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Background Lung injury imposed by hyperoxia is the main cause of bronchopulmonary dysplasia in newborns. These injuries are generated from the early stage of hyperoxia through the main biologic effects of cell death and inflammatory response. Interleukin (IL)-10 is a potent anti-inflammatory cytokine that may have the inhibitory effects on these biologic actions induced by hyperoxia. Purpose Based on our former in vitro studies investigating the effect of recombinant IL-10 (rIL-10) on protecting cultured alveolar type II cells exposed to short-term hyperoxia, we performed the in vivo study to investigate the effect of rIL-10 in newborn rats aged P4 exposed to hyperoxia. Methods Rats were classified into 3 groups; the control group exposed to normoxia for 24 hours; the hyperoxia group exposed to 65% hyperoxia for 24 hours; and the IL10 group treated with intratracheal instillation of rIL-10 prior to exposure to 65% hyperoxia for 24 hours. Following each treatment, the rats were euthanized. Individual lobes of the right lung were prepared for hematoxyling and eosin (H&E) staining and immunohistochemical staining for thyroid transcription factor-1 (TTF1). Bronchoalveolar lavage (BAL) was performed in the left lung to analyze cell counts and cytokines. Results The IL10 group showed preserved air spaces similar to the control group, with decreased cellularity compared to the hyperoxia group, whereas the hyperoxia group showed markedly reduced air spaces with increased cellularity compared to the IL10 group. And, the IL10 group showed more TTF1-positive cells, which represented alveolar type II cells, compared to the hyperoxia group. Inflammatory cells, such as neutrophils and lymphocytes and proinflammatory cytokines of tumor necrosis factor-α, IL-1α, IL-8, and macrophage inflammatory protein-1α were significantly lower in BAL fluid of the IL10 group compared to the hyperoxia group. Conclusion These results indicate that rIL-10 may be a promising pharmaceutical measure for protecting newborn lungs from injury induced at the early stage of hyper oxia.

Abstract Age-related macular degeneration (AMD) is one of the leading causes of blindness. AMD is currently incurable; the best solution is to prevent its occurrence. To develop drugs for AMD, it is crucial to have a model system that mimics the symptoms and mechanisms in patients. It is most important to develop safer and more effective anti-AMD drug. In this study, the dose of A2E and the intensity of blue light were evaluated to establish an appropriate atrophic in vitro model of AMD and anti-AMD effect and therapeutic mechanism of Codonopsis lanceolata. The experimental groups included a control group an AMD group treated with A2E and blue light, a lutein group treated with 25 μM lutein after AMD induction, and three groups treated with different doses of C. lanceolata (10, 20, and 50 μg/mL) after AMD induction. Intrinsic apoptotic pathway (Bcl-2 family), anti-oxidative system (Keap1/Nrf2/HO-1 antioxidant response element), and anti-carbonyl effect (4-hydroxynonenal [4-HNE]) were evaluated using immunofluorescence, MTT, TUNEL, FACS, and western blotting analyses. A2E accumulation in the cytoplasm of ARPE-19 cells depending on the dose of A2E. Cell viability of ARPE-19 cells according to the dose of A2E and/or blue light intensity. The population of apoptotic or necrotic cells increased based on the A2E dose and blue light intensity. Codonopsis lanceolata dose-dependently prevented cell death which was induced by A2E and blue light. The antiapoptotic effect of that was caused by activating Keap1/Nrf2/HO-1 pathway, suppressing 4-HNE, and modulating Bcl-2 family proteins like increase of antiapoptotic proteins such as Bcl-2 and Bcl-XL and decrease of proapoptotic protein such as Bim. Based on these findings, 30 μM A2E and 20 mW/cm2 blue light on adult retinal pigment epithelium-19 cells was an appropriate condition for AMD model and C. lanceolata shows promise as an anti-AMD agent.

Reliable traffic forecasts are critical for successful planning and financing of transportation projects. However, the accuracy evaluation results of the predicted traffic volumes often indicate significant discrepancies between the actual and predicted traffic volumes. These discrepancies are mainly due to both limitations and uncertainties in traffic demand forecasting models; therefore, researchers are continuously attempting to estimate the error and bias in traffic forecasts. To enhance these endeavors, a Monte Carlo simulation (MCS)- based approach is proposed in this paper as an alternative to the stochastic traffic demand forecast. This approach uses a sequential process to capture the effects of model inputs and variables on the error and bias in traffic demand forecasting. The approach proposed in this study was developed in three steps. First, the key factors causing errors and biases in traffic demand forecasts were identified based on a comprehensive review of traffic forecasting practices. Second, the effects of each variable on traffic volumes were quantified using MCS. Lastly, the statistical approach was constructed to provide an interval estimation of traffic volumes based on the findings of MCS. Through these steps, the inherent uncertainties in socioeconomic variables and heterogeneities in passenger behaviors with regard to traffic demand modeling were considered. Then, simulation experiments were conducted to investigate the applicability of the proposed approach to a real-world network. This approach is expected to reasonably capture the stochastic nature of future traffic volumes and quantify the risks associated with the error and bias in traffic demand forecasting. The findings of this study indicate that traffic forecasting practitioners can use the proposed approach with ease. The analysis results showed that the proposed approach clearly captured the changes in link traffic volumes owing to the statistical changes in the value of time (VOT). The experiments indicated that the uncertainties in VOT perceived by road users can be used to estimate the risks of toll road financing. The elasticity of traffic volume to VOT for each link, which can be used as a key input to the road project feasibility study, can be derived from the MCS-based analysis implemented in this study.

In order to create an entrepreneurial ecosystem at the national level, this study aims to examine the mediating role of entrepreneurial orientation between entrepreneurial resources and startup activities. Our empirical results based on samples from the Adult Population Survey (APS) and Global Entrepreneurship Monitor (GEM) data revealed that entrepreneurial resources have a positive impact on startup activation and entrepreneurial orientation plays a significant role as a mediator in the entrepreneurial resource-startup activation relationship. Our results suggest that in a business ecosystem where entrepreneurial resources persistently exist, individuals are more likely to participate in startup activation, and entrepreneurial orientation can promote startup activity not only in countries rich in entrepreneurial resources but also in emerging countries where they are scarce. Therefore, this study emphasizes the need for efforts to increase entrepreneurial orientation as well as entrepreneurial resources to create an entrepreneurial ecosystem where startups actively appear.

Although there have been many studies related to construction site safety that have tried to reduce accidents, no significant improvement has been reported. Because of the complex nature of construction work processes, it is important to have a scenario-based worksite safety management system instead of reports such as safety guidelines and manuals. This study utilizes accumulated construction site accident big data, namely Construction Safety Management Integrated Information (CSI), to establish accident scenarios for different work types. To propose accident occurrence scenarios, the hazard profile managed by CSI and prior research analyses are employed for each work type and cause materials at the construction site. For accident occurrence association rules, we developed a framework based on Work Breakdown Structure–Risk Breakdown Structure (WBS-RBS) for reinforced concrete work, temporary work, and earthwork, considering 25,986 accident cases. Subsequently, association analysis was conducted to derive association rules for each work type. The accident occurrence scenarios were extracted by classifying work types (project type, activity type) and cause materials (object, location). The analysis generated 145 association rules, and 76 association rules for reinforced concrete work, temporary work, and earthwork work were extracted to derive accident scenarios, considering scenarios with high accident frequency. Furthermore, by establishing association rules between work processes, we derived accident types and occurrence rules frequently observed at construction sites. These rules formed the basis for constructing accident occurrence scenarios for each construction type based on WBS-RBS. These findings facilitate the development of appropriate safety management plans and effective accident countermeasures tailored to specific construction types and causes. The developed scenarios will help to improve construction site safety by providing useful information for safety managers and worker training.

This study proposes a multiview stereo (MVS) method that is based on the forward and backward propagation of matching costs for the incremental refinement of multiview disparity maps. The volume-based MVS method requires numerous three-dimensional (3D) memory volumes to compute, store, and process the stereo matching costs. However, owing to memory limitations, conventional MVS methods allocate the memory of the 3D cost volumes only to the reference and its neighbor views. Thus, each reference view can only use the matching costs from a limited number of neighbor views. This study addresses this inherent MVS problem and proposes a new method by employing a forward and backward cost propagation (FBCP). First, a subpart of the input views is used to obtain disparity maps with a dense MVS method. Once all matching costs of the subpart views are sufficiently refined, the FBCP is performed for a new neighbor view. Immediately after the cost volume of the new view is computed, all matching costs of the subpart are forward propagated and fused with the initial cost of the new view. Furthermore, the new fused cost is backward propagated into the subpart to refine the previous costs again using the new fused cost. All cost volumes can be incrementally computed and refined without any limitation on the number of views using the proposed FBCP scheme. In the final step, all disparity maps are obtained from the refined cost volumes and fused into single point clouds. Moreover, we propose the use of surface consensus to obtain accurate fused point clouds for the fusion of the disparity maps. The performance of the proposed method is evaluated using the fused point clouds. The proposed method achieves less than 0.5 mm in mean distance error and about 82 percentage F-score within 2 mm distance threshold value.

In this article, we investigate the market efficiency of global stock markets using the multifractal detrended fluctuation analysis methodology and analyze the results by dividing them into developed, emerging, and frontier groups. The static analysis results reveal that financially advanced countries, such as Switzerland, the UK, and the US, have more efficient stock markets than other countries. Rolling window analysis shows that global issues dominate the developed country group, while emerging markets are vulnerable to foreign capital movements and political risks. In the frontier group, intensive domestic market issues vary, making it difficult to distinguish similar dynamics. Our findings have important implications for international investors and policymakers. International investors can establish investment strategies based on the degree of market efficiency of individual stock markets. Policymakers in countries with significant fluctuations in market efficiency should consider implementing new regulations to enhance market efficiency. Overall, this study provides valuable insights into the market efficiency of global stock markets and highlights the need for careful consideration by international investors and policymakers.

This research was conducted for the synthesis and application of ophthalmic lens materials with improved oxygen permeability and durability. Polyvinylpyrrolidone (PVP), N-vinyl-2-pyrrolidone (NVP), 3-(trifluoromethyl)styrene (3-TFMSt), and magnesium oxide nanoparticles were used as additives for the basic combination of 2-hydroxyethyl methacrylate (HEMA). Additionally, the materials were copolymerized with ethylene glycol dimethacrylate (EGDMA) as the cross-linking agent and azobisisobutyronitrile (AIBN) as the initiator. The addition of magnesium oxide nanoparticles was found to increase the tensile strength from 0.0631 to 0.0842 kgf/mm2. Copolymerization with a small amount of 3-TFMSt of about 1% increased the tensile strength to 0.1506 kgf/mm2 and the oxygen permeability from 6.00 to 9.64 (cm2/s)∙(mLO2/mL·mmHg)∙10−11. The contact lens material produced using N-vinyl-2-pyrrolidone and magnesium oxide nanoparticles as additives satisfied the basic physical properties required for hydrogel contact lenses and is expected to be used usefully as a material for fabricating high-performance hydrogel lenses.

Background/Aims: The complicated differentiation processes of cells in skeletal muscle against inflammation that induce muscle atrophy are not fully elucidated. Given that skeletal muscle is a secretory organ, we evaluated the effects of inflammation on myogenic signals and myokine expression, and the roles of inflammatory exosomes released by myotubes in myogenic differentiation. Methods: Inflammation was induced by treatment of fully differentiated C2C12 myotubes with a cytokine mixture of TNF-α and INF-γ. Exosome-like vesicles (ELVs) were isolated from conditioned media of control or inflamed myotubes and incubated with myoblasts. The expression of molecular switches that contribute to myogenic differentiation, including several kinases, their downstream targets, and myokines, were evaluated using immunoblot analysis in inflamed myotubes and in myoblasts treated with ELVs. Results: Inflammation activated molecular mechanisms contributing to muscle atrophy, including AMPK, p-38 MAPK and JNK, while inhibiting Akt-mediated myogenic signals. In addition, inflammation induced myostatin expression with suppression of a myostatin-counteracting myokine, decorin. Well-characterized ELVs released from inflamed myotubes induced myoblast inflammation and inhibited myogenic mechanisms while stimulating atrophic signals. Conclusion: Inflammation of skeletal muscle induces muscle atrophy via multiple mechanisms, including the regulation of myokines and kinases. Inflammatory ELVs are likely to contribute to inflammation-induced muscle atrophy.

Abstract The objective of this study was to determine the effect of ionizing radiation (IR) exposure of parents on carcinogenesis of the next generation focusing on the epigenetic perspective to clarify the relationship between radiation dose and carcinogenesis in F1 generation SD rats. F1 generations from pregnant rats (F0) who were exposed to gamma rays were divided into three groups according to the dose of radiation: 10 rad, 30 rad, and untreated. They were intraperitoneally injected with 50 mg/kg of diethylnitrosamine (DEN). Carcinogenesis was analyzed by examining expression levels of tumor suppressor genes (TSG) and other related genes by methylation-specific polymerase chain reaction (MSP). DNA methylation in liver tissues was evaluated to discern epigenetic regulation of transgenerational carcinogenesis vulnerability following IR exposure. Numerous studies have proved that transcriptional inactivation due to hypermethylation of TSG preceded carcinogenesis. Results of this study revealed hypermethylation of tumor suppressor gene SOCS1 in group treated with 30 rad. In addition, genes related to DNA damage response pathway (GSTP1, ATM, DGKA, PARP1, and SIRT6) were epigenetically inactivated in all DEN treated groups. In the case of proto-oncogene c-Myc, DNA hypermethylation was identified in the group with low dose of IR (10 rad). Results of this study indicated that each TSG had different radiation threshold level (dose-independent way) and DEN treatment could affect DNA methylation profile irrelevant of ionizing radiation dose.

In this paper, we propose a multi-view stereo matching method, EnSoft3D (Enhanced Soft 3D Reconstruction) to obtain dense and high-quality depth images. Multi-view stereo is one of the high-interest research areas and has wide applications. Motivated by the Soft3D reconstruction method, we introduce a new multi-view stereo matching scheme. The original Soft3D method is introduced for novel view synthesis, while occlusion-aware depth is also reconstructed by integrating the matching costs of the Plane Sweep Stereo (PSS) and soft visibility volumes. However, the Soft3D method has an inherent limitation because the erroneous PSS matching costs are not updated. To overcome this limitation, the proposed scheme introduces an update process of the PSS matching costs. From the object surface consensus volume, an inverse consensus kernel is derived, and the PSS matching costs are iteratively updated using the kernel. The proposed EnSoft3D method reconstructs a highly accurate 3D depth image because both the multi-view matching cost and soft visibility are updated simultaneously. The performance of the proposed method is evaluated by using structured and unstructured benchmark datasets. Disparity error is measured to verify 3D reconstruction accuracy, and both PSNR and SSIM are measured to verify the simultaneous enhancement of view synthesis.

The functional hydrogel lens containing 2-hydroxyethylmethacrylate (HEMA) was manufactured by thermal polymerization. The physical properties of the produced hydrogel lens were measured and analyzed. In this study, HEMA, ethylene glycol dimethacrylate (EGDMA), and azobisisobutyronitrile (AIBN) were used for thermal copolymerization. Additionally, poly (ethylene glycol) methyl ether methacrylate (PEGMEMA), 3-(Triethoxysilyl) propyl isocyanate (TEPI), and cerium(Ⅳ) oxide nanoparticles were used as additives to make a functional hydrogel lens. The mixture was heated at 100 °C for 90 min to produce the hydrogel ophthalmic lens by the cast mold method. The resulting physical properties showed that the water content and refractive index of the sample were in the ranges of 38.06~42.11% and 1.426~1.436, respectively. The addition of cerium oxide nanoparticles lowered the contact angle and allowed the hydrogel lens to block UV light. The tensile strength was also improved by 52.13% through cerium oxide nanoparticles, and up to 123.4% by using TEPI. Based on the results of this study, the produced ophthalmic lens is suitable for durable, UV-blocking high-performance lenses.

Plants produce a wide variety of natural volatile organic compounds (NVOCs), many of which are unique to each species. These compounds serve many purposes, such as fending off herbivores and adapting to changes in temperature and water supply. Interestingly, although NVOCs are synthesized to deter herbivores, many of these compounds have been found to possess several therapeutic qualities, such as promoting nerve stability, enhancing sleep, and suppressing hyperresponsiveness, in addition to acting as antioxidants and anti-inflammatory agents. Therefore, many NVOCs are promising drug candidates for disease treatment and prevention. Given their volatile nature, these compounds can be administered to patients through inhalation, which is often more comfortable and convenient than other administration routes. However, the development of NVOC-based drug candidates requires a careful evaluation of the molecular mechanisms that drive their therapeutic properties to avoid potential adverse effects. Furthermore, even compounds that appear generally safe might have toxic effects depending on their dose, and therefore their toxicological assessment is also critical. In order to enhance the usage of NVOCs this short review focuses not only on the biological activities and therapeutic mode of action of representative NVOCs but also their toxic effects.

We prepared hydrogel contact lenses containing nanoparticles of neodymium oxide and methacrylic acid (MA) to investigate their effect on the physical and chemical properties of the lens. Neodymium oxide nanoparticles improved the tensile strength without affecting wettability. The tensile strength, wettability, and light transmittance were all increased when MA was added in a specific ratio. To confirm the safety of the newly used nanoparticles, test on absorbance, eluate, and pH change were conducted and it was found that the safety level was satisfactory. In conclusion, it was confirmed that durable contact lenses can be manufactured with neodymium oxide nanoparticles, and most of the basic elements of the lens such as transparency, strength, and wettability could be improved using MA, which is a hydrophilic material. It is believed that the study will be helpful as part of basic research to use new materials.

For efficient and rational utilization of limited bridge maintenance budgets, a method which could be applied to project-level and network-level bridge maintenance decision making issues considering the performance and direct and indirect value of each bridge is proposed. A representative bridge performance is shown as a risk level which is a combination of risk degrees indicated by condition state and safety factor and the replacement value was calculated by considering the direct construction cost and implicit value of bridges in consideration of traffic environments according to the location. The risk matrix was composed using the risk level and the replacement value, and the risk grade which represented the overall risk of each bridge was defined. The model to convert the phased risk level of each bridge to the risk index which was the continuous and quantitative index by applying the utility theory was presented, and the formalized model for calculating network-level performance index considering the risk index and relative importance of each bridge was suggested. In order to consider actual applicability of the suggested method, an analysis on a large number of actual bridges was carried out. A prior preparation regarding the stable distribution of budget and structural and environmental risks is possible so that it would be possible to quantify objective decision making for bridge maintenance.

Abstract Cynomolgus monkeys as nonhuman primates are valuable animal models because they have a high level of human gene homology. There are many reference values for hematology and biochemistry of Cynomolgus monkeys that are needed for proper clinical diagnosis and biomedical research conduct. The body weight information and blood type are also key success factors in allogeneic or xenogeneic models. Moreover, the biological parameters could be different according to the origin of the Cynomolgus monkey. However, there are limited references provided, especially of Cambodia origin. In this study, we measured average body weight of 2,518 Cynomolgus monkeys and analyzed hematology and serum biochemistry using 119 males, and determined blood types in 642 monkeys with Cambodia origin. The average body weight of male Cynomolgus monkeys were 2.56±0.345 kg and female group was 2.43± 0.330 kg at the age from 2 to 3 years. The male group showed relatively sharp increased average body weight from the 3 to 4 age period compared to the female group. In hematology and biochemistry, it was found that most of the data was similar when compared to other references even though some results showed differences. The ABO blood type result showed that type A, B, AB, and O was approximately 15.6, 33.3, 44.2, and 6.9%, respectively. The main blood type in this facility was B and AB. These biological background references of Cambodia origin could be used to provide important information to researchers who are using them in their biomedical research.

(1) Background: Virtual reality (VR) is a useful device for rehabilitation therapy. The purpose of this study was to examine the effect of virtual reality exercise program on sitting balance with spinal cord injury; (2) Methods: 20 subjects who selected on the basis of the screening criteria were divided into the experimental group (n = 10) who underwent the virtual reality exercise program and rehabilitation therapy and the control group (n = 10) who underwent a regular sitting balance training program and a regular rehabilitation therapy. Each intervention consisted of a 30-min session a day, three times a week, for eight weeks. In order to measure functions of the sitting balance, FSA (force sensitive application) and LOS (limit of stability) were used before and after the treatment intervention; (3) Results: We found significant differences for the FSA, LOS between pre-test and post-test in the 2 groups; (4) Conclusions: The findings of this study suggest that virtual reality exercise program can be applied as a useful approach for spinal cord injury patients.

Exosomes are extracellular vesicles that contain molecules that regulate the metabolic functions of adjacent or remote cells. Recent in vitro, in vivo and clinical studies support the hypothesis that exosomes released from various cell types play roles in the progression of metabolic disorders including type 2 diabetes. Based on this concept and advances in other diseases, the proteins, mRNA, microRNA and lipids in exosomes isolated from biological fluids have been proposed as biomarkers in metabolic disorders. However, several problems with the development of clinically applicable biomarkers have not been resolved. In this review, the biologic functions of exosomes are briefly introduced, and we discuss the technical and practical pros and cons of different methods of exosome isolation for the identification of exosomal biomarkers of metabolic disorders. Standardization of preanalytical variables and isolation of high-purity exosomes from fully characterized biological fluids will be necessary for the identification of useful exosomal biomarkers that can provide insights into the pathogenic mechanisms of complications of metabolic syndrome and of whole-body metabolism.

The phase behavior of amphiphilic Pluronic block copolymers in aqueous solution is of importance for a broad spectrum of practical applications but has not been fully exploited yet. Here, the phase behavior of the mixture of the Pluronic P65 and P105 triblock copolymer, (which have the same composition of PEO and PPO but the different molecular weight) and organic derivative, 5-methyl salicylic acid (5mS), in aqueous solution has been investigated by using small angle neutron scattering (SANS). According to the temperature and the 5mS concentration, SANS measurements showed that the P65-5mS mixtures sequentially transform into a random coil, sphere, vesicle, cylinder, and vesicle again, while the P105-5mS mixtures form spherical particles with two different sizes without any topological phase transition. Upon heating, the formation of two different kinds of the vesicle structure of amphiphilic block copolymer in aqueous solution is very unusual. This phase behavior was explained as the coupled effect of the simultaneous increase of the hydrophobicity of the polymer and the solubility of 5mS molecules upon heating. This result gives fundamental information for the practical use of Pluronic polymers in nano- and bio-science and it provides a simple route for the fabrication of the nanostructure without a complicated procedure.

Objective: Tinnitus may be associated with various brain changes. However, the degenerative changes in patients with tinnitus have not been extensively investigated. We aimed to evaluate degenerative, structural, and functional brain changes in patients with mild cognitive impairment (MCI) who also suffer from tinnitus. Materials and methods: This study included participants aged 60 to 80 years with MCI and a hearing level better than 40 dB. The participants were classified into two groups: MCI with tinnitus (MCI-T) and MCI without tinnitus (MCI-NT). All patients underwent Tinnitus Handicap Inventory (THI), 3 T brain MRI, F18-florapronol PET, and F18-FDG PET. Results: The MCI-T group exhibited higher ß-amyloid deposition in the superior temporal gyrus, temporal pole, and middle temporal gyrus compared to the MCI-NT group (p < 0.05 for all). Additionally, the MCI-T group showed increased metabolism in the inferior frontal gyrus, insula, and anterior cingulate cortex (ACC) (p < 0.005 for all). The THI score was strongly correlated with increased volume in the insula, ACC, superior frontal gyrus, supplementary motor area, white matter near the hippocampus, and precentral gyrus (p < 0.05 for all). Moreover, the MCI-T group demonstrated higher metabolic activity in the default mode network (DMN) and lower activity in the executive control network (ECN) (p < 0.05 for all). In the MCI-T group, the posterior DMN was positively correlated with the visual network and negatively with the ECN, whereas in the MCI-NT group, it correlated positively with the ECN. Conclusion: The MCI-T group exhibited greater ß-amyloid accumulation in the auditory cortex and more extensive changes across various brain networks compared with the MCI-NT group, potentially leading to diverse clinical symptoms such as dementia with semantic deficits or depression. Tinnitus in MCI patients may serve as a biomarker for degenerative changes in the temporal lobe and alterations in brain network dynamics. [ABSTRACT FROM AUTHOR]

In eukaryotes, a primary protein quality control (PQC) process involves the destruction of conformationally misfolded proteins through the ubiquitin-proteasome system. Because approximately one-third of eukaryotic proteomes fold and assemble within the endoplasmic reticulum (ER) before being sent to their destinations, the ER plays a crucial role in PQC. The specific functions and biochemical roles of several E3 ubiquitin ligases involved in ER-associated degradation in mammals, on the other hand, are mainly unknown. We identified 2 E3 ligases, ubiquitin protein ligase E3 component Nrecognin 1 (UBR1) and ubiquitin protein ligase E3 component N-recognin 2 (UBR2), which are the key N-recognins in the Ndegron pathway and participate in the ER stress response in mammalian cells by modulating their stability. Cells lacking UBR1 and UBR2 are hypersensitive to ER stress-induced apoptosis. Under normal circumstances, these proteins are polyubiquitinated through Lys48-specific linkages and are then degraded by the 26S proteasome. In contrast, when cells are subjected to ER stress, UBR1 and UBR2 exhibit greater stability, potentially as a cellular adaptive response to stressful conditions. Although the precise mechanisms underlying these findings require further investigation, our findings show that cytoplasmic UBR1 and UBR2 have anti-ER stress activities and contribute to global PQC in mammals. These data also reveal an additional level of complexity within the mammalian ER-associated degradation system, implicating potential involvement of the N-degron pathway. [ABSTRACT FROM AUTHOR]

In tauopathy conditions, such as Alzheimer's disease (AD), highly soluble and natively unfolded tau polymerizes into an insoluble filament; however, the mechanistic details of this process remain unclear. In the brains of AD patients, only a minor segment of tau forms β-helix-stacked protofilaments, while its flanking regions form disordered fuzzy coats. Here, it is demonstrated that the tau AD nucleation core (tau-AC) sufficiently induced self-aggregation and recruited full-length tau to filaments. Unexpectedly, phospho-mimetic forms of tau-AC (at Ser324 or Ser356) show markedly reduced oligomerization and seeding propensities. Biophysical analysis reveal that the N-terminus of tau-AC facilitates the fibrillization kinetics as a nucleation motif, which becomes sterically shielded through phosphorylation-induced conformational changes in tau-AC. Tau-AC oligomers are efficiently internalized into cells via endocytosis and induced endogenous tau aggregation. In primary hippocampal neurons, tau-AC impaired axon initial segment plasticity upon chronic depolarization and is mislocalized to the somatodendritic compartments. Furthermore, it is observed significantly impaired memory retrieval in mice intrahippocampally injected with tau-AC fibrils, which corresponds to the neuropathological staining and neuronal loss in the brain. These findings identify tau-AC species as a key neuropathological driver in AD, suggesting novel strategies for therapeutic intervention. [ABSTRACT FROM AUTHOR]