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Glucose metabolism in fish remains a controversial area of research as many fish species are traditionally considered glucose-intolerant. Although energy homeostasis remodeling has been observed in fish with inhibited fatty acid β-oxidation (FAO), the effects and mechanism of the remodeling caused by blocked glucose uptake remain poorly understood. In this study, we blocked glucose uptake by knocking out glut2 in zebrafish. Intriguingly, the complete lethality, found in Glut2-null mice, was not observed in glut2−/− zebrafish. Approxiamately 30% of glut2−/− fish survived to adulthood and could reproduce. The maternal zygotic mutant glut2 (MZglut2) fish exhibited growth retardation, decreased blood and tissue glucose levels, and low locomotion activity. The decreased pancreatic β-cell numbers and insulin expression, as well as liver insulin receptor a (insra), fatty acid synthesis (chrebp, srebf1, fasn, fads2, and scd), triglyceride synthesis (dgat1a), and muscle mechanistic target of rapamycin kinase (mtor) of MZglut2 zebrafish, suggest impaired insulin-dependent anabolic metabolism. Upregulated expression of lipolysis (atgl and lpl) and FAO genes (cpt1aa and cpt1ab) in the liver and proteolysis genes (bckdk, glud1b, and murf1a) in muscle were observed in the MZglut2 zebrafish, as well as elevated levels of P-AMPK proteins in both the liver and muscle, indicating enhanced catabolic metabolism associated with AMPK signaling. In addition, decreased amino acids and elevated carnitines of the MZglut2 zebrafish supported the decreased protein and lipid content of the whole fish. In summary, we found that blocked glucose uptake impaired insulin signaling-mediated anabolism via β-cell loss, while AMPK signaling-mediated catabolism was enhanced. These findings reveal the mechanism of energy homeostasis remodeling caused by blocked glucose uptake, which may be a potential strategy for adapting to low glucose levels.

The effects of dietary yeast hydrolysate on the growth performance, gut health, and digestion of juvenile yellow catfish were evaluated throughout a 62-day feeding trial. Isonitrogenous and isoenergetic experimental diets were prepared. The positive control fishmeal (FM) diet contained 40 % FM. The negative control plant protein diet (PM group) contained 18 % soybean meal (SBM) and 18 % rapeseed meal (RSM). In other two test diets, 1 % and 5 % of yeast hydrolysate (1 % YH and 5 % YH group) were used to replace SBM and RSM (1:1) of PM group, respectively. The results showed no significant differences in the growth performance of yellow catfish among all groups. However, daily food intake was significantly increased in 5 % YH compared with the control PM. Besides, the apparent digestibility coefficient (ADC) of dry matter improved in 1 % YH, compared with FM. And the YH groups had significantly higher total EAA concentrations in plasma than PM group. The 1 %−5 % YH supplement in plant protein diet could improve the length of gut villi and density of distal intestinal microvilli, and enhance the antioxidant capacity of mid intestine and distal intestine. Compared with PM, YH groups increased the digestive capacity of proximal intestine and mid intestine. It is concluded that 1 %−5 % of dietary yeast hydrolysate improved intestine health, food consumption and absorptive ability of yellow catfish.

IntroductionResveratrol (RES) is a polyphenol organic compound with antioxidant and anti-inflammatory properties. This study aimed to determine whether and how RES can alleviate liver injury in lipopolysaccharide (LPS)-induced gibel carp.MethodsGibel carp were fed a diet with or without RES and were cultured for 8 weeks, followed by LPS injection.Results and discussionThe results suggested that RES attenuated the resulting oxidative stress and inflammation by activating the Nrf2/Keap1 pathway and inhibiting the NF-κB pathway, as confirmed by changes in oxidative stress, inflammation-related gene expression, and antioxidant enzyme activity. Furthermore, RES cleared damaged mitochondria and enhanced mitochondrial biogenesis to mitigate reactive oxygen species (ROS) accumulation by upregulating the SIRT1/PGC-1α and PINK1/Parkin pathways and reducing p62 expression. Overall, RES alleviated LPS-induced oxidative stress and inflammation in gibel carp through mitochondria-related mechanisms.

At present, there are great technical difficulties in achieving microstructure and mechanical properties uniformity in large-size billets prepared by severe plastic deformation technology. How to improve the process route to realize the microstructure and mechanical properties uniformity of the billets has become an urgent problem to be solved at present. In this paper, GWZ932K alloy is used for two reciprocating upsetting-extrusion (RUE) deformation methods with a cumulative strain of 5.38. The influence of isothermal temperature reciprocating upsetting-extrusion (IT-RUE) and decreasing temperature reciprocating upsetting-extrusion (DT-RUE) on the microstructure and mechanical properties uniformity of GWZ932K alloy is discussed in detail. The results show both IT-RUE and DT-RUE deformation methods can effectively refine grains. IT-RUE can prepare Mg alloy billet with uniform microstructure and mechanical properties from center region (CR) to edge region (ER). The microstructure and mechanical properties of the billet prepared by DT-RUE show obvious gradient characteristics from CR to ER. After 4 passes IT-RUE deformation, double-peak textures appear on the (0001) basal texture of the ER, middle region (1/2R) and CR, which is mainly attributed to the occurrence of dynamic recrystallization (DRX) behavior. It should be noted that changes in the deformation temperature will not cause changes in the DRX mechanism. The deformation mechanisms of continuous dynamic recrystallization (CDRX) and discontinuous dynamic recrystallization (DDRX) jointly promote grain refinement.

The effects of deep cryogenic treatment (DCT) on the tensile property and microstructure of Mg-9Gd-4Y–2Zn-0.5Zr(wt.%) alloy were investigated by comparing the alloy treated by solution treatment, deep cryogenic treatment and aging treatment (ST + DCT + AT) and that treated by solution treatment and aging treatment (ST + AT). The lamellar 14H-type long-period stacking ordered (14H-LPSO) in grain was precipitated in the alloy treated by ST + AT. However, the particle and needle-like Mg5RE (RE = Gd, Y) phases instead of the lamellar 14H-LPSO were precipitated, and a high-density dislocation existed in the alloy treated by ST + DCT. The greater ultimate tensile strength (UTS) and yield strength (YS) of the alloy treated by ST + DCT + AT were obtained because of the precipitation of the Mg5RE phases. The trend, the UTS and YS firstly increased then decreased with the increasing of soaking time, is corresponding to the volume fraction increasing and size-coarsening of Mg5RE precipitates, respectively. The greater elongation (EL) was obtained after the short-time DCT for 0–2 h (DCT0h-DCT2h) and the smaller EL was obtained for the long soaking time (>DCT2h). The fracture mode of the samples is all quasi-cleavage fracture.

The accurate evaluation of operators’ mental workload in human-machine systems plays an important role in ensuring the correct execution of tasks and the safety of operators. However, the performance of cross-task mental workload evaluation based on physiological metrics remains unsatisfactory. To explore the changes in dynamic functional connectivity properties with varying mental workload in different tasks, four mental workload tasks with different types of information were designed and a newly proposed dynamic brain network analysis method based on EEG microstate was applied in this paper. Six microstate topographies labeled as Microstate A-F were obtained to describe the task-state EEG dynamics, which was highly consistent with previous studies. Dynamic brain network analysis revealed that 15 nodes and 68 pairs of connectivity from the Frontal-Parietal region were sensitive to mental workload in all four tasks, indicating that these nodal metrics had potential to effectively evaluate mental workload in the cross-task scenario. The characteristic path length of Microstate D brain network in both Theta and Alpha bands decreased whereas the global efficiency increased significantly when the mental workload became higher, suggesting that the cognitive control network of brain tended to have higher function integration property under high mental workload state. Furthermore, by using a SVM classifier, an averaged classification accuracy of 95.8% for within-task and 80.3% for cross-task mental workload discrimination were achieved. Results implies that it is feasible to evaluate the cross-task mental workload using the dynamic functional connectivity metrics under specific microstate, which provided a new insight for understanding the neural mechanism of mental workload with different types of information.

Benzene is used as an industrial solvent, which may result in chronic benzene poisoning (CBP). Several studies suggested that CBP was associated with mitochondrial epigenetic regulation. This study aimed to explore the potential relation between CBP and mitochondrial DNA (mtDNA) methylation. This prospective observational study enrolled CBP patients admitted to Shenzhen Prevention and Treatment Center for Occupational Diseases hospital and healthy individuals between 2018 and 2021. The white blood cell (WBC), red blood cell (RBC), hemoglobin (HB), and platelet (PLT) counts and mtDNA methylation levels were measured using blood flow cytometry and targeted bisulfite sequencing, respectively. A total of 90 participants were recruited, including 30 cases of CBP (20 females, mean age 43.0 ± 8.0 years) and 60 healthy individuals (42 females, mean age 43.5 ± 11.5 years). This study detected 168 mitochondrial methylation sites >0 in all study subjects. The mtDNA methylation levels in the CBP cases were lower than the healthy individuals [median ± interquartile-range (IQR), 25th percentile, 75th percentile: (1.140 ± 0.570, 0.965, 1.535)% vs. median ± IQR, 25th percentile, 75th percentile: (1.705 ± 0.205,1.240,2.445)%, P < 0.05]. Additionally, the spearman correlation analysis showed that the mtDNA methylation levels were positively correlated with the counts of circulating leukocytes [WBC (r = 0.048, P = 0.036)] and platelets [PLT (r = 0.129, P < 0.01)]. We provided solid evidence of association between CBP and aberrant mtDNA methylation.

Objectives: Improper reprocessing of endoscopes may result in healthcare-associated infections. Regular microbiological surveillance is an important means of evaluating the quality of endoscope reprocessing. We evaluated the effectiveness of reprocessing endoscopes (including the protocols on steps to be taken in the event of any positive microbiological results) in a sterile supply unit (SSU) and an endoscopy unit in a Singapore tertiary-care academic hospital. Methods: Singapore General Hospital (SGH) is a 1,750-bed, tertiary-care, academic medical center in Singapore with 2 main SSUs: 1 inpatient endoscopy unit and 1 outpatient endoscopy unit. We reviewed microbiological surveillance results from endoscopes following reprocessing from January 2018 to December 2021. In total, 160 endoscopes (27 bronchoscopes, 58 gastroscopes, 52 colonoscopes, 6 duodenoscopes, 5 echoscopes, 5 cystoscopes, 5 rhinolaryngoscopes, and 5 enteroscopes) and 15 automated endoscope reprocessors (AERs) were evaluated for the presence of microorganisms. Samples were obtained by swabbing the tip of the scope and the biopsy channel. Fluid was flushed from the biopsy channel after reprocessing, and this water from the AERs was sampled after waterline disinfection. Results: Of the 15,783 samples collected, 15,667 (99.3%) yielded no growth; 36 (0.2%) were positive for gut and environmental flora; and 80 (0.5%) were positive for low-concern organisms such as skin flora. Conclusions: Microbiological surveillance yielded a high percentage of negative results confirming the effectiveness of endoscope reprocessing. This quality-assurance process is necessary and beneficial in achieving patient safety.

Excessive carbohydrate intake leads to metabolic disorders in fish. However, few literatures have reported the appropriate carbohydrate level for zebrafish, and the metabolic response to dietary carbohydrate remains largely unknown in zebrafish. This study assessed the responses of zebrafish and zebrafish liver cell line (ZFL) to different carbohydrate levels. In vivo results showed that ≥30% dietary dextrin levels significantly increased the plasma glucose content, activated the expression of hepatic glycolysis-related genes, and inhibited the expression of hepatic gluconeogenesis-related genes in zebrafish. Oil red O staining, triglyceride content, and Hematoxylin-Eosin staining results showed that dietary dextrin levels of ≥30% significantly increased lipid accumulation and liver damage, as well as processes related to glycolipid metabolism and inflammation in zebrafish. In ZFL, the transcription factor sterol regulatory element binding protein-1c signal intensity, 4,4-difluoro-1,3,5,7,8-pentamethyl-4-bora-3a,4a-diaza-s-indacene (BODIPY 493/503) signal intensity, and triglyceride content were also significantly increased when incubated in high glucose, along with abnormal glycolipid metabolism and increased inflammation-related genes. In conclusion, we demonstrated that the maximum dietary carbohydrate level in adult zebrafish should be less than 30%. Excess dietary carbohydrates (30%–50%) caused hepatic steatosis and damage to zebrafish, similar to that seen in aquaculture species. Thus, this study assessed responses to different carbohydrate levels in zebrafish and illustrated that zebrafish is an optimal model for investigating glucose metabolism in some aquatic animals.

The present study investigated the sequential regulation signals of high-carbohydrate diet (HCD)-induced hepatic lipid deposition in gibel carp (Carassius gibelio). Two isonitrogenous and isolipidic diets, containing 25% (normal carbohydrate diet, NCD) and 45% (HCD) corn starch, were formulated to feed gibel carp (14.82 ± 0.04 g) for 8 weeks. The experimental fish were sampled at 2nd, 4th, 6th, and 8th week. In HCD group, the hyperlipidemia and significant hepatic lipid deposition (oil red O area and triglyceride content) was found at 4th, 6th, and 8th week, while the significant hyperglycemia was found at 2nd, 4th, and 8th week, compared to NCD group (P

Nuclear magnetic resonance (NMR) is a crucial technique for analyzing mixtures consisting of small molecules, providing non-destructive, fast, reproducible, and unbiased benefits. However, it is challenging to perform mixture identification because of the offset of chemical shifts and peak overlaps that often exist in mixtures such as plant flavors. Here, we propose a deep-learning-based mixture identification method (DeepMID) that can be used to identify plant flavors (mixtures) in a formulated flavor (mixture consisting of several plant flavors) without the need to know the specific components in the plant flavors. A pseudo-Siamese convolutional neural network (pSCNN) and a spatial pyramid pooling (SPP) layer were used to solve the problems due to their high accuracy and robustness. The DeepMID model is trained, validated, and tested on an augmented data set containing 50,000 pairs of formulated and plant flavors. We demonstrate that DeepMID can achieve excellent prediction results in the augmented test set: ACC = 99.58%, TPR = 99.48%, FPR = 0.32%; and two experimentally obtained data sets: one shows ACC = 97.60%, TPR = 92.81%, FPR = 0.78% and the other shows ACC = 92.31%, TPR = 80.00%, FPR = 0.00%. In conclusion, DeepMID is a reliable method for identifying plant flavors in formulated flavors based on NMR spectroscopy, which can assist researchers in accelerating the design of flavor formulations.

Per- and polyfluoroalkyl substances (PFASs) are bioaccumulative and widely distributed persistent organic pollutants (POPs). Understanding the distribution of and ecological risks posed by PFASs is critical, particularly for PFAS emissions and accumulation from a common urban pollution source. The transformation characteristics and ecological risks of PFASs from a typical aging municipal landfill leachate were systematically monitored and assessed over five years in this study. The results showed that the total PFAS concentrations (ΣPFASs) in the rivers were between 26.4 and 464.3 ng/L, whereas in sediment, ΣPFASs ranged from 9.5 to 58.5 ng/g (w/w). The presence of perfluorooctanoic acid (PFOA) was the most prominent PFAS in both water (39.4–152.3 ng/L) and sediment (1.1–56.1 ng/g). In a five-year monitoring study, the concentration of PFASs in the aging landfill decreased by 23.3%, with higher mean concentrations observed during summer (307.6 ng/L) compared to winter (250.4 ng/L). As for the pollution distribution, the suspended particulate matter–water partition coefficient (log Kd) of carboxylic acid (PFCAs) and perfluoroalkane sulfonic acids (PFSAs) ranged from 1.53 to 2.65, and from 1.77 to 2.82, respectively. PFSAs and long-chain PFCAs exhibited a greater propensity for sediment association compared to short-chain PFCAs. An ecological risk assessment of four typical PFASs, PFOA, perfluorooctane sulfonate (PFOS), perfluorobutanoic acid (PFBA), and perfluorobutane sulfonic acid (PFBS), utilizing the hazard quotient method revealed that the rivers surrounding the typical aging landfill exhibited a low contamination risk for PFOA, while no ecological risks were associated with the other three FPASs. This study contributes to an enhanced comprehension of the occurrence, distribution, and risk of PFASs in the rivers in rivers and sediment surrounding a typical aging landfill site in China, thereby providing crucial reference information for ensuring water quality safety.

Understanding of the buffer scale effect on water quality changes analysis in arid and humid regions is of great significance for exploring the best scale for water quality pollution and scientific planning of land use. The objective of this study is to determine the optimal buffer scales (500, 1000, 1500, 2000, 2500 and 3000 m) of land use that affect ammonia nitrogen (NH3-N) and total phosphorus (TP) in the Jing-Bortala River Watershed (JBRW) (arid region) and the Liyang Region (LR) (humid region) under a site buffer. PLS-SEM was used to fit the pathway relationships between the influencing factors and water quality to investigate the driving factors of NH3-N and TP in different seasons. The results showed that: (1) seasonal fluctuations in NH3-N and TP concentrations were found in both the arid and humid regions, with the arid region having higher values than humid region; the coefficient of variation (CV) of NH3-N and TP was higher in arid and humid region, and the CV of NH3-N and TP were higher in spring and autumn in arid region than that in spring and autumn in humid region; (2) the 2500 m (0.262 ≤ R2 ≤ 0.633) buffer is the optimal scale for studying NH3-N and TP in arid region, whereas the 2000 m (0.262 ≤ R2 ≤ 0.686) scale works well in humid region; and (3) farmland (NDVI) was the largest influencing factor for NH3-N and TP changes in arid region, accounting for 28.95 % of the average percent total impacts. Furthermore, water area (NDWI) was the predominant influencing factor in humid region, occupying 33.93 % of the average percent total impacts. The influence of land use type (indices) on surface water quality is greater than that of environmental factors. Thus, these new insights into an appropriate buffer scale can be used as a guide for water pollution management in arid and humid environments.

Abstract Acute kidney injury (AKI) is a sudden kidney dysfunction caused by aberrant reactive oxygen species (ROS) metabolism that results in high clinical mortality. The rapid development of ROS scavengers provides new opportunities for AKI treatment. Herein, the use of hydrogen‐terminated germanene (H‐germanene) nanosheets is reported as an antioxidative defense nanoplatform against AKI in mice. The simulation results show that 2D H‐germanene can effectively scavenge ROS through free radical adsorption and subsequent redox reactions. In particular, the H‐germanene exhibits high accumulation in injured kidneys, thereby offering a favorable opportunity for treating renal diseases. In the glycerol‐induced murine AKI model, H‐germanene delivers robust antioxidative protection against ROS attack to maintain normal kidney function indicators without negative influence in vivo. This positive in vivo antioxidative defense in living animals demonstrates that the present H‐germanene nanoplatform is a powerful antioxidant against AKI and various anti‐inflammatory diseases.

Prunella vulgaris L.(P. vulgaris) is a perennial herb belonging to the Labiate family and widely distributed in China, Japan, Korea and Europe. Medical monographs and previous studies have shown that P. vulgaris has significant anti-breast cancer activity, and its use in breast treatment has a long history. However, systematically reports about the material basis and mechanism of P. vulgaris on anti-breast cancer activity are limited. In the present study, we first screened the best active fraction from the crude extract (PVE) and ethanol eluted fractions of P. vulgaris by using MDA-MB-231, MCF-7, 4T1 cell models in vitro and a 4T1-BALB/c transplanted tumour mouse breast cancer model in vivo. Furthermore, the anti-breast cancer mechanism of the best active fraction was investigated. The results demonstrated that PVE and ethanol fractions exhibited anti-breast cancer activity, especially with the 50% ethanol eluted fraction (PV50), which effectively regulated the 4T1 cell cycle, inhibited tumour cell proliferation, and promoted cancer cell apoptosis. In case of in vivo assays, PV50 inhibited tumour growth and lung metastasis, as well as inducing cell apoptosis by promoting damage of nuclear DNA and increasing expression of cleaved caspase-3. In addition, the chemical compositions of PV50 were analyzed by HPLC and UPLC-MS/MS, which were identified as flavonoids, moderately polar triterpenes, and a small amount of phenolic acid. The PV50 could be applied as natural sources against breast cancer in the pharmaceutical industry. These findings provide a basis for understanding the mechanism of the anti-breast cancer activity of P. vulgaris.

Microalgae have beneficial effects on the performance of fish as additives and they are becoming a promising alternative to fishmeal as macronutrient ingredients. However, the impact on the fish intestinal microbiome and the function, caused by microalgae as protein sources in diets, remains unclear. This study aimed to determine the composition and potential function of the intestinal microbial community of largemouth bass (Micropterus salmoides) fed diets at five replacement levels (0, 25, 50, 75 and 100%) of fishmeal by Chlorella meal in a basal diet (400 g kg−1) after 8 weeks. The results showed significant decreases in unique amplicon sequence variants in the intestine at the higher levels of fishmeal replacement. At 50% of fishmeal replacement, dietary inclusions of Chlorella meal had no impact on species richness and Shannon diversity and the community structure of the intestinal microbiota. However, high levels of fishmeal replacement (75 and 100%) significantly induced intestinal community disturbance and diversity loss in largemouth bass. Responding to the high fishmeal replacement level, the dominant genus Cetobacterium and Pleslomonas sharply increased and several taxa from Lactobacillus decreased significantly. Functional data predicted by PICRUSt revealed that nutrition-related metabolism was dominant in the intestinal microbiota of fish fed all the five diets, although some potential functions, particularly amino acid and lipid metabolisms, and energy metabolism, were upregulated firstly, and then downregulated in fish fed diets with the increase of dietary Chlorella meal. Meanwhile, certain pathways were not enriched in intestinal microbiome until up to 75% of fishmeal replacement, such as carbohydrate metabolism, and cofactors and vitamins metabolism. To conclude, this study reveals that fishmeal replacement (50%) by Chlorella meal at the level of 237 g kg−1 in diets is feasible for largemouth bass without impairing the microbiome structure and the metabolism function, providing an alternative strategy for evaluating the possibility of fishmeal replacement by microalgae in aquafeeds.

In this paper, we propose a new fluorescence emission difference microscopy (FED) technique based on polarization modulation. An electro-optical modulator (EOM) is used to switch the excitation beam between the horizontal and vertical polarization states at a high frequency, which leads to solid- and donut-shaped beams after spatial light modulation. Experiment on the fluorescent nanoparticles demonstrates that the proposed method can achieve [Formula: see text] spatial resolution. Using the proposed system, the dynamic imaging of subcellular structures in living cells over time is achieved.

Magnesium (Mg) alloys attract considerable attention in the fields of aerospace, defense technology, and automobile production, owing to the advantages of their low density, their highly specific strength/stiffness, and their good damping and electromagnetic shielding performance. However, low strength and poor ductility limit further application. Severe plastic deformation is considered the most promising means of producing ultrafine-grained Mg alloys and improving their mechanical properties. To this end, high-pressure torsion (HPT) is one of the most effective techniques. This article outlines the microstructure, texture, and mechanical properties of Mg alloys processed using HPT. The effects of deformation parameters, such as processing temperature, turns, applied pressure, and rotation speed, on the grain refinement and secondary phases are discussed. Textural evolution is detailed in light of both intrinsic and extrinsic factors, such as cumulative strain and the composition of the alloy elements. The subsequent enhancement of mechanical properties and mechanisms, and the significant contribution of the HPT process to strength are further reviewed. Given the advantages of HPT for grain refinement and structural modification, researchers have proposed several novel processes to extend the industrial application of these alloys.

High carbohydrate diet (HCD) causes metabolism disorder and intestinal damages in aquaculture fish. Berberine has been applied to improve obesity, diabetes and NAFLD. However, whether berberine contributes to the alleviation of HCD-induced intestinal damages in aquaculture fish is still unclear. Here we investigated the effects and mechanism of berberine on HCD-induced intestinal damages in largemouth bass (Micropterus salmoides). We found dietary berberine (50 mg/kg) improved the physical indexes (VSI and HSI) without affecting the growth performance and survival rate of largemouth bass. Importantly, the results showed that dietary berberine reduced the HCD-induced tissue damages and repaired the barrier in the intestine of largemouth bass. We observed dietary berberine significantly suppressed HCD-induced intestinal apoptosis rate (from 31.21 to 8.35%) and the activity level of Caspase3/9 (P < 0.05) by alleviating the inflammation (il1β, il8, tgfβ, and IL-6, P < 0.05) and ER stress (atf6, xbp1, perk, eif2α, chopa, chopb, and BIP, P < 0.05) in largemouth bass. Further results showed that dietary berberine declined the HCD-induced excessive lipogenesis (oil red O area, TG content, acaca, fasn, scd, pparγ, and srebp1, P < 0.05) and promoted the lipolysis (hsl, lpl, cpt1a, and cpt2, P < 0.05) via activating adenosine monophosphate-activated protein kinase (AMPK, P < 0.05) and inhibiting sterol regulatory element-binding protein 1 (SREBP1, P < 0.05) in the intestine of largemouth bass. Besides, we also found that dietary berberine significantly promoted the hepatic lipid catabolism (hsl, lpl, cpt1a, and cpt2, P < 0.05) and glycolysis (pk and ira, P < 0.05) to reduce the systematic lipid deposition in largemouth bass fed with HCD. Therefore, we elucidated that 50 mg/kg dietary berberine alleviated HCD-induced intestinal damages and improved AMPK/SREBP1-mediated lipid metabolism in largemouth bass, and evaluated the feasibility for berberine as an aquafeed additive to enhance the intestinal function of aquaculture species.

Particle settling is the process by which particulates move toward the bottom of a liquid, which can affect the sediment transport and energy balance of marine systems. However, the deficiency in understanding the resolved fluid–particle interactions with complex boundaries in the settling process awaits resolution. This study employs a hybrid approach that combines computational fluid dynamics (CFD) with the discrete element method (DEM) to fully simulate the free-settling behavior of polyhedral particles in water. The accuracy of the method is verified by comparing numerical results with experimental data of ellipsoidal particle settling. Two series of tests with horizontal and vertical particle release directions are established to investigate the effects of particle shape features, such as the aspect ratio (AR) and corner (C), on the particles’ mechanical behavior and hydrodynamic characteristics. The results demonstrate that particle shape exerts a substantial influence on fluid resistance, rotational motion, and fluid disturbance throughout the settling process. The maximum velocities in vertically released cases are roughly 1.2–1.3 times greater than those in horizontally released cases. The study highlights the potency of the resolved CFD-DEM method as a robust technique for comprehending fluid–particle phenomena within the marine geotechnical engineering, including sedimentation and erosion of seabed sediments.

To elucidate the relation of flavor in soy sauce (SS) kept at room temperature (SSAT) and SS kept under accelerated aging condition (SSAA), four analytical instruments, including electronic nose (E-nose), electronic tongue (E-tongue), gas chromatography–mass spectrometry-olfactory combined with solvent assisted flavor evaporation, and amino acid analyzer, were applied for analyzing the overall flavor profiles and flavor constituents in SSAT and SSAA. The results of E-nose and E-tongue showed overall flavor profile in SSAT for 3 weeks was similar to that of SSAA for 1 week, and 6 weeks (SSAT) was similar to 2 weeks (SSAA). In SS, a total of 35 odor-active compounds were identified and quantitated, and 22 compounds with odor activity value ≥1 were determined as key odorants. The compounds with the highest concentration were 4-hydroxy-2,5-dimethyl-3(2H)-furanone (28,756 μg/mL), followed by acetic acid (8838 μg/mL) and maltol (7984 μg/mL). The heatmap and hierarchical cluster analysis indicated that the concentrations of key odorants and amino acids in SSAT for 3 weeks was close to those of SSAA for 1 week, and 6 weeks (SSAT) was similar to 2 weeks (SSAA). Based on the results obtained above, it was concluded that the flavor changes in SSAA for 1 week were equivalent to those in SSAT for 3 weeks.

The creep characteristics of sliding zones strongly influence slope deformation and long-term stability, as well as the occurrence of landslide catastrophes. In this paper, large-scale triaxial creep tests were performed on the strongly weathered argillaceous sandstone sliding zone of the Huaipa landslide in the Henan Province, China, to study its creep characteristics and long-term strength in natural and saturated states. Three-dimensional numerical simulations were conducted to analyze the deformation creep law and catastrophic evolution mechanism of the slope after excavation and rainfall. The results show that the sliding zone underwent appreciable creep deformation prior to failure, and that the progression of specimen damage with an increasing stress level followed decay creep → steady creep → accelerated creep. The stress level played a decisive role in the creep deformation, with higher stress levels resulting in higher instantaneous displacement, creep displacement, and longer times required to reach steady creep. The stress level also determined the specimen’s creep stage. When the stress level was low, the adjustment of the specimen’s internal structure was dominated by air space compression and particle movement, whereas particle fragmentation mostly occurred at high stress levels. The long-term rock strength was approximately 62–66% of the instantaneous strength, the internal friction angle decreased by approximately 8° relative to the instantaneous strength, and the cohesion decreased by approximately 30%. The slope foot unloaded and deformed owing to the excavation of a bauxite mine at its front edge, after which the slope deformed via creep. The landslide disaster occurred when the deformation was significantly accelerated and the slope started to slide as a whole once the sliding zone became water saturated owing to continuous rainfall. The simulation results indicate that the landslide can be divided into a front edge bulging zone, central sliding zone, and trailing edge tension zone, which provides valuable insight on the creep deformation evolution process and the disaster mechanism of the landslide under the action of front edge excavation and rainfall.

Abstract Previously, we had cross-sectionally explored the characteristics of T cell receptor (TCR) repertoires from occupational medicamentosa-like dermatitis due to trichloroethylene (OMDT) patients, now we further analyzed the dynamic features of OMDT TCR repertoires. Peripheral blood TCR β-chain complementarity-determining region 3 (CDR3) genes were detected with the high throughput sequencing in 24 OMDT cases in their acute, chronic and recovery stages, respectively, and in 24 trichloroethylene-exposed healthy controls. The TCR repertoire diversity, TRBV/TRBD/TRBJ gene usage and combination, frequencies of CDR3 nucleotide (nt) and amino acid (aa) sequences in the cases in different stages and in the controls were analyzed. TRBV6-4 and TRBV7-9 frequencies significantly differed between the cases and controls (both P

In the present work, two processing routes (A and B) with 3 CEE-AEC passes are performed on Mg–13Gd–4Y–2Zn–0.4Zr alloys, and the resultant microstructure evolution, texture analysis and mechanical properties are investigated systematically. The core difference between the two processing routes is the orientation between the expansion and extrusion steps, i.e., they are parallel to each other for on route A and perpendicular to each other for route B. The results show that a remarkable grain refinement is achieved via both processing routes due to dynamic recrystallization (DRX). Fine equiaxed grains are observed in the samples processed with route B with a final size of 3.6 ± 0.4 µm compared to the grain size of 4.5 ± 0.5 µm with route A. With an increasing number of CEE-AEC passes, the overall texture intensity decreases, and the basal texture gradually changes to the mixed texture components. The shear deformation introduced by the asymmetrical extrusion cavity promotes a broad angular distribution of the basal planes on routes A and B, leading to an obvious increase in the Schmid factor for the activation of the basal 〈a〉 slip system. The tensile test at ambient temperature reveals that the comprehensive mechanical properties are improved, and the conventional mechanical anisotropy of as-received alloys is alleviated by successive CEE-AEC processing, which is mainly derived from the competitive balance relation between the grain refinement and texture modification.

Different temperature enamel firings were applied on a Ti-containing hot rolled enamel steel. The microstructure, mechanical properties and resistance to fish-scaling were characterized by optical microscopy, transmission electron microscopy, tensile test and hydrogen permeation test. The results show that both ferrite grain size and TiC particles size were increased after enamel firing. The yield strength, tensile strength and resistance to fish-scaling of experimental steel decrease with increasing firing temperature, which can be attributed to the increase in ferrite grain size and TiC particles size. TiC precipitates significantly affect the resistance to fish-scaling, and small sized TiC particles are beneficial for the high resistance to fish-scaling.

ObjectiveThe diagnosis of Parkinson’s disease (PD) remains challenging. Although 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) has revealed the metabolic abnormalities associated with PD at systemic levels, the underlying rich-club organization of the metabolic connectome in these patients remains largely unknown.Materials and MethodsThe data of 49 PD patients and 49 well-matched healthy controls (HCs) were retrieved and assessed. An individual metabolic connectome based on the standard uptake value (SUV) was built using the Jensen-Shannon Divergence Similarity Estimation (JSSE) method to compare the rich-club properties between PD patients and HC.ResultsOur results showed the rich-club organization of metabolic networks (normalized rich-club coefficients > 1) in the PD and HC group were within a range of thresholds. Further, patients with PD demonstrated lower strength and degree in rich-club connections compared with HCs (strength: HCs = 55.70 ± 8.52, PDs = 52.03 ± 10.49, p = 0.028; degree: HCs = 56.55 ± 8.60, PDs = 52.85 ± 10.62, p = 0.029), but difference between their feeder and local connections was not significant.ConclusionIndividual metabolic networks combined with rich club analysis indicated that PD patients had decreased rich club connections but similar feeder and local connections compared with HCs, indicating rich club connections as a promising marker for early diagnosis of PD.

Gleeble-3500 thermal simulator was applied to realize the rotary backward extrusion forming of Mg-13Gd-4Y-2Zn-0.5Zr (wt%) alloy at different circumferential strain rate from 0.009 s−1 to 0.027 s−1 at 400 °C and the dynamic recrystallization mechanism and texture evolution were studied. The results show that the grain size of the alloy was obviously refined after rotary backward extrusion. As the circumferential strain rate increased, the dynamic recrystallization fraction gradually increased causing the grain size decreased and the distribution of microstructure became more uniform. At the same time, the texture of {0001}, {10-10}, {11-20} was weakened and the grain orientation distribution became more random. With the increase of circumferential strain rate, the discontinuous dynamic recrystallization mechanism became dominant, which promoted the weakening of texture and grain refinement of the alloy.

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a public health emergency of international concern. SARS-CoV-2 RNA detection is the diagnostic criterion for coronavirus disease 2019 (COVID-19). Nevertheless, RNA detection has many limitations, such as being time-consuming and cost-prohibitive, and it must be performed in specialized laboratories. Virus antibody detection is a routine method for screening for multiple viruses, but data about SARS-CoV-2 antibody detection are limited. Method Throat swabs and blood were collected from 67 suspected SARS-CoV-2 infection patients at the Affiliated Hospital of Zunyi Medical University and Zunyi Fourth People’s Hospital isolated observation departments. Throat swab samples were subjected to SARS-CoV-2 RNA detection by real-time PCR. Blood was used subjected to SARS-CoV-2 IgG/IgM detection by an enzyme-linked immunosorbent assay (ELISA) and gold immunochromatography assay (GICA). Blood underwent C-reactive protein detection by immunoturbidimetry, and white blood cells, neutrophil percentages and lymphocyte percentages were counted and calculated, respectively. Clinical symptoms, age and lifestyle habits (smoking and drinking) in all patients were recorded. Data were analysed using SPSS version 19. The results were confirmed by T and χ2 tests; correlations with detection results were analysed by kappa coefficients. Odds ratio (OR) and corrected OR values were analysed by logistic regression. P

This paper provided an efficient single pass severe plastic deformation (SPD) method, annular channel angular extrusion (ACAE), for fabricating AZ80 magnesium alloy shell part. The effect of ACAE process on the microstructure homogeneity, texture, and mechanical properties of extruded part was experimentally investigated. For comparison, conventional backward extrusion (BE) was also conducted on processing AZ80 part with same specification. The results showed that ACAE process has a better capacity to refine the microstructure and dramatic improve the deformation homogeneity of the extruded part than BE process. Due to two strong shear deformations were implemented, ACAE process could also concurrently modify the basal texture more notably than BE process. In particular, a bimodal texture was found in ACAE extruded part, which was greatly related to the enhanced synergetic action of basal slip and secondary slip caused by the effective shear stress. More uniform and superior hardness along the thickness and height of part were achieved via ACAE process. Further surveying of tensile tests also showed that the part fabricated by ACAE process exhibited significantly higher and far more homogeneous tensile properties with an excellent balance of strength and ductility. The remarkable enhanced tensile properties of ACAE extruded part could be primarily attributed to the significant grain refinement, which provided a powerful grain boundary strengthening effect and meaningfully suppressed the development of twin-sized cracks during tensile deformation. It was established that ACAE process seemed to be a very promising single pass SPD method for manufacturing Mg-based alloy shell parts with more homogeneous microstructure and superior performance.

Abstract Background Fibrosis is an integral component of the pathogenesis of acute lung injury and is associated with poor outcomes in patients with acute respiratory distress syndrome (ARDS). Fibrocytes are bone marrow-derived cells that traffic to injured tissues and contribute to fibrosis; hence their concentration in the peripheral blood has the potential to serve as a biomarker of lung fibrogenesis. We therefore sought to test the hypothesis that the concentration and phenotype of circulating fibrocytes in patients with ARDS predicts clinical outcomes. Methods For the animal studies, C57Bl/6 mice were infected with experimental Klebsiella pneumoniae in a model of acute lung injury; one-way ANOVA was used to compare multiple groups and two-way ANOVA was used to compare two groups over time. For the human study, 42 subjects with ARDS and 12 subjects with pneumonia (without ARDS) were compared to healthy controls. Chi-squared or Fisher’s exact test were used to compare binary outcomes. Survival data was expressed using a Kaplan-Meier curve and compared by log-rank test. Univariable and multivariable logistic regression were used to predict death. Results In mice with acute lung injury caused by Klebsiella pneumonia, there was a time-dependent increase in lung soluble collagen that correlated with sequential expansion of fibrocytes in the bone marrow, blood, and then lung compartments. Correspondingly, when compared via cross-sectional analysis, the initial concentration of blood fibrocytes was elevated in human subjects with ARDS or pneumonia as compared to healthy controls. In addition, fibrocytes from subjects with ARDS displayed an activated phenotype and on serial measurements, exhibited intermittent episodes of markedly elevated concentration over a median of 1 week. A peak concentration of circulating fibrocytes above a threshold of > 4.8 × 106 cells/mL cells correlated with mortality that was independent of age, ratio of arterial oxygen concentration to the fraction of inspired oxygen, and vasopressor requirement. Conclusions Circulating fibrocytes increase in a murine model of acute lung injury and elevation in the number of these cells above a certain threshold is correlated with mortality in human ARDS. Therefore, these cells may provide a useful and easily measured biomarker to predict outcomes in these patients.

Abstract Small molecular PD‐1 inhibitors are lacking in current immuno‐oncology clinic. PD‐1/PD‐L1 antibody inhibitors currently approved for clinical usage block interaction between PD‐L1 and PD‐1 to enhance cytotoxicity of CD8+ cytotoxic T lymphocyte (CTL). Whether other steps along the PD‐1 signaling pathway can be targeted remains to be determined. Here, we report that methylene blue (MB), an FDA‐approved chemical for treating methemoglobinemia, potently inhibits PD‐1 signaling. MB enhances the cytotoxicity, activation, cell proliferation, and cytokine‐secreting activity of CTL inhibited by PD‐1. Mechanistically, MB blocks interaction between Y248‐phosphorylated immunoreceptor tyrosine‐based switch motif (ITSM) of human PD‐1 and SHP2. MB enables activated CTL to shrink PD‐L1 expressing tumor allografts and autochthonous lung cancers in a transgenic mouse model. MB also effectively counteracts the PD‐1 signaling on human T cells isolated from peripheral blood of healthy donors. Thus, we identify an FDA‐approved chemical capable of potently inhibiting the function of PD‐1. Equally important, our work sheds light on a novel strategy to develop inhibitors targeting PD‐1 signaling axis.

Abstract Background Serum miRNA was once found as potential disease survival index,thus we investigated the role of miRNA in predicting prognosis in loco-regionally advanced NPC patients treated with CCRT. Methods This study included two phases: (i) We enrolled 3 NPC patients with recurrence or distant metastasis (experimental group, EG) and 3 NPC patients in clinical remission (control group, CG),who were treated with CCRT within 5 years. The paired serum was collected before and after treatment and biomarkers were discovered by LNA-TaqMan Human MicroRNA Arrays. (ii) we used the bioinformatic analysis, marker selection and an independent validation by qRT-PCR to analyse the serums of 29 NPC patients with recurrent disease or distant metastasis and 19 NPC patients in clinical remission treated with CCRT. Using the Kaplan-Meier method, log-rank test and Cox regression model to estimate the accuracy of the miRNAs to predict PFS and OS, and identified factors significantly associated with prognosis, respectively. Results Using fold change≥2.0 or ≤ 0.5 and p ≤ 0.05 as cutoff levels, we identified 1 up-regulated and 6 down-regulated miRNAs, 1 up-regulated and 9 down-regulated miRNAs in EG versus CG before and after CCRT, respectively. After these down-regulated miRNAs were dealed with bioinformatics analysis and normalization, only 5 different miRNAs were significantly reduced, which there were no significant difference in the expression of miRNA-26b, miRNA-29a and miRNA-125b before CCRT, and the expression of miRNA-143 and miRNA-29b after CCRT in the serum samples of 48 NPC patients. Based on this, we calculated a risk score with the expression of miRNA-26b、miRNA-29a、miRNA-125b、miRNA-29b、miRNA-143 and then classified patients as high or low risk group. Cox regression model suggested that combining miRNA-29a and miRNA-125b before CCRT with miRNA-26b after CCRT was independent prognostic factors for PFS (HR = 3.149, 95%CI:1.018–9.115, p = 0.034), whereas combining the former two is independent for OS (HR = 5.146, 95%CI:1.674–15.817, p = 0.04). Conclusions For loco-regionally advanced NPC patients treated with CCRT, especially high-risk patients- serum miRNAs, such as miRNA-29a, miRNA-125b and miRNA-26b etc., play an important role in predicting prognosis factors of PFS and OS, which will contribute to the strategic direction for future research.

Objective: We aimed to use an individual metabolic connectome method, the Jensen-Shannon Divergence Similarity Estimation (JSSE), to characterize the aberrant connectivity patterns and topological alterations of the individual-level brain metabolic connectome and predict the long-term surgical outcomes in temporal lobe epilepsy (TLE).Methods: A total of 128 patients with TLE (63 females, 65 males; 25.07 ± 12.01 years) who underwent Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) imaging were enrolled. Patients were classified either as experiencing seizure recurrence (SZR) or seizure free (SZF) at least 1 year after surgery. Each individual’s metabolic brain network was ascertained using the proposed JSSE method. We compared the similarity and difference in the JSSE network and its topological measurements between the two groups. The two groups were then classified by combining the information from connection and topological metrics, which was conducted by the multiple kernel support vector machine. The validation was performed using the nested leave-one-out cross-validation strategy to confirm the performance of the methods.Results: With a median follow-up of 33 months, 50% of patients achieved SZF. No relevant differences in clinical features were found between the two groups except age at onset. The proposed JSSE method showed marked degree reductions in IFGoperc.R, ROL. R, IPL. R, and SMG. R; and betweenness reductions in ORBsup.R and IOG. R; meanwhile, it found increases in the degree analysis of CAL. L and PCL. L, and in the betweenness analysis of PreCG.R, IOG. R, PoCG.R, PCL. L and PCL.R. Exploring consensus significant metabolic connections, we observed that the most involved metabolic motor networks were the INS-TPOmid.L, MTG. R-SMG. R, and MTG. R-IPL.R pathways between the two groups, and yielded another detailed individual pathological connectivity in the PHG. R-CAU.L, PHG. R-HIP.L, TPOmid.L-LING.R, TPOmid.L-DCG.R, MOG. R-MTG.R, MOG. R-ANG.R, and IPL. R-IFGoperc.L pathways. These aberrant functional network measures exhibited ideal classification performance in predicting SZF individuals from SZR ones at a sensitivity of 75.00%, a specificity of 92.79%, and an accuracy of 83.59%.Conclusion: The JSSE method indicator can identify abnormal brain networks in predicting an individual’s long-term surgical outcome of TLE, thus potentially constituting a clinically applicable imaging biomarker. The results highlight the biological meaning of the estimated individual brain metabolic connectome.

An 8-week feeding trial was conducted to explore the effects of replacement of dietary fishmeal by cottonseed protein concentrate (CPC) on growth performance, liver health, and intestine histology of largemouth bass. Four isoproteic and isolipidic diets were formulated to include 0, 111, 222, and 333 g/kg of CPC, corresponding to replace 0% (D1), 25% (D2), 50% (D3), and 75% (D4) of fishmeal. Two hundred and forty largemouth bass (15.11 ± 0.02 g) were randomly divided into four groups with three replicates per group. During the experiment, fish were fed to apparent satiation twice daily. Results indicated that CPC could replace up to 50% fishmeal in a diet for largemouth bass without significant adverse effects on growth performance. However, weight gain rate (WGR), specific growth rate (SGR), feed efficiency (FE), and condition factor (K) of the largemouth bass were significantly decreased when 75% of dietary fishmeal that was replaced by CPC. The whole body lipid content was increased with the increasing of dietary CPC levels. Oil red O staining results indicated that fish fed the D4 diet showed an aggravated fat deposition in the liver. Hepatocytes exhibited serious degeneration, volume shrinkage, and inflammatory cells infiltration in the D4 group. Intestinal villi appeared shorter and sparse with severe epithelial damage in the D4 group. The transcription levels of anti-inflammatory cytokines, such as transforming growth factor β (tgf-β), interleukin 10 (il-10), and interleukin 11 β (il-11β), were downregulated in the D4 group. The lipid metabolism-related genes carnitine palmitoyl transferase 1 (cpt1), peroxisome proliferator-activated receptor α (pparα), and target of rapamycin (TOR) pathway were also significantly downregulated in the D4 group. It was concluded that suitable replacement of fishmeal by less than 222 g CPC/kg diet had a positive effect on growth performance of fish, but an excessive substitution of 75% fishmeal by CPC would lead to the suppressed growth, liver inflammation, and intestinal damage of largemouth bass.

Two types of cantilevers are studied in this paper. One type is based on the piezoresistive design and the other type was the regular silicone based cantilevers. The regular cantilevers were measured with the help of the image analysis, so as to measure the real deflection when the regular cantilevers are calibrated based on cantilever on cantilever method. The standard uncertainty of the stiffness measurement is smaller than 3%. The resolution of the piezoresistive cantilever is 0.098 mN/m.

In this paper, the influence of reversibility on the uncertainty of torque measurement is studied. The reversibility distribution of the standard torque sensor is not a known common distribution, so its coverage factor k cannot be determined like other well-defined distribution. In order to explore the reversibility characteristics of the torque sensor, the original definition of coverage factor will be used for calculation and analysis. By using discrete and continuous analysis methods, we discuss the actual distribution characteristics of torque applied in increasing and decreasing steps, and then calculate the coverage interval, and finally determine the coverage factor k. By kernel density estimation, the discrete random variable is transformed into continuous random variable, and the probability density function of unknown distribution is obtained. The center method and the shortest coverage interval are used for the discussion. Finally, the coverage factors in 95% and 99% confidence intervals are 1.794 and 2.439, respectively.

The product innovation design is an innovation-intensive process that requires abundant knowledge and design experience, even across industries and disciplines, as a resource for problem solving. Therefore, designers need to have a good command of more design knowledge in this process. However, due to varied expressions of design knowledge (function, principle, structure) in different fields lead to the difficulty in representation of design knowledge, which makes designers unable to innovate by directly using design knowledge. Therefore, to solve the problem above, this paper, analogous to biological gene, proposes a product innovation process model based on functional gene extraction and construction. The proposed process model normalizes design knowledge through functional genes and help designers acquire design knowledge in different fields, which further promotes the product innovation design. The process model consists of four following steps. First, Obtain the overall function of product based on user needs and decompose it. Second, Build the functional gene model based on digital twin ones to expand the breadth of design knowledge and facilitate the retrieval. Third, Screen similar functional gene by the functional similarity algorithm. Finally, Obtain the design scheme through recombination, transcription, and translation of the functional gene. The feasibility of the research method is verified by using a shared bicycle parking device as an example.

Annual mass balance is an important reflection of glacier status that is also very sensitive to climate fluctuations. However, there is no effective and universal albedo-based method for the reconstruction of annual mass balance due to the scarcity of field observations. Here, we present an improved albedo–mass balance (IAMB) method to estimate annual glacier surface mass balance series using remote sensing techniques. The averaged glacier-wide albedo derived with the MODImLab algorithm during the summer season provides an effective proxy of the annual mass change. Defined as the variation in the albedo as a function of elevation change, the altitude–albedo gradient (∂z/∂α) can be obtained from a glacier digital elevation model (DEM) and optical images. The Chhota Shigri glacier situated in the western Himalayas was selected to test and assess the accuracy of this method over the period from 2003 to 2014. Reconstructed annual mass budgets correlated well with those from the observed records, with an average difference and root mean square error (RMSE) of −0.75 mm w.e. a−1 and 274.91 mm w.e. a−1, respectively, indicating that the IAMB method holds promise for glacier mass change monitoring. This study provides a new technique for annual mass balance estimation that can be applied to glaciers with no or few mass balance observations.

This paper considers a delayed claim risk model with stochastic return and Brownian perturbation in which each main claim may be accompanied with a delayed claim occurring after a stochastic period of time, and the price process of the investment portfolio is described as a geometric Lévy process. By means of the asymptotic results for randomly weighted sum of dependent subexponential random variables we obtain some asymptotics for finite-time ruin probability. A simulation study is also performed to check the accuracy of the obtained theoretical result via the crude Monte Carlo method.

Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors have been available on market for the treatment of breast, ovarian and prostatic cancer. Promisingly, the newly developed proteolysis targeting chimaeras (PROTACs) may provide a more potential strategy based on the degradation of PARP-1. Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown.

Hyperhomocysteinemia induces stress response in endoplasmic reticulum (ERS). Here, we tested whether blockage of homocysteine (Hcy) induced ERS and subsequent apoptosis in vascular smooth muscle cells can be inhibited by blockage of PERK/eIF2α/ATF4/CHOP signaling. Short-term exposure of vascular smooth muscle cells to Hcy led to the phosphorylation of PERK (pPERK), which in turn, phosphorylated eIF2 alpha (peIF2α) and inhibited the unfolded protein response. Long-term Hcy exposure, however, increased the expression of ATF-4 and CHOP and led to apoptosis. Treatment of cells with salubrinal, a specific inhibitor for eIF2α decreased the expression of ATF-4 and CHOP, and prevented apoptosis. Together, the results show that PERK pathway is involved in Hcy-induced vascular smooth muscle cell apoptosis and that blocking the PERK pathway protects against this injury.

Abstract Background The current prognosis of thymic epithelial tumors (TETs) is according to the World Health Organization (WHO) histologic classification and the Masaoka staging system. These methods of prognosis have certain limitations in clinical application and there is a need to seek new method for determining the prognosis of patients with TETs. To date, there have been no studies done on the use of DNA methylation biomarkers for prognosis of TETs. The present study was therefore carried out to identify DNA methylation biomarkers that can determine the overall survival in patients with TETs. Methods Bioinformatic analysis of TCGA 450 K methylation array data, transcriptome sequencing data, WHO histologic classification and Masaoka staging system was performed to identify differentially expressed methylation sites between thymoma and thymic carcinoma as well as the different DNA methylation sites associated with the overall survival in patients with TETs. Using pyrosequencing, 4 different methylation sites (cg05784862, cg07154254, cg02543462, and cg06288355) were sequenced from tumor tissues of 100 Chinese patients with TETs. A prognostic model for TETs was constructed using these four methylation sites. Results The TCGA dataset showed 5155 and 6967 hyper- and hypomethylated CpG sites in type A–B3 group and type C group, respectively, of which 3600 were located within the gene promoter regions. One hundred thirty-four genes were silenced by promoter hypermethylation and 174 mRNAs were upregulated. Analysis of univariate and multivariate Cox regression showed significant association between the methylation levels of 187 sites and the overall survival in patients with TETs. cg05784862(KSR1), cg07154254(ELF3), cg02543462(ILRN), and cg06288355(RAG1) were identified as independent prognostic factors for overall survival in patients with TETs after adjusting for Masaoka staging in 100 Chinese patients. The prognostic model which consists of the four abovementioned genes had higher accuracy for predicting the 5-year overall survival in patients with TETs as compared to the Masaoka clinical staging. (Time-dependent ROC analysis AUC 1.000 vs 0.742, P = 2.7 × 10−6). Conclusions The methylation levels of cg05784862(KSR1), cg07154254(ELF3), cg02543462(ILRN), and cg06288355(RAG1) sites are associated with the progression of TETs and may serve as new biomarkers for predicting the overall survival in patients with TETs.

The tropomyosin receptor kinases (TRKs) have been validated as effective targets in anticancer drug discovery. Two first-generation TRK inhibitors have been approved into market and displayed an encouraging therapeutic response in cancer patients harboring TRK fusion proteins. However, acquired resistance mediated by secondary TRK mutations especially in the xDFG motif remains an unsolved challenge in the clinic. Herein, we report the preclinical pharmacological results of JND4135, a new type II pan-TRK inhibitor, in overcoming TRK mutant resistance, including the xDFG mutations in vitro and in vivo. At a low nanomolar level, JND4135 displays a strong activity against wild-type TRKA/B/C and secondary mutations involving xDFG motif substitutions in kinase assays and cellular models; occupies the TRK proteins for an extended time; and has a slower dissociation rate than other TRK inhibitors. Moreover, by intraperitoneal injection, JND4135 exhibits tumor growth inhibition (TGI) of 81.0% at a dose of 40 mg/kg in BaF3-CD74-TRKA-G667C mice xenograft model. Therefore, JND4135 can be considered as a lead compound for drug discovery overcoming the resistance of TRK inhibitor drugs mediated by xDFG mutations.

In recent years, although resin composite has played an important role in the restoration of tooth defects, it still has several disadvantages, including being biodegraded by saliva, bacteria and other enzymes in the oral cavity, which may result in repair failure. This factor is not conducive to the long-term survival of the prosthesis in the mouth. In this article, we review the causes, influencing factors and prevention methods of resin biodegradation. Biodegradation is mainly caused by esterase in saliva and bacteria, which breaks the ester bond in resin and causes the release of monomers. The mechanical properties of the prosthesis can then be affected. Meanwhile, cathepsin and MMPs are activated on the bonding surface, which may decompose the dentin collagen. In addition, neutrophils and residual water on the bonding surface can also aggravate biodegradation. Currently, the primary methods to prevent biodegradation involve adding antibacterial agents to resin, inhibiting the activity of MMPs and enhancing the crosslinking of collagen fibers. All of the above indicates that in the preparation and adhesion of resin materials, attention should be paid to the influence of biodegradation to improve the prosthesis’s service life in the complex environment of the oral cavity.

Smart Grids (SGs) are governed by advanced computing, control technologies, and networking infrastructure. However, compromised cybersecurity of the smart grid not only affects the security of existing energy systems but also directly impacts national security. The increasing number of cyberattacks against the smart grid urgently necessitates more robust security protection technologies to maintain the security of the grid system and its operations. The purpose of this review paper is to provide a thorough understanding of the incumbent cyberattacks’ influence on the entire smart grid ecosystem. In this paper, we review the various threats in the smart grid, which have two core domains: the intrinsic vulnerability of the system and the external cyberattacks. Similarly, we analyze the vulnerabilities of all components of the smart grid (hardware, software, and data communication), data management, services and applications, running environment, and evolving and complex smart grids. A structured smart grid architecture and global smart grid cyberattacks with their impact from 2010 to July 2022 are presented. Then, we investigated the the thematic taxonomy of cyberattacks on smart grids to highlight the attack strategies, consequences, and related studies analyzed. In addition, potential cybersecurity solutions to smart grids are explained in the context of the implementation of blockchain and Artificial Intelligence (AI) techniques. Finally, technical future directions based on the analysis are provided against cyberattacks on SGs.

The present study addresses the cardiac arrhythmia (CA) classification problem using the deep learning (DL)-based method for electrocardiography (ECG) data analysis. Recently, various DL techniques have been utilized to classify arrhythmias, with one typical approach to developing a one-dimensional (1D) convolutional neural network (CNN) model to handle the ECG signals in the time domain. Although the CA classification in the time domain is very prevalent, current methods’ performances are still not robust or satisfactory. This study aims to develop a solution for CA classification in two dimensions by introducing the recurrence plot (RP) combined with an Inception-ResNet-v2 network. The proposed method for nine types of CA classification was tested on the 1st China Physiological Signal Challenge 2018 dataset. During implementation, the optimal leads (lead II and lead aVR) were selected, and then 1D ECG segments were transformed into 2D texture images by the RP approach. These RP-based images as input signals were passed into the Inception-ResNet-v2 for CA classification. In the CPSC, Georgia, and the PTB_XL ECG databases of the PhysioNet/Computing in Cardiology Challenge 2020, the RP-based method achieved an average F1-score of 0.8521, 0.8529, and 0.8862, respectively. The results suggested the excellent generalization ability of the proposed method. To further assess the performance of the proposed method, we compared the 2D RP-image-based solution with the published 1D ECG-based works on the same dataset. Also, it was compared with two traditional ECG transform into 2D image methods, including the time waveform of the ECG recordings and time-frequency images based on continuous wavelet transform (CWT). The proposed method achieved the highest average F1-score of 0.844, with only two leads of the 12-lead ECG original data, which outperformed other works. Therefore, the promising results indicate that the 2D RP-based method has a high clinical potential for CA classification using fewer lead ECG signals.

Although immune checkpoint inhibitors (ICIs) have shown remarkable benefit for treatment of advanced non-small lung cancer (NSCLC), only a minority of patients can achieve durable responses and the most patients produce an ultra-rapid progressive disease. Here, we collected the availably published datasets and mined the determinants of response to immunotherapy on pathway levels. One hundred six NSCLC patients treated with immunotherapy were combined from Rizvi et al. and Hellman et al. studies (whole exon sequencing). Two independent validation datasets consisted of the MSKCC cohort (targeted sequencing) and data by Anagnostou and colleagues (whole exon sequencing). The Cancer Genome Atlas (TCGA) somatic mutation and gene expression data were applied to explore the immunobiology features. In the first combined cohort, we detected NOTCH pathway altered in 71% patients with durable clinical benefit (DCB) while only 36% among no durable benefit (NDB) (p = 0.005). Compared to NDB group, co-occurrence of NOTCH and at least two DDR (co-DDR) pathway was discovered in DCB group and contributed to a prolonged progression-free survival (PFS) [22.1 vs 3.6 months, p < 0.0001, HR, 0.34, 95% confidence interval (CI), 0.2–0.59]. In two independent datasets, co-occurrence of NOTCH+/co-DDR+ was also validated to be a better immunotherapy efficacy [Cohort 2: 13 vs 6 months, p = 0.034, HR, 0.55, 95% CI, 0.31–0.96; Cohort 3: 21 vs 11 months, p = 0.067, HR, 0.45, 95% CI, 0.18–1.1]. By analyzing TCGA cohort, we found patients with coexisting NOTCH+/co-DDR+ pathway had a higher TMB, more infiltration of CD4+T cells. Overall, co-occurrence of NOTCH and co-DDR pathway reflect a better immunotherapy efficacy in advanced NSCLC. This genomic predictor show promise in stratifying patients that suit for immunotherapy for future clinical practice.

For the fabrication of curved microstructures, the fabrication fidelity is greatly affected by the nonlinear relationship between the gray levels of the digital micromirror device (DMD) and the exposure dose in DMD gray-scale lithography. In this study, a method is proposed for the high fidelity fabrication of curved microstructures using DMD based dynamical ultraviolet lithography. A target curved microstructure is mapped into multiple discretized exposure profiles to control DMD mirrors. By extracting the same rows in all the discretized exposure profiles and arranging all the extracted rows in sequence, binary frame images to be exposed are constructed and then combined into a dynamical digital mask. With the proposed method, the nonlinear modulation of the DMD in gray-scale lithography is replaced with a linear binary modulation; thus, the dynamical modulation range of the DMD has been improved. We demonstrate the effectiveness of the method by theoretically simulating and experimentally fabricating a curved microlens array, compared with DMD gray-scale lithography. The experimental results show that the fabrication deviation in the edge region of the fabricated curved microlens array has been effectively decreased. This method may have great potential for the precision and low-cost industrial production of curved microstructures.

Background: Pulmonary Fibrosis (PF) is an interstitial lung disease characterized by excessive accumulation of extracellular matrix in the lungs, which disrupts the structure and gas exchange of the alveoli. There are only two approved therapies for PF, nintedanib (Nib) and pirfenidone. Therefore, the use of Chinese medicine for PF is attracting attention. Tianlongkechuanling (TL) is an effective Chinese formula that has been applied clinically to alleviate PF, which can enhance lung function and quality of life.Purpose: The potential effects and specific mechanisms of TL have not been fully explored, yet. In the present study, proteomics was performed to explore the therapeutic protein targets of TL on Bleomycin (BLM)-induced Pulmonary Fibrosis.Method: BLM-induced PF mice models were established. Hematoxylineosin staining and Masson staining were used to analyze histopathological changes and collagen deposition. To screen the differential proteins expression between the Control, BLM, BLM + TL and BLM + Nib (BLM + nintedanib) groups, quantitative proteomics was performed using tandem mass tag (TMT) labeling with nanoLC-MS/MS [nano liquid chromatographymass spectrometry]). Changes in the profiles of the expressed proteins were analyzed using the bioinformatics tools Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). The protein–protein interactions (PPI) were established by STRING. Expressions of α-smooth muscle actin (α-SMA), Collagen I (Col1a1), Fibronectin (Fn1) and enzymes in arginase-ornithine pathway were detected by Western blot or RT-PCR.Result: TL treatments significantly ameliorated BLM-induced collagen deposition in lung tissues. Moreover, TL can inhibit the protein expressions of α-SMA and the mRNA expressions of Col1a1 and Fn1. Using TMT technology, we observed 253 differentially expressed proteins related to PPI networks and involved different KEGG pathways. Arginase-ornithine pathway is highly significant. The expression of arginase1 (Arg1), carbamoyltransferase (OTC), carbamoy-phosphate synthase (CPS1), argininosuccinate synthase (ASS1), ornithine aminotransferase (OAT) argininosuccinate lyase (ASL) and inducible nitric oxide synthase (iNOS) was significantly decreased after TL treatments.Conclusion: Administration of TL in BLM-induced mice resulted in decreasing pulmonary fibrosis. Our findings propose that the down regulation of arginase-ornithine pathway expression with the reduction of arginase biosynthesis is a central mechanism and potential treatment for pulmonary fibrosis with the prevention of TL.