained the enhanced replication ability. Thus, we conclude that the replication advantage of GI virus in pigs and poultry is the result of three critical NS2B/NS3 substitutions. This may lead to more efficient transmission of GI virus than GIII virus in the amplifying host-mosquito cycle.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Despite decades of speculation that inhibiting endogenous insulin degradation might treat type-2 diabetes, and the identification of IDE (insulin-degrading enzyme) as a diabetes susceptibility gene, ...the relationship between the activity of the zinc metalloprotein IDE and glucose homeostasis remains unclear. Although Ide(-/-) mice have elevated insulin levels, they exhibit impaired, rather than improved, glucose tolerance that may arise from compensatory insulin signalling dysfunction. IDE inhibitors that are active in vivo are therefore needed to elucidate IDE's physiological roles and to determine its potential to serve as a target for the treatment of diabetes. Here we report the discovery of a physiologically active IDE inhibitor identified from a DNA-templated macrocycle library. An X-ray structure of the macrocycle bound to IDE reveals that it engages a binding pocket away from the catalytic site, which explains its remarkable selectivity. Treatment of lean and obese mice with this inhibitor shows that IDE regulates the abundance and signalling of glucagon and amylin, in addition to that of insulin. Under physiological conditions that augment insulin and amylin levels, such as oral glucose administration, acute IDE inhibition leads to substantially improved glucose tolerance and slower gastric emptying. These findings demonstrate the feasibility of modulating IDE activity as a new therapeutic strategy to treat type-2 diabetes and expand our understanding of the roles of IDE in glucose and hormone regulation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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