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Abstract Cancer cells alter their metabolism and epigenetics to support cancer progression. However, very few modulators connecting metabolism and epigenetics have been uncovered. Here, we reveal that serine hydroxymethyltransferase-2 (SHMT2) generates S-adenosylmethionine (SAM) to epigenetically repress phosphatase and tensin homolog (PTEN), leading to papillary thyroid cancer (PTC) metastasis depending on activation of AKT signaling. SHMT2 is elevated in PTC, and is associated with poor prognosis. Overexpressed SHMT2 promotes PTC metastasis both in vitro and in vivo. Proteomic enrichment analysis shows that AKT signaling is activated, and is positively associated with SHMT2 in PTC specimens. Blocking AKT activation eliminates the effects of SHMT2 on promoting PTC metastasis. Furthermore, SHMT2 expression is negatively associated with PTEN, a negative AKT regulator, in PTC specimens. Mechanistically, SHMT2 catalyzes serine metabolism and produces activated one-carbon units that can generate SAM for the methylation of CpG islands in PTEN promoter for PTEN suppression and following AKT activation. Importantly, interference with PTEN expression affects SHMT2 function by promoting AKT signaling activation and PTC metastasis. Collectively, our research demonstrates that SHMT2 connects metabolic reprogramming and epigenetics, contributing to the poor progression of PTC.

Despite standard treatment for non-small cell lung cancer (NSCLC) being surgical resection, cancer recurrence and complications, such as induction of malignant pleural effusion (MPE) and significant postoperative pain, usually result in treatment failure. In this study, an alginate-based hybrid hydrogel (SOG) is developed that can be injected into the resection surface of the lungs during surgery. Briefly, endoplasmic reticulum-modified liposomes (MSLs) pre-loaded with the signal transducer and activator of transcription 3 (STAT3) small interfering RNA and lidocaine hydrochloride are encapsulated in SOG. Once applied, MSLs strongly downregulated STAT3 expression in the tumor microenvironment, resulting in the apoptosis of lung cancer cells and polarization of tumor-associated macrophages towards the M1-like phenotype. Meanwhile, the release of lidocaine hydrochloride (LID) was beneficial for pain relief and natural killer cell activation. Our data demonstrated MSL@LID@SOG not only efficiently inhibited tumor growth but also potently improved the quality of life, including reduced MPE volume and pain relief in orthotopic NSCLC mouse models, even with a single administration. MSL@LID@SOG shows potential for comprehensive clinical management upon tumor resection in NSCLC, and may alter the treatment paradigms for other cancers.

Abstract Mitochondria dysfunction contributes to acute liver injuries, and mitochondrial regulators, such as PGC-1α and MCJ, affect liver regeneration. Therefore, identification of mitochondrial modulators may pave the way for developing therapeutic strategies. Here, ZHX2 is identified as a mitochondrial regulator during acute liver injury. ZHX2 both transcriptionally inhibits expression of several mitochondrial electron transport chain genes and decreases PGC-1α stability, leading to reduction of mitochondrial mass and OXPHOS. Loss of Zhx2 promotes liver recovery by increasing mitochondrial OXPHOS in mice with partial hepatectomy or CCl4-induced liver injury, and inhibition of PGC-1α or electron transport chain abolishes these effects. Notably, ZHX2 expression is higher in liver tissues from patients with drug-induced liver injury and is negatively correlated with mitochondrial mass marker TOM20. Delivery of shRNA targeting Zhx2 effectively protects mice from CCl4-induced liver injury. Together, our data clarify ZHX2 as a negative regulator of mitochondrial OXPHOS and a potential target for developing strategies for improving liver recovery after acute injuries.

This study discusses the planning of a regional-scale water–food nexus (WFN) system using an inexact fuzzy chance constraint programming (IFCCP) method. The IFCCP approach can handle uncertainties expressed as interval and fuzzy parameters, as well as the preferences of decision makers. An inexact fuzzy chance constraint programming-based water–food nexus (IFCCP-WFN) model has been developed for the City of Jinan with the consideration of various restrictions related to water and land availability, as well as food and vegetable demands. Solutions for the planting areas for different crops in different periods have been generated under the different preferences of decision makers. The water resource availability would be the priority factor affecting the WFN system under demanding conditions, in which wheat cultivation would be dominated by this factor under fuzzy confidence levels of 0.2 and 0.5, and the planting area of corn would be determined by this factor under high fuzzy confidence levels (e.g., 0.8). In addition, the reliability of irrigation would decrease with increasing fuzzy confidence levels under demanding conditions, limiting the planting areas for crops and leading to a decreasing trend of the system benefit. Adequate water resources would be available for irrigation under optimistic conditions, implying no significant contributions to the planting schemes. Nevertheless, increasing food loss rates would result in more planting areas to satisfy food requirements and thus a greater system benefit under advantageous conditions. Compared with the developed IFCCP-WFN model, the interval-linear-programming-based water–food nexus (ILP-WFN) model can merely reflect the lower and upper bounds of uncertain parameters and neglects the inherent distributional information within the fuzzy parameters. Thus, the ILP-WFN model is unable to reveal the inherent impacts of the fuzzy parameters on the resulting planting strategies.

Glutamine is critical for tumor progression, and restriction of its availability is emerging as a potential therapeutic strategy. The metabolic plasticity of tumor cells helps them adapting to glutamine restriction. However, the role of cholesterol metabolism in this process is relatively unexplored. Here, we reported that glutamine deprivation inhibited cholesterol synthesis in hepatocellular carcinoma (HCC). Reactivation of cholesterol synthesis enhanced glutamine-deprivation-induced cell death of HCC cells, which is partially duo to augmented NADPH depletion and lipid peroxidation. Mechanistically, glutamine deprivation induced lipophagy to transport cholesterol from lipid droplets (LDs) to endoplasmic reticulum (ER), leading to inhibit SREBF2 maturation and cholesterol synthesis, and maintain redox balance for survival. Glutamine deprivation decreased mTORC1 activity to induce lipophagy. Importantly, administration of U18666A, CQ, or shTSC2 viruses further augmented GPNA-induced inhibition of xenograft tumor growth. Clinical data supported that glutamine utilization positively correlated with cholesterol synthesis, which is associated with poor prognosis of HCC patients. Collectively, our study revealed that cholesterol synthesis inhibition is required for the survival of HCC under glutamine-restricted tumor microenvironment.

Summary: Emerging evidence shows that pancreatic β-cell function and quality are key determinants in the progression of type 2 diabetes (T2D). The transcription factor zinc finger homeobox 2 (Zhx2) is involved in proliferation and development of multiple cells. However, the exact role of Zhx2 in β-cells and T2D remains completely unknown. Here, we report that Zhx2 orchestrates β-cell mass and function by regulating paired box protein pax-6 (Pax6). We found that β-cell-specific knockout Zhx2 (Zhx2BKO) mice showed a decrease in β-cell proliferation and glucose homeostasis. Under prediabetic and diabetic conditions, we discovered glucose intolerance in both Zhx2BKO-HFD mice and Zhx2BKO-db/db mice, with reduced β-cell mass and insulin secretion. Mechanistically, we demonstrated that Zhx2 targeted the Pax6 promoter region (−1740∼-1563; −862∼-559; −251∼+75), enhanced promoter activity. Overall, Zhx2 maintains β-cell function by transcriptionally regulating Pax6, which provides a therapeutic target for diabetes intervention.

The consolidation of ceramic particles into the metallic matrix is promising to translate their exceptional properties from the micro-scale to the macro world. Herein, four different 15-5PH stainless steel (SS) matrix composites: 15-5PH/TiB2, 15-5PH/TiN, 15-5PH/TiC and 15-5PH/WC were fabricated by directed energy deposition (DED). The introduction of TiB2 particles substantially refines the martensite grain size, however, fails to achieve the performance improvement due to the elemental segregation of Cr and formation of considerable macro- and micro-cracks. The TiN composite realises a simultaneous enhancement of strength and ductility due to grain refinement, however, fails to enhance the corrosion resistance due to the Cr element segregation. The WC and TiC composites achieve the balance between the improved strength and ductility coupled with simultaneous enhancement of corrosion resistance. This work demonstrates the substantial potential in developing martensitic SS matrix composites with excellent strength-ductility synergy and corrosion resistance.

Abstract Background Thyroid cancer is the most common malignant endocrine tumour, and metastasis has become the main reason for treatment failure. However, the underlying molecular mechanism of thyroid cancer metastasis remains poorly understood. We investigated the role of the tumour suppressor zinc fingers and homeoboxes 2 (ZHX2) in the metastasis of thyroid cancer. Methods To study the role of ZHX2 in thyroid cancer metastasis, we evaluated the EMT process using cell migration, wound healing and lung metastatic tumour formation in vitro and in vivo models. Results ZHX2 expression was significantly decreased in thyroid cancer tissues, which correlated with poor prognosis of thyroid cancer patients. ZHX2 knockdown significantly promoted the migration of thyroid cancer cells. Mechanistically, ZHX2 associated with the S100 calcium binding protein A14 (S100A14) promoter to decrease the transcription of S100A14. Moreover, S100A14 was highly expressed in human thyroid cancer samples, and its expression negatively correlated with ZHX2 expression. Conclusions Inhibition of S100A14 attenuated the ZHX2 knockdown-induced enhanced metastasis of thyroid cancer cells both in vitro and in vivo. The evidence presented here suggests that ZHX2 inhibits the progression of thyroid cancer by blocking S100A14-mediated metastasis.

With the rapid global demand for mariculture products in recent years, the use of antibiotics has increased intensively in the mariculture area. Current research on antibiotic residues in mariculture environments is limited, and less information is available on the presence of antibiotics in tropical waters, limiting a comprehensive understanding of their environmental presence and risk. Therefore, this study investigated the environmental occurrence and distribution of 50 antibiotics in the near-shore aquaculture waters of Fengjia Bay. A total of 21 antibiotics were detected in 12 sampling sites, including 11 quinolones, 5 sulfonamides, 4 tetracyclines, and 1 chloramphenicol; the quinolones pyrimethamine (PIP), delafloxacin (DAN), flurofloxacin (FLE), ciprofloxacin (CIP), norfloxacin (NOR), pefloxacin (PEF), enrofloxacin (ENO), and minocycline (MNO) of the tetracycline class were detected in all sampling points. The total antibiotic residue concentrations in the study area ranged from 153.6 to 1550.8 ng/L, the tetracycline antibiotics were detected in the range of 10 to 1344.7 ng/L, and the chloramphenicol antibiotics were detected in the range of 0 to 106.9 ng/L. The detected concentrations of quinolones ranged from 81.3 to 136.1 ng/L, and the residual concentrations of sulfonamide antibiotics ranged from 0 to 313.7 ng/L. The correlation analysis with environmental factors revealed that pH, temperature, conductivity, salinity, NH3−-N, and total phosphorus had a strong correlation with antibiotics. Based on PCA analysis, the main sources of antibiotic pollution in the area were determined to be the discharge of farming wastewater and domestic sewage. The ecological risk assessment indicated that the residual antibiotics in the water environment of the near-shore waters of Fengjiawan had certain risks to the ecosystem. Among them, CIP, NOR, sulfamethoxazole (TMP), ofloxacin (OFL), enrofloxacin (ENO), sulfamethoxazole (SMX), and FLE showed medium to high risk. Therefore, it is recommended to regulate the use of these antibiotics and the discharge and treatment of culturing wastewater, and measures should be taken to reduce the environmental pollution caused by antibiotics and to monitor the long-term ecological risk of antibiotics in the region. Overall, our results provide an important reference for understanding the distribution and ecological risk of antibiotics in Fengjiawan.

The unphosphorized and phosphatized spur gears produced in the same batch are divided into three groups，the unphosphorized gear group， the single phosphated gear group and the double phosphated gear group， the scuffing performance test is carried out in groups on the gear contact fatigue tester. At the same time， the helix curve of the test gears detected by the gear measuring center D80 is used to accurately calculate the gluing area and the depth of the gluing groove mark. The results show that， under the same operating conditions， the loading torque of the phosphated gear is much greater than that of the unphosphorized gear， and the operating time of the phosphated gear is much more than that of the unphosphorized gear. It is concluded that， phosphating can significantly improve the anti scuffing performance of gears.

Several factors could affect the function of the electromagnet control system when a high-speed maglev train runs over a bridge. To enhance the robustness of the electromagnet control system to the high-speed maglev train running over the bridge, a fuzzy active control rule is introduced into the currently used proportional–integral–derivative (PID) control system. Numerical analyses are then conducted with a high-speed maglev train passing through a series of simply supported beams. The numerical results with the fuzzy PID active control are compared with the maglev train–bridge system with the equivalent linearized electromagnetic forces. The comparative results show that the introduction of the fuzzy PID control system has improved the comfort of the maglev train and that the overall dynamic response of the bridge is reduced. There is an obvious time delay for the maximum dynamic response of the bridge to the high speed of the train.

ObjectivePapillary thyroid carcinoma (PTC) accounts for the majority of thyroid cancer and affects a large number of individuals. The pathogenesis of PTC has not been completely elucidated thus far. Metabolic reprogramming is a common feature in tumours. Our previous research revealed the reprogramming of lipid metabolism in PTC. Further studies on lipid metabolism reprogramming may help elucidate the pathogenesis of PTC.MethodsClinical samples of PTC and para-tumour tissue were analysed using lipidomic, proteomic, and metabolomic approaches. A multi-omics integrative strategy was adopted to identify the important pathways in PTC. The findings were further confirmed using western blotting, tissue microarray, bioinformatics, and cell migration assays.ResultsMulti-omics data and the results of integrated analysis revealed that the three steps of fatty acid metabolism (hydrolysis, transportation, and oxidation) were significantly enhanced in PTC. Especially, the expression levels of LPL, FATP2, and CPT1A, three key enzymes in the respective steps, were elevated in PTC. Moreover, LPL, FATP2 and CPT1A expression was associated with the TNM stage, lymph node metastasis of PTC. Moreover, high levels of FATP2 and CPT1A contributed to poor prognosis of PTC. In addition, ectopic overexpression of LPL, FATP2 and CPT1A can each promote the migration of thyroid cancer cells.ConclusionsOur data suggested that enhanced fatty acid metabolism supplied additional energy and substrates for PTC progression. This may help elucidating the underlying mechanism of PTC pathogenesis and identifying the potential therapeutic targets for PTC.

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has currently spread worldwide, leading to high morbidity and mortality. As the putative receptor of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) is widely distributed in various tissues and organs of the human body. Simultaneously, ACE2 acts as the physiological counterbalance of ACE providing homeostatic regulation of circulating angiotensin II levels. Given that some ACE2 variants are known to cause an increase in the ligand-receptor affinity, their roles in acquisition, progression and severity of COVID-19 disease have aroused widespread concerns. Therefore, we summarized the latest literature and explored how ACE2 variants and epigenetic factors influence an individual’s susceptibility to SARS-CoV-2 infection and disease outcome in aspects of ethnicity, gender and age. Meanwhile, the possible mechanisms for these phenomena were discussed. Notably, recombinant human ACE2 and ACE2-derived peptides may have special benefits for combating SARS-CoV-2 variants and further studies are warranted to confirm their effects in later stages of the disease process. As the uncertainty regarding the severity and transmissibility of disease rises, a more in-depth understanding of the host genetics and functional characteristics of ACE2 variants will not only help explain individual clinical differences of the disease, but also contribute to providing effective measures to develop solutions and manage future outbreaks of SARS-CoV-2.

HCN catalytic hydrolysis mechanism over Cu-ZSM-5 was investigated based on the density functional theory (DFT) with 6-31++g (d, p) basis set. Five paths (A, B, C, D, and E) were designed. For path A and path B, the first step is the nucleophilic attack of water molecule. Next, the hydrogen atom of H2O is transferred to the nitrogen atom first for path A, while in path B, the hydrogen atom of the HCN is first transferred to the nitrogen atom. In path C, HCN isomerizes to HNC initially, and the remaining steps are similar to that of path A. The H atom of HCN shifts to Cu-ZSM-5 initially in path D, and the H atom is transferred to N atom subsequently. The last step is the attack on water molecule. The first step for path E is similar to that of path D. The next step is the attack on water molecule, in which the H atom of water molecule shifts to N atom, and the H on Cu-ZSM-5 shifts to the N atom. Meanwhile, the H atom of oxygen atom is transferred to the N atom. The results show that path C is the most favorable path, with the lowest free energy barrier (35.45 kcal/mol). The results indicate that the Cu-ZSM-5 strongly reduces the energy barrier of HCN and isomerizes to HNC, making it an effective catalyst for HCN hydrolysis.

In this paper, a trajectory optimization strategy for the hypersonic morphing aircraft is proposed, and the AMPI method is used to generate the online trajectory with initial state errors. Firstly, the aerodynamic model and propulsion model of the hypersonic morphing aircraft were established considering the wingspan and the scramjet. Secondly, the optimization strategy was proposed via Gauss pseudospectral method considering the control variables including angle of attack (AOA) and wingspan. The optimized trajectory met the final constraints and path constraints with the objective to minimize the time of the ascent phase. Then, the AMPI method was used to generate online trajectory without solving OCP or NLP on the base of trajectory database calculated by the optimization strategy. The simulation results indicate high accuracy of AMPI method and the final errors corresponding to different initial errors were acceptable. The mean value of the CPU time of the method was about 0.1 second, which shows real-time capability.

The influences of microstructure and elemental distribution on pitting corrosion resistance and passive film in different regions of a super duplex stainless steel welded joint were investigated. The banded microstructure disappeared after welding and transformed to the coarse equiaxed ferrite grains in the heat-affected zone. Three types of austenitic microstructure formed in the weld center, only two types occurred in the weld cap and weld root. It is found that the elements Ni and N were enriched in austenite, while Cr and Mo were concentrated in the ferrite. The Cr2N was found precipitating in some specific regions with a lower austenite content, which led to the relatively poorer resistance to pitting corrosion in the heat-affected zone, weld root, and weld cap. The ferrite observed in each studied region of the joint was prone to experiencing selective corrosion due to its lower pitting resistance equivalent number. The content of Cr in the region around the Cr2N disappeared, so that Cr-depletion was formed as the original location of pitting. The electrochemical impedance spectroscopy results also showed that no difference exists in the passive film structure in all of the regions of the joint, and regular banded microstructure was helpful to the passive film.

In order to cover the complexity of coding and extend the generality on the road vehicle-bridge iteration, a process to solve vehicle-bridge interaction considering varied vehicle speed based on a convenient combination of Matlab Simulink and ANSYS is presented. In this way, the road vehicle is modeled in state space and the corresponding motion equations are solved using Simulink. The finite element model for the bridge is established and solved using ANSYS. The so-called inter-history iteration method is adopted to realize the interaction between the vehicle model and the bridge model. Different from typical method of road vehicle-bridge interaction in the vertical direction, a detailed longitudinal force model is set up to take into account the effects of varied vehicle speed. In the force model, acceleration and braking of the road vehicle are treated differently according to their mechanical nature. In the case studies based on a simply supported beam, the dynamic performance of the road vehicle and the bridge under varied vehicle speeds is calculated and discussed. The vertical acceleration characteristics of the midpoint of beam under varied vehicle speed can be grouped into two periods. The first one is affected by the load transform between the wheels, and the other one depends on the speed amplitude. Sudden change of the vertical acceleration of the beam and the longitudinal reaction force are observed as the wheels move on or off the bridge, and the bridge performs different dynamic responses during acceleration and braking.

Groundwater remediation technology of Pump-Treat and Vertical anti-Seepage is an effective treatment to retard the migration and diffusion of pollutants. It is widely used to prevent and retard the long-term leakage of pollutants in landfills. Based on the groundwater infiltration, dispersion and source-sink interaction, this research work has established a three-dimensional coupled model of hydrologic and contaminant transport was constructed with Modelflow groundwater modelling. It ultimately provides a scientific basis for the prevention and control treatment of groundwater pollution in the actual construction of the site. According to the data of borehole sampling, stratigraphic section and pumping test, the site is vertically divided into three layers, namely the upper weak aquifer, the sandy pebble aquifer and the mudstone weak aquifer. The groundwater system in the assessment area is generalized as non-homogeneous anisotropy, spatial three-dimensional structure, unsteady groundwater flow system. It takes convection and dispersion of contaminant into consideration when transport characteristics of hexavalent chromium (Cr6+) contaminant with pump-treat and vertical curtain in groundwater environment were numerically analysed. The retention effects of curtain grouting were researched and predicted. The results showed that the Cr6+ concentration of groundwater was decreasing from 317 mg/L to 180 mg/L under the condition of continuous pumping without curtain grouting with removal efficiency of 43%; and the Cr6+ concentration of groundwater was decreasing from 317 mg/L to 80 mg/L under the condition of continuous pumping with curtain grouting with removal efficiency of 75%.

Marek’s disease (MD) has been occurring with increasing frequency in chickens in recent years. To our knowledge, however, there has been no report of the very virulent plus (vv+) MD virus (MDV) field isolate in China. Studies have shown that dual infection with immunosuppressive viruses such as chicken infectious anemia virus (CIAV) occurs frequently in chickens developing MD. In this study, we performed a designed set of in vivo experiments, which comprised five different groups of chickens, including the group of CVI988/Rispens-vaccinated chickens, the groups of CVI988/Rispens-vaccinated chickens infected with MDV or CIAV or both viruses (MDV and CIAV), and the group of MDV-challenged chickens. The effects of CIAV dual infection on the immunization of commercial MDV vaccine CVI988/Rispens were evaluated. The results show that infection of the SD15 strain of CIAV significantly reduced the weight and antibody titers to avian influenza virus (AIV)/Newcastle disease virus (NDV) inactivated vaccines of chickens immunized with the CVI988/Rispens, and resulted in the atrophy of thymus/bursa and the enlargement of spleen. The CVI988/Rispens vaccination conferred good immune protection for chickens challenged with 2000 PFU of the GX0101 strain of MDV. However, dual infection with SD15 significantly reduced the body weight, antibody titers induced by AIV/NDV inactivated vaccines and protective index of CVI988/Rispens, and resulted in the aggravation of the immunosuppression, mortality, and viremia of GX0101 in CVI988/Rispens-immunized/GX0101-challenged chickens. Overall, CIAV infection significantly reduced the protective effects of the CVI988/Rispens vaccine against MDV, implying that concurrent infection with CIAV may be a major contributor in the frequent attacks of MD in China in recent years.