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High levels of intracellular endotrophin in adipocytes mediate COPII vesicle supplies to autophagosome to impair autophagic flux and contribute to systemic insulin resistance in obesity
No full textExtracellular matrix (ECM) homeostasis plays a crucial role in metabolic plasticity and endocrine function of adipose tissue. High levels of intracellular endotrophin, a cleavage peptide of type VI collagen alpha 3 chain (Col6a3), have been frequently observed in adipocyte in obesity and diabetes. However, how endotrophin intracellularly traffics and influences metabolic homeostasis in adipocyte remains unknown. Therefore, we aimed to investigate the trafficking of endotrophin and its metabolic effects in adipocytes depending on lean or obese condition. In adipocytes during obesity, the majority of endosomal endotrophin escapes lysosomal degradation and is released into the cytosol to mediate direct interactions between SEC13, a major component of coat protein complex II (COPII) vesicles, and autophagy-related 7 (ATG7), leading to the increased formation of autophagosomes. Autophagosome accumulation disrupts the balance of autophagic flux, resulting in adipocyte death, inflammation, and insulin resistance. These adverse metabolic effects were ameliorated by either suppressing ATG7 with siRNA ex vivo or neutralizing endotrophin with monoclonal antibodies in vivo. In conclusions, high levels of intracellular endotrophin-mediated autophagic flux impairment in adipocyte contribute to metabolic dysfunction such as apoptosis, inflammation, and insulin resistance (IR) in obesit
COL6A3 regulates adult neurogenesis in the hippocampus by modulating cellular senescence within the neural stem cell niche
No full textIn the adult mammalian hippocampus, new neurons arise from neural stem and progenitor cells, a process known as adult neurogenesis. Adult neurogenesis plays a vital role in cognitive functions like learning and memory. Recent studies suggest that extracellular matrix (ECM) molecules are involved in the process of adult neurogenesis. In our research, we have identified Collagen Type VI Alpha 3 Chain (COL6A3) as a regulator of adult neurogenesis in the hippocampus. In COL6A3-deficient mice, we observed a significant increase in neuronal development within the dentate gyrus (DG) region of the hippocampus and senescence markers in neural stem cells of the same region were reduced. Additionally, COL6A3-deficient mice exhibited enhanced learning and memory abilities that rely on the hippocampus. Our results confirm that COL6A3 is a regulator of adult neurogenesis in the hippocampus by modulating the cellular senescence of neural stem cells. This suggests its potential as a therapeutic target for neurodegenerative diseases such as Alzheimer's disease (AD
Improved regression model for anaerobic ammonium oxidation by repeated and prolonged batch assay under stressful salinity and pH conditions
No full textThe aim of this study was to propose repeated and prolonged batch (RPB) assay as a promising specific anammox activity (SAA) methodology assessing the anammox activity under stressed salinity and pH conditions. Response surface analysis (RSA) was used as a regression tool to evaluate statistical significance. The feasibility of RPB was investigated at 0 to 15 g-NaCl/L of salinity and pH 6 to 8 with reflecting the results of preliminary SAA. As a result, conventional SAA was statistically insignificant. In addition, the RSA results obtained from repeated batch did not meet the statistical significance despite ten times iterative reaction. Interestingly, the RPB assay (i.e., applied both repeated and prolonged reaction) was effective to obtain the reliable results. Candidadus Brocadia and Candidadus Jettenia were functional anammox microbiome during RPB. Outcomes of this study suggest that RPB assay can be applied to accurately determine the anammox activity under various stressful conditions
Targeting FLT3-TAZ signaling to suppress drug resistance in blast phase chronic myeloid leukemia
No full textBackgroundAlthough the development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) rendered chronic myeloid leukemia (CML) a manageable condition, acquisition of drug resistance during blast phase (BP) progression remains a critical challenge. Here, we reposition FLT3, one of the most frequently mutated drivers of acute myeloid leukemia (AML), as a prognostic marker and therapeutic target of BP-CML.MethodsWe generated FLT3 expressing BCR::ABL1 TKI-resistant CML cells and enrolled phase-specific CML patient cohort to obtain unpaired and paired serial specimens and verify the role of FLT3 signaling in BP-CML patients. We performed multi-omics approaches in animal and patient studies to demonstrate the clinical feasibility of FLT3 as a viable target of BP-CML by establishing the (1) molecular mechanisms of FLT3-driven drug resistance, (2) diagnostic methods of FLT3 protein expression and localization, (3) association between FLT3 signaling and CML prognosis, and (4) therapeutic strategies to tackle FLT3+ CML patients.ResultsWe reposition the significance of FLT3 in the acquisition of drug resistance in BP-CML, thereby, newly classify a FLT3+ BP-CML subgroup. Mechanistically, FLT3 expression in CML cells activated the FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway, which conferred resistance to a wide range of BCR::ABL1 TKIs that was independent of recurrent BCR::ABL1 mutations. Notably, FLT3+ BP-CML patients had significantly less favorable prognosis than FLT3- patients. Remarkably, we demonstrate that repurposing FLT3 inhibitors combined with BCR::ABL1 targeted therapies or the single treatment with ponatinib alone can overcome drug resistance and promote BP-CML cell death in patient-derived FLT3+ BCR::ABL1 cells and mouse xenograft models.ConclusionHere, we reposition FLT3 as a critical determinant of CML progression via FLT3-JAK-STAT3-TAZ-TEAD-CD36 signaling pathway that promotes TKI resistance and predicts worse prognosis in BP-CML patients. Our findings open novel therapeutic opportunities that exploit the undescribed link between distinct types of malignancies
Ceria tubular nanoarchitecture antioxidants achieve sustainable fuel cell devices via tuning the oxophilicity of Pt catalytic surfaces and radical scavenging
No full textThe durability of polymer electrolyte membrane fuel cells (PEMFCs) crucially depends on the use of antioxidants to prevent electrocatalyst degradation. Here, we report for the first time, by in situ X-ray absorption and H2O2 electrochemistry, that ceria significantly weakens the Pt-surface oxophilicity, which determines oxygen reduction (ORR) activity and durability, within the PEMFC cathode. Ceria mitigates catalyst disintegration and improves ORR durability by Pt oxophilicity reduction and its inherent radical scavenging behavior. We also found that the antioxidation efficacy of ceria could be finely tuned through nanostructuring. Among various ceria nanostructures, tubular ceria nanoarchitectures (CeOx NT), designed to have the largest surface area and abundant oxygen vacancies, enable the most potent interaction between Pt and Ce without direct chemical contact with Pt. The nanotubular structure confers superior multifunctional antioxidant therapeutic efficacy to Pt/C catalyst in PEMFCs, resulting in outstanding durability that retains 94% of initial performance after 100-hour tests
Investigation of theoretical maximum water yield and efficiency-optimized temperature for cyclopentane hydrate-based desalination
No full textHydrate-based desalination (HBD) shows promise as a freshwater production technology for saline water. Liquidphase hydrate formers, with their ability to facilitate hydrate formation at atmospheric pressure, have gained attention for their high energy efficiency in HBD. This study explored cyclopentane (CP) HBD by experimentally measuring the thermodynamic properties of CP hydrate in saline solutions and developing a theoretical framework to estimate the water yield of CP HBD under various operating conditions. The measured dissociation enthalpy of CP hydrate was found to be 12 % and 22 % lower compared to those of propane and R134a hydrates, respectively. The equilibrium dissociation temperatures of CP hydrate at different NaCl concentrations under atmospheric pressure were experimentally measured and then predicted using the Hu-Lee-Sum correlation. The theoretically achievable maximum salinity and water yield for CP HBD were calculated in the temperature range of 268-280 K and the initial salinity range of 0-8 wt.%. Additionally, the concept of HBD heat efficiency, representing the maximum amount of pure water producible per unit of heat, was introduced to identify an optimal operating condition for the HBD process. Efficiency-maximized temperatures, where the HBD heat efficiency reached its peaks, were determined for various initial salinities in the process, for example, 273.4 K for NaCl 3.5 wt.% solution. This novel approach provides invaluable guidance for determining the most energy-efficient operating conditions in the HBD process and establishes a solid foundation for further advancements in this field
Decoupling of mechanical properties and ionic conductivity in a low molecular weight polymer nanocomposites with highly connected particle aggregates
No full textHypothesis: High molecular weight polymer nanocomposites (PNCs) with good thermal stability and elevated mechanical strengths can serve as composite polymer electrolytes (CPEs) and thus have been considered as an alternative to conventional liquid electrolytes. However, resolving low ionic conductivity issues of CPEs arising from the low chain mobility derived from a long polymer chain remains challenging.Experiments: Here, we introduce PNCs for use in CPEs which show 1.4 x 10-4 S/cm of ionic conductivity at room temperature with a high shear modulus of 107 Pa using a low molecular weight poly(ethylene glycol) (PEG) matrix and dopamine-modified PEG brush polymer grafted-silica nanoparticles.Findings: We found that densely interconnected supramolecular particle networks can decouple the mechanical strength and ionic conductivity, as the Li-doped interfacial polymer layer supports a direct lithium-ion transport pathway. The extensive structural and rheological studies characterized by small-angle X-ray scattering and oscillatory rheometry experiments revealed that particle connections through interfacial polymer layers play an important role in supporting the elevated mechanical and electrochemical properties with a good thermal stability of PNCs