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The binding of insulin to the insulin receptor (IR) triggers a cascade of receptor conformational changes and autophosphorylation, leading to the activation of metabolic and mitogenic pathways. Recent advances in the structural and functional analyses of IR have revealed the conformations of the extracellular domains of the IR in inactive and fully activated states. However, the early activation mechanisms of this receptor remain poorly understood. The structures of partially activated IR in complex with aptamers provide clues for understanding the initial activation mechanism. In this review, we discuss the structural and functional features of IR complexed with various ligands and propose a model to explain the sequential activation mechanism. Moreover, we discuss the structures of IR complexed with biased agonists that selectively activate metabolic pathways and provide insights into the design of selective agonists and their clinical implications. Decoding the Sequential Activation of Insulin Receptor New insights into insulin receptor activation mechanisms reveal a stepwise process, providing a basis for designing functionally selective insulin receptor agonists. Cryo-EM structures of the insulin receptor in various states, from inactive to fully active, have been analyzed, and a model for insulin-induced activation has been proposed. This model suggests that insulin binding leads to transient intermediate states before reaching the fully active conformation. These intermediate states display functional selectivity biased toward metabolic effects rather than mitogenic signaling. Understanding these activation mechanisms may aid in the development of novel therapeutic strategies for diabetes and other insulin-related disorders.

Owing to the growing interest in environmental problems worldwide, it is essential to schedule power generation considering the effects of pollutants. To address this, we propose an optimal approach that solves the combined economic emission dispatch (CEED) with maximum emission constraints by considering demand response (DR) program. The CEED consists of the sum of operation costs for each generator and the pollutant emissions. An environment-based demand response (EBDR) program is used to implement pollutant emission reduction and facilitate economic improvement. Through the weighting update artificial bee colony (WU-ABC) algorithm, the penalty factor that determines the weighting of the two objective functions is adjusted, and an optimal operation solution for a microgrid (MG) is then determined to resolve the CEED problem. The effectiveness and applicability of the proposed approach are demonstrated via comparative analyses at a modified grid-connected MG test system. The results confirm that the proposed approach not only satisfies emission constraints but also ensures an economically superior performance compared to other approaches. These results present a useful solution for microgrid operators considered environment issues.

The gastrointestinal tract is a specialized organ in which dynamic interactions between host cells and the complex environment occur in addition to food digestion. Together with the chemical barrier of the mucosal layer and the cellular immune system, the epithelial cell layer performs a pivotal role as the first physical barrier against external factors and maintains a symbiotic relationship with commensal bacteria. The tight junction proteins, including occludin, claudins, and zonula occludens, are crucial for the maintenance of epithelial barrier integrity. To allow the transport of essential molecules and restrict harmful substances, the intracellular signaling transduction system and a number of extracellular stimuli such as cytokines, small GTPases, and post-translational modifications dynamically modulate the tight junction protein complexes. An imbalance in these regulations leads to compromised barrier integrity and is linked with pathological conditions. Despite the obscurity of the causal relationship, the loss of barrier integrity is considered to contribute to inflammatory bowel disease, obesity, and metabolic disorders. The elucidation of the role of diseases in barrier integrity and the underlying regulatory mechanisms have improved our understanding of the intestinal barrier to allow the development of novel and potent therapeutic approaches. Gut health: intestinal barrier function underpins health and disease A better understanding of how the cells that line the inside of the intestines allow nutrients in, while keeping harmful substances and pathogens out could lead to new therapies for inflammatory bowel disease, obesity, and other conditions. A team from South Korea led by Sung Ho Ryu from Pohang University of Science and Technology review the regulatory mechanisms that help maintain the intestinal epithelial barrier. They discuss the role of tight junction proteins in forming a seal between adjacent cells and the various signaling pathways that loosen or tighten these junctions to enable limited transport. Loss of barrier integrity because of genetics, gut microbes, auto-immunity, diet, or other factors is often implicated in disease, and restoring barrier function with drugs or probiotics could help ameliorate many health problems.

Owing to the increasing utilization of renewable energy resources, distributed energy resources (DERs) become inevitably uncertain, and microgrid operators have difficulty in operating the power systems because of this uncertainty. In this study, we propose a two-stage optimization approach with a hybrid demand response program (DRP) considering a risk index for microgrids (MGs) under uncertainty. The risk-based hybrid DRP is presented to reduce both operational costs and uncertainty effect using demand response elasticity. The problem is formulated as a two-stage optimization that considers not only the expected operation costs but also risk expense of uncertainty. To address the optimization problem, an improved multi-layer artificial bee colony (IML-ABC) is incorporated into the MG operation. The effectiveness of the proposed approach is demonstrated through a numerical analysis based on a typical low-voltage grid-connected MG. As a result, the proposed approach can reduce the operation costs which are taken into account uncertainty in MG. Therefore, the two-stage optimal operation considering uncertainty has been sufficiently helpful for microgrid operators (MGOs) to make risk-based decisions.

This paper presents the VCHP platform as a solution to address PV curtailment and line congestion in scenarios of increasing renewable energy penetration. Solar PV generation profiles and load profiles were generated for three scenarios (2025, 2030, and 2035) using data provided by KPX. Modifications were made to the IEEE 30 Bus model to accurately reflect the Korean power system, including the introduction of PCA and LCA at relevant buses. Line congestion was evaluated using metrics such as TUR, STUR, and TLR. The research findings indicate that integrating the VCHP platform in all scenarios effectively alleviates line congestion, as shown by the TUR remaining below 1. Importantly, the reduction in line losses exceeds the decrease in power flow, demonstrating the effectiveness of VCHP in reducing power losses. The results suggest that as renewable energy sources increase, line congestion issues may arise in the existing power system. However, integrating the proposed VCHP platform is a valuable solution for effectively utilizing surplus PV energy and improving the stability of the power grid. The adoption of such a platform can significantly enhance the operation and management of the power system.

The outbreak of the COVID-19 pandemic is a substantial threat to the health of all populations worldwide, and old age is a robust risk factor for poor prognosis of COVID-19 infection. To reduce the fatality rate of COVID-19 infection, further understanding of elderly patients with COVID-19 is necessary. We aimed to investigate the prognostic factors in elderly patients with COVID-19. This was a multicenter and retrospective study. Overall, 340 elderly patients with COVID-19 were enrolled in 3 hospitals in Daegu, South Korea. Death and severe pneumonia requiring oxygen treatment were defined as poor clinical outcomes. Of the patients studied, 15% died and 35.2% were classified as having severe pneumonia. In binary logistic regression analysis, activities of daily living (ADL) impairment, fever during hospitalization, initial infiltration on chest radiograph, and initial increased C-reactive protein (CRP) were significantly associated with severe pneumonia (OR = 5.33, p < 0.001; OR = 3.2, p = 0.002; OR = 2.32, p = 0.044; and OR = 1.33, p < 0.001, respectively). ADL impairment, comorbidity, fever during hospitalization, and initial increased CRP were significantly associated with death (OR = 7.13, p < 0.001; OR = 3.28, p = 0.005; OR = 3.15, p = 0.032, and OR = 1.18, p < 0.001, respectively). ADL impairment, fever, and initial CRP were poor prognostic factors in elderly patients with COVID-19. Understanding these poor prognostic factors is necessary to control the disease in elderly patients.

Insulin binding to the insulin receptor (IR) triggers signaling pathways that regulate glucose uptake and cell growth. In previous work, we identified a DNA aptamer, A62, which partially activates the IR. During engineering aptamers for improved in vivo stability, we discovered that crosslinking two A62 aptamers with linkers of varying lengths led to full phosphorylation of the IR, although activation remained selective to the AKT pathway. Here, to elucidate the mechanism behind this aptamer-induced full activation of the IR, we determined the structure of the IR in complex with a dimeric form of A62 (A62D) linked by an eight-nucleotide connector. We identified three distinct conformations of the IR: arrowhead-shaped, pseudo-arrowhead-shaped and pseudo-gamma-shaped. The pseudo-gamma-shaped conformation closely resembles the structure of a fully active IR bound by a single insulin molecule. In these configurations, only one A62 monomer (A62M) within the A62D dimer binds to the IR dimer. This binding brings the IR monomers into close proximity, promoting intermolecular trans -phosphorylation. Our findings provide valuable structural insights for the development of novel therapeutic strategies targeting the IR. Aptamer engineering reveals insulin receptor activation mechanism Insulin is a hormone that helps control blood sugar levels. When insulin-induced signaling does not work properly, it can lead to diabetes. Researchers have been exploring new ways to treat diabetes by targeting the insulin receptor (IR), a protein that insulin binds to. In this study, researchers developed a new molecule called A62D, which is made of two DNA aptamer molecules linked together. Using cryo-electron microscopy, they found that A62D can fully activate the IR by bringing two IR molecules close together. This is important because the new aptamer induces crosslinking of the IR molecules to enhance the trans -autophosphorylation, thereby improve their signaling for better treatments for diabetes. The study showed that A62D can make the IR more active than previous treatments, which only partially activated it. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

A levelized cost of energy (LCOE) is a methodology for comparing power generation costs in the transition to renewable energy (RE). However, the major limitation of evaluating RE based on the LCOE is that it does not consider indirect costs, such as the environmental and curtailment effect. This paper proposes the real LCOE (rLCOE) approach that accounts for indirect and direct generation costs. The mathematical approach to estimating indirect costs is derived from economic theory. The indirect effects, which quantify all benefits generated due to RE, is related to the variability of the share RE in the energy generation mix. The rLCOE enhances the accuracy of the economic comparison of power generation costs and the derivation of the optimal quantities of RE because external effects are incorporated into the LCOE principles. This approach has taken into account electricity demand, fuel prices, and environmental costs for each energy source to adequately compare generation costs. Simulations have been performed to demonstrate the application of the rLCOE approach in the Korean power market. Here, the unit variation of costs with the RE share were analyzed. The results show that indirect cost savings of an additional unit of RE begin to fall in scenario 3 in contrast to the result of LCOE approach indicating higher generation costs with RE share, especially, the proportion of RE in the generation mix is higher than 20%. Thus, the optimal power generation can be evaluated using the rLCOE approach.

Most previous genome-wide association studies (GWASs) on Parkinson’s disease (PD) focus on the European population. There are several sex-specific clinical differences in PD, but little is known about its genetic background. We aimed to perform an ethnicity-specific and sex-specific GWAS on PD in the Korean population. A total of 1050 PD patients and 5000 controls were included. For primary analysis, we performed a GWAS using a logistic additive model adjusted for age and sex. The same statistical models were applied to sex-specific analyses. Genotyping was performed using a customized microarray chip optimized for the Korean population. Nine single nucleotide polymorphisms (SNPs) including four in the SNCA locus and three from the PARK16 locus were associated with PD in Koreans. The rs34778348 in the LRRK2 locus showed a strong association, though failed to pass cluster quality control. There were no notable genome-wide significant markers near the MAPT or GBA1 loci. In the female-only analysis, rs34778348 in LRRK2 and the four other SNPs in the SNCA showed a strong association with PD. In the male-only analysis, no SNP surpassed the genome-wide significance threshold under Bonferroni correction; however, the most significant signal was rs708726 in the PARK16 locus. This ethnicity- and sex-specific GWAS on PD implicate the pan-ethnic effect of SNCA , the universal but East-Asian inclined effect of PARK16 , the East Asian-specific role of LRRK2 G2385R variants, and the possible disproportionate effect of SNCA and PARK16 between sexes for PD susceptibility. These findings suggest the different genetic contributions to sporadic PD in terms of ethnicity and sex.

Dementia is one of the most disabling nonmotor symptoms of Parkinson’s disease (PD). However, the risk factors contributing to its development remain unclear. To investigate genetic variants associated with dementia in PD, we performed microarray genotyping based on a customized platform utilizing variants identified in previous genetic studies. Microarray genotyping was performed in 313 PD patients with dementia, 321 PD patients without dementia, and 635 healthy controls. The primary analysis was performed using a multiple logistic regression model adjusted for age and sex. SNCA single nucleotide polymorphism (SNP) rs11931074 was determined to be most significantly associated with PD (odds ratio = 0.66, 95% confidence interval = 0.56–0.78, p = 7.75 × 10−7). In the analysis performed for patients with PD only, MUL1 SNP rs3738128 (odds ratio = 2.52, 95% confidence interval = 1.68–3.79, p = 8.75 × 10−6) was found to be most significantly associated with dementia in PD. SNPs in ZHX2 and ERP29 were also associated with dementia in PD. This microarray genomic study identified new loci of MUL1 associated with dementia in PD, suggesting an essential role of mitochondrial dysfunction in the development of dementia in patients with PD.