UPF3B modulates endoplasmic reticulum stress through interaction with inositol-requiring enzyme-1α.

The unfolded protein response (UPR) is a conserved and adaptive intracellular pathway that relieves the endoplasmic reticulum (ER) stress by activating ER transmembrane stress sensors. As a consequence of ER stress, the inhibition of nonsense-mediated mRNA decay (NMD) is due to an increase in the phosphorylation of eIF2α, which has the effect of inhibiting translation. However, the role of NMD in maintaining ER homeostasis remains unclear. In this study, we found that the three NMD factors, up-frameshift (UPF)1, UPF2, or UPF3B, were required to negate the UPR. Among these three NMD factors, only UPF3B interacted with inositol-requiring enzyme-1α (IRE1α). This interaction inhibited the kinase activity of IRE1α, abolished autophosphorylation, and reduced IRE1α clustering for ER stress. BiP and UPF3B jointly control the activation of IRE1α on both sides of the ER membrane. Under stress conditions, the phosphorylation of UPF3B was increased and the phosphorylated sites were identified. Both the UPF3BY160D genetic mutation and phosphorylation at Thr169 of UPF3B abolished its interaction with IRE1α and UPF2, respectively, leading to activation of ER stress and NMD dysfunction. Our study reveals a key physiological role for UPF3B in the reciprocal regulatory relationship between NMD and ER stress.

High-throughput quantification of quasistatic, dynamic and spall strength of materials across 10 orders of strain rates.

The response of metals and their microstructures under extreme dynamic conditions can be markedly different from that under quasistatic conditions. Traditionally, high strain rates and shock stresses are achieved using cumbersome and expensive methods such as the Kolsky bar or large spall experiments. These methods are low throughput and do not facilitate high-fidelity microstructure-property linkages. In this work, we combine two powerful small-scale testing methods, custom nanoindentation, and laser-driven microflyer (LDMF) shock, to measure the dynamic and spall strength of metals. The nanoindentation system is configured to test samples from quasistatic to dynamic strain-rate regimes. The LDMF shock system can test samples through impact loading, triggering spall failure. The model material used for testing is magnesium alloys, which are lightweight, possess high-specific strengths, and have historically been challenging to design and strengthen due to their mechanical anisotropy. We adopt two distinct microstructures, solutionized (no precipitates) and peak-aged (with precipitates) to demonstrate interesting upticks in strain-rate sensitivity and evolution of dynamic strength. At high shock-loading rates, we unravel an interesting paradigm where the spall strength vs. strain rate of these materials converges, but the failure mechanisms are markedly different. Peak aging, considered to be a standard method to strengthen metallic alloys, causes catastrophic failure, faring much worse than solutionized alloys. Our high-throughput testing framework not only quantifies strength but also teases out unexplored failure mechanisms at extreme strain rates, providing valuable insights for the rapid design and improvement of materials for extreme environments.

Alternative glucose uptake mediated by ß-catenin/RSK1 axis under stress stimuli in mammalian cells.

Cells adapt to stress conditions by increasing glucose uptake as cytoprotective strategy. The efficiency of glucose uptake is determined by the translocation of glucose transporters (GLUTs) from cytosolic vesicles to cellular membranes in many tissues and cells. GLUT translocation is tightly controlled by the activation of Tre-2/BUB2/CDC16 1 domain family 4 (TBC1D4) via its phosphorylation. The mechanisms of glucose uptake under stress conditions remain to be clarified. In this study, we surprisingly found that glucose uptake is apparently increased for the early response to three stress stimuli, glucose starvation and the exposure to lipopolysaccharide (LPS) or deoxynivalenol (DON). The stress-induced glucose uptake was mainly controlled by the increment of ß-catenin level and the activation of RSK1. Mechanistically, ß-catenin directly interacted with RSK1 and TBC1D4, acting as the scaffold protein to recruit activated RSK1 to promote the phosphorylation of TBC1D4. In addition, ß-catenin was further stabilized due to the inhibition of GSK3ß kinase activity which is caused by activated RSK1 phosphorylating GSK3ß at Ser9. In general, this triple protein complex consisting of ß-catenin, phosphorylated RSK1, and TBC1D4 were increased in the early response to these stress signals, and consequently, further promoted the phosphorylation of TBC1D4 to facilitate the translocation of GLUT4 to the cell membrane. Our study revealed that the ß-catenin/RSK1 axis contributed to the increment of glucose uptake for cellular adaption to these stress conditions, shedding new insights into cellular energy utilization under stress.

1-Methylcyclopropene treatment delays the softening of Actinidia arguta fruit by reducing cell wall degradation and modulating carbohydrate metabolism.

The rapid softening of hardy kiwifruit (Actinidia arguta) fruit significantly reduces its marketing potential. Therefore, the effect of 1-methylcyclopropene (1-MCP) on the softening of A. arguta fruit was investigated. Results indicated that A. arguta fruit treated with 1-MCP maintained a higher level of firmness, titratable acidity, ascorbic acid, total phenolics, and flavonoids content, relative to non-treated fruit. Fruit treated with 1-MCP and placed in long-term cold storage had higher sensory scores, as determined by a taste panel and supported by electronic nose and tongue data. Notably, 1-MCP delayed the degradation of cell wall components, including pectin, cellulose, and hemicellulose, by reducing the activity of cell-wall-modifying enzymes. In addition, 1-MCP reduced the activity of carbohydrate metabolism-related enzymes, resulting in fruit with higher levels of starch and sucrose and lower levels of glucose, fructose and sorbitol. Collectively, these results indicate that 1-MCP can be used to delay the softening of A. arguta fruit and extend its storage and shelf life.

Study on the Pharmacological Mechanism of Icariin for the Treatment of Alzheimer's Disease Based on Network Pharmacology and Molecular Docking Techniques.

The purpose of this study is to explore the pharmacological mechanism of icariin (ICA) in the treatment of Alzheimer's disease (AD) based on network pharmacology and network molecular docking technology. In order to investigate the regulatory effect of ICA on the expression level of AD pathological phosphorylation regulatory proteins, this study further explored the possible molecular mechanism of ICA regulating AD autophagy through network pharmacology. Macromolecular docking network was verified by Autodock Vina 1.1.2 software. The main active ingredients of ICA, the physicochemical properties, and pharmacokinetic information of ICA were predicted using online databases and relevant information. The results showed that the targets of MAPK3, AKT1, HSP90AA1, ESR1, and HSP90AA1 were more critical in the treatment of AD. Autophagy, apoptosis, senescence factors, phosphatidylinositide 3-kinase/protein kinase B (P13K/AKT) signaling pathway, MAKP, mTOR, and other pathways were significantly associated with AD. Docking of ICA with HIF-1, BNIP3, PINK1, and Parkin pathway molecules showed that the key targets of the signaling pathway were more stably bound to ICA, which may provide a better pathway for ICA to regulate autophagy by providing a better pathway. ICA can improve AD, and its mechanism may be related to the P13K/AKT, MAKP, and mTOR signaling pathways, thereby regulating autophagy-related proteins.

Uncertainty Quantification of Material Properties in Ballistic Impact of Magnesium Alloys.

The design and development of cutting-edge light materials for extreme conditions including high-speed impact remains a continuing and significant challenge in spite of steady advances. Magnesium (Mg) and its alloys have gained much attention, due to their high strength-to-weight ratio and potential of further improvements in material properties such as strength and ductility. In this paper, a recently developed computational framework is adopted to quantify the effects of material uncertainties on the ballistic performance of Mg alloys. The framework is able to determine the largest deviation in the performance measure resulting from a finite variation in the corresponding material properties. It can also provide rigorous upper bounds on the probability of failure using known information about uncertainties and the system, and then conservative safety design and certification can be achieved. This work specifically focuses on AZ31B Mg alloys, and it is assumed that the material is well-characterized by the Johnson-Cook constitutive and failure models, but the model parameters are uncertain. The ordering of uncertainty contributions for model parameters and the corresponding behavior regimes where those parameters play a crucial role are determined. Finally, it is shown that how this ordering provides insight on the improvement of ballistic performance and the development of new material models for Mg alloys.

Phosphorylation-mediated interaction between human E26 transcription factor 1 and specific protein 1 is required for tumor cell migration.

Transcription factors, human E26 transcription factor 1 (Ets1) and specific protein 1 (Sp1), are known to induce gene expression in tumorigenicity. High Ets1 expression is often associated with colorectal tumorigenesis. In this study, we discover that metastasis and clone formation in SW480 cells mainly depend on the direct interaction between Ets1 and Sp1 instead of high Ets1 expression. The interaction domains are further addressed to be the segment at Sp1(626-708) and the segment at Ets1(244-331). In addition, the phosphorylation inhibition of Ets1 at Tyr283 by either downregulation of Src kinase or Src family inhibitor treatment decreases the interaction between Sp1 and Ets1 and suppresses SW480 migration. Either administration or overexpression of the peptides harboring the interaction segment strongly inhibits the colony formation and migration of SW480 cells. Our findings suggest that the interaction between Ets1 and Sp1 rather than Ets1 alone promotes transformation in SW480 cells and provide new insight into the Ets1 and Sp1 interaction as an antitumour target in SW480 cells.

Ultrasound-Assisted Extraction of Total Flavonoids from Pteris cretica L.: Process Optimization, HPLC Analysis, and Evaluation of Antioxidant Activity.

In the present work, the ultrasonic-assisted extraction (UAE) of total flavonoids (TF) from Pteris cretica L. was optimized by response surface methodology (RSM) on the basis of a single-factor experiment. The optimized UAE parameters were as follows: Ethanol concentration 56.74%, extraction time 45.94 min, extraction temperature 74.27 °C, and liquid/solid ratio 33.69 mL/g. Under the optimized conditions, the total flavonoids yield (TFY) was 4.71 ± 0.04%, which was higher than that obtained by heat reflux extraction (HRE). The extracts were further analyzed by HPLC, and five major flavonoids, including rutin, quercitrin, luteolin, apigenin, and luteolin-7-O-glucoside, were identified and quantified. Furthermore, the results of the antioxidant test showed that the TF extract obtained under optimized UAE conditions exhibited good 2,2-diphenyl-1-picrylhydrazyl radical (DPPH•) and 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS+•), nitric oxide radical (NO•) scavenging activities, and ferrous ion (Fe2+) chelating capacity, with IC50 values of 74.49, 82.92, 89.12, and 713.41 µg/mL, respectively. Results indicated that the UAE technique developed in this work was an efficient, rapid, and simple approach for the extraction of flavonoids with antioxidant activity from P. cretica.

Preparative Purification of Total Flavonoids from Sophora tonkinensis Gagnep. by Macroporous Resin Column Chromatography and Comparative Analysis of Flavonoid Profiles by HPLC-PAD.

For the full development and utilization of Sophora tonkinensis Gagnep., this study was primarily intended to established a simple and efficient approach for the preparative purification of total flavonoids from S. tonkinensis by macroporous resin column chromatography (MRCC). The adsorption and desorption characteristics of the total flavonoids on ten macroporous resins were first studied, and AB-8 resin was chosen as the most suitable, and the adsorption data were best fitted to the pseudo-second-order kinetics model and Langmuir isotherm model. Furthermore, the technological parameters for the purification of the total flavonoids were optimized using column chromatography. After a sample one-step purification procedure, the content of the total flavonoids increased by about 4.76-fold from 12.14% to 57.82%, with a recovery yield of 84.93%. In addition, the comparative analysis of the flavonoid extracts before and after purification was performed by high-performance liquid chromatography coupled with photodiode-array detection (HPLC-PAD). The results showed that the contents of six major flavonoids in the purified product were all higher than before the purification. Therefore, the AB-8 MRCC established in this work was a promising method for the industrial-scale purification of the total flavonoids from S. tonkinensis.

[Current status of malaria control knowledge awareness of primary and sec- ondary school students in Xuzhou City].

OBJECTIVE: To understand the current status of malaria control knowledge awareness of primary and secondary school students and its influencing factors in Yunlong District, Xuzhou City, so as to provide the evidence for improving the malaria prevention work. METHODS: A total of 800 students from 4 urban and rural primary and secondary schools were randomly selected and investigated with questionnaires. RESULTS: The total awareness rate of malaria control knowledge was 61.27%, and the awareness rates of symptoms of malaria and malaria prevention were only 38.99% and 57.59% respectively. The main approach of obtaining the malaria control knowledge was media (51.52%). The univariate analysis showed that sex, area and different education levels affected the awareness rates of malaria control knowledge (P < 0.05), and the Logistic analysis showed that the awareness rate of malaria control knowledge of country students was lower than that of urban students (P < 0.05), and the awareness rate of malaria control knowledge of the secondary school students was higher than that of the primary school students (P < 0.05). CONCLUSIONS: The awareness rate of malaria control knowledge of primary and secondary school students in Yunlong District is lower than that required by the national standard. Therefore, the health education of malaria control should be strengthened, especially in countryside school students and primary school students.