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Recently, the role of the gut microbiota in diseases, including cardiovascular disease (CVD), has gained considerable research attention. Trimethylamine-N-oxide (TMAO), which is formed during ʟ-carnitine metabolism, promotes the formation of atherosclerotic plaques, causing thrombosis. Here, we elucidated the anti-atherosclerotic effect and mechanism of ginger (Zingiber officinale Roscoe) essential oil (GEO) and its bioactive compound citral in Gubra Amylin NASH (GAN) diet with ʟ-carnitine-induced atherosclerosis female ApoE−/− mice. Treatment with GEO at both low and high doses and citral inhibited the formation of aortic atherosclerotic lesions, improved plasma lipid profile, reduced blood sugar, improved insulin resistance, decreased plasma TMAO levels, and inhibited plasma inflammatory cytokines, especially interleukin-1β. Additionally, GEO and citral treatment modulated gut microbiota diversity and composition by increasing the abundance of beneficial microbes and decreasing the abundance of CVD-related microbes. Overall, these results showed that GEO and citral may serve as potential dietary supplements for CVD prevention by improving gut microbiota dysbiosis.

Dietary emulsifiers have been linked to various diseases. The recent discovery of the role of gut microbiota-host interactions on health and disease warrants the safety reassessment of dietary emulsifiers through the lens of gut microbiota. Hydrophilic (lecithin (LEC), sucrose esters (SUC), carboxymethylcellulose (CMC)) and lipophilic (mono- and diglycerides (MDG)) emulsifiers are common dietary emulsifiers with high exposure levels in the population. This study proved that SUC and CMC induced hyperglycemia and hyperinsulinemia. MDG impaired circulating lipid and glucose metabolism. Both hydrophilic and lipophilic emulsifiers changed the intestinal microbiota diversity and induced gut microbiota dysbiosis. Hydrophilic emulsifiers have no impact on mucus–bacterial interactions, whereas MDG tended to cause bacterial encroachment into the inner mucus layer and enhance inflammation potential by raising circulating lipopolysaccharide. Our findings demonstrated the safety concerns associated with using dietary emulsifiers, suggesting that they could lead to metabolic syndromes.

Supplementary Figure 2 from Multiparameter Computational Modeling of Tumor Invasion

Supplementary Figure 1 from Multiparameter Computational Modeling of Tumor Invasion

Supplementary Figure 3 from Multiparameter Computational Modeling of Tumor Invasion

Supplementary Methods, Figure Legends 1-3 from Multiparameter Computational Modeling of Tumor Invasion

Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), one of the leading hereditary kidney diseases, and Alzheimer’s disease etc. There are no targeted therapies. ADTKD is also a genetic form of renal fibrosis and chronic kidney disease, which affects 500 million people worldwide. For the first time, in our newly generated mouse model recapitulating human ADTKD-UMODcarrying a leadingUMODdeletion mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are severely impaired, leading to cGAS- STING activation and tubular injury. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel endoplasmic reticulum stress-regulated secreted protein. We provide the first study that inducible tubular overexpression of MANF after the onset of disease stimulates autophagy/mitophagy and clearance of the misfolded UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, resulting in protection of kidney function. Conversely, genetic ablation of endogenous MANF upregulated in the mutant mouse and human tubular cells worsens autophagy suppression and kidney fibrosis. Together, we discover MANF as a novel biotherapeutic protein and elucidate previously unknown mechanisms of MANF in regulating organelle homeostasis to treat ADTKD, which may have broad therapeutic application to treat various proteinopathies.

We experimentally demonstrate a nano-scale stochastic Stirling heat engine operating in the underdamped regime. The setup involves an optically levitated silica particle that is subjected to a power-varying optical trap and periodically coupled to a cold/hot reservoir via switching on/off active feedback cooling. We conduct a systematic investigation of the engine's performance and find that both the output work and efficiency approach their theoretical limits under quasi-static conditions. Furthermore, we examine the dependence of the output work fluctuation on the cycle time and temperature difference between the hot and cold reservoirs. We observe that the distribution has a Gaussian profile in the quasi-static regime, whereas it becomes asymmetric and non-Gaussian as the cycle duration time decreases. This non-Gaussianity is qualitatively attributed to the strong correlation of the particle's position within a cycle in the non-equilibrium regime. Our experiments provide valuable insights into stochastic thermodynamics in the underdamped regime and open up new possibilities for the design of future nano-machines.

Gut microbiota and its metabolites, along with host metabolism of ʟ-carnitine, play a crucial role in cardiovascular disease (CVD) development, forming Trimethylamine-N-oxide (TMAO), an atherosclerosis risk factor. TMAO promotes the formation of atherosclerotic plaques and platelet aggregation potential, causing thrombosis. A high-fat diet and carnitine administration can accelerate CVD progression. Ginger (Zingiber officinale Roscoe) essential oil (GEO) and its bioactive compound citral have lipid lowering and anti-inflammatory effects, which may prevent CVD; however, their ability to prevent atherosclerosis through gut microbiota modulation remains to be elucidated. Furthermore, the Gubra Amylin NASH (GAN) diet is a palm oil-containing high-fat diet for inducing steatohepatitis; however, the study of the GAN diet in combination with ʟ-carnitine for inducing atherosclerosis in mouse model has not been investigated yet. We examined the CVD-protecting effect of GEO and citral against the formation of aortic atherosclerosis and linked them with changes in the gut microbiota and its metabolites in the ʟ-carnitine/GAN diet-treated apolipoprotein E-deficient (ApoE−/−) mouse model. GEO and citral demonstrated CVD protective function by alleviating aortic atherosclerotic lesions. They reduced blood sugar, improved insulin resistance, decreased plasma TMAO levels, and inhibited serum inflammatory cytokines, especially interleukin-1β. Moreover, they demonstrated their ability to modulate gut microbiota diversity and composition into a favourable direction. Collectively, GEO and citral may serve as potential prebiotics for CVD prevention by improving dysbiosis.

Analysis of policy and mechanism of green behaviour, as well as the role of technology, in the relationship between policy and low carbon development in China was a primary goal of the study. Finance also played a significant role in the relationship, but only when technology was present. Finance plays a significant part in China's policy and mechanism for green behaviour and low carbon development. It was also revealed that the existence of technological variables in China's policy and mechanism of green behaviour and low carbon development has a beneficial impact on the interaction between policy and mechanism. As a result of the study, it is recommended that countries adjust to the urgent circumstances under the long-term goals for tackling climate change and to overcome the "Middle Income Trap" within innovation-driven and low carbon development

Diet and gut microbiota contribute to non-alcoholic steatohepatitis (NASH) progression. High-fat diets (HFDs) change gut microbiota compositions and induce gut dysbiosis and intestinal barrier leakage, which facilitates portal influx of pathogen-associated molecular patterns [e.g., lipopolysaccharides (LPS)] to the liver and triggers inflammation in NASH. The current therapeutic drugs for NASH have adverse side effects; however, several foods and herbs have exhibited hepatoprotection. We investigated ginger essential oil (GEO) against palm oil-containing HFDs in LPS-injected murine NASH model. GEO prevented NASH development by increasing plasma alanine aminotransferase levels; increasing antioxidant catalase, glutathione reductase, and glutathione levels; and reducing hepatic pro-inflammatory cytokine levels. GEO alleviated hepatic inflammation through mediated NLR family pyrin domain-containing 3 inflammasome and LPS/Toll-like receptor 4 signaling pathways. GEO further increased beneficial bacterial abundance and reduced NASH-associated bacterial abundance. GEO may, therefore, prevent NASH by inhibiting hepatic inflammation and modulating the gut microbiota and its metabolite-related pathway.

Untethered helical magnetic devices (UHMDs) have the potential to navigate bodily fluids using permanent-magnet robotic systems for minimally invasive diagnostic and surgical procedures. These devices can be actuated by robotically moving rotating permanent magnets (RPMs) to achieve controllable steering and propulsion simultaneously in a wireless manner. To date, the vast majority of motion control systems using UHMDs are constrained to operate in the absence of a dynamic flow field and prior work did not rigorously address the fundamental roles of rheological, magnetic, and geometric characteristics of the UHMD and its surroundings on the resulting stability. In this work, we show how to construct the region of attraction of a UHMD driven by two synchronized RPMs inside fluid-filled lumen around an equilibrium point. We first present the governing hydrodynamic model of a magnetically-driven UHMD to describe its behavior against the flow of blood serum. Then we validate the model using 1-D frequency response characterization and show that it captures the measured linear relationship between the actuation frequency and propulsive thrust at various flow fields. We find that a region of asymptotic stability can be achieved around an equilibrium point allowing a 6-mm-long UHMD to overcome maximum volumetric flow field of 1.2 l/hr (i.e., 2.65 cm/s).

A high-fat diet (HFD) animal model has an indispensable role in the research of gut-liver axis by generating an imbalance of gut microbiota and intestinal leakage, resulting in translocation of harmful bacterial metabolites and lipopolysaccharides (LPSs) to the liver, triggering immune responses, and stimulating non-alcoholic steatohepatitis (NASH). Replacing trans-fat with palm oil in HFDs is an emerging animal model with human translatability in terms of liver biopsy phenotype and transcriptome changes. We developed the NASH and fibrosis mouse model using a palm oil-containing high-fat diet (P-HFD) combined with LPS to simulate gut dysbiosis and endotoxemia and examined the role of carbon tetrachloride (CCl4) on the gut-liver axis. The mice were fed P-HFD with or without intraperitoneal LPS/CCl4 injections. NASH/fibrosis progression and gut microbiota shift were examined at 4, 8, 12, 16, 20, and 24 weeks (n = 192). The P-HFD animal model showed obesogenic and metabolic changes, hepatomegaly, NASH phenotype, increased gut dysbiosis, changes in gut microbiota and its function, reduced beneficial bacteria, increased pathogenic related microbiome, intestinal leakage, and endotoxemia. P-HFD with LPS supplementation resulted in comparable NASH phenotypes compared with the P-HFD group, but worsened the degree of intestinal microbiota dysbiosis by increasing the occurrence of pathogenic bacteria and reducing beneficial microbiota. P-HFD with CCl4 resulted in a liver fibrosis phenotype and produced a more severe gut microbiota shift. These mouse models could be informative for a researcher focused on the gut-liver axis and could be used as valuable tool for preclinical drug testing.

Previous studies showed a sequence encoding an auxiliary protein (PlaS) downstream of the phospholipase A1 (PlaA1) gene of Serratia marcescens. There is an interaction between PlaA1 and PlaS, which may be closely related to the high enzymatic activity property of phospholipase A1. In order to further investigate the interaction mechanism, it is necessary to explore binding sites of the interaction between PlaA1 and PlaS and the regulatory mechanism for enzymatic properties by molecular docking and site-directed mutagenesis. The results showed that the active center site of PlaA1 was encapsulated internally, and a “catalytic pocket” was formed externally by Leu197-Ser249. The docking process of PlaA1 and PlaS involved 29 and 30 amino acids, respectively, of which Phe186 and Lys238 of PlaA1 are involved in forming π-bonds and multiple hydrogen bonds. Therefore, Phe186 and Lys238 were site-directed mutated to Ala to obtain the mutant enzymes PlaA1 and PlaA1 , respectively. The results showed that the mutant enzymes showed no significant changes in optimum temperature and pH but poor stability. The kinetic parameters indicated that the affinity between PlaA1 and substrates was weakened, and the catalytic efficiency was reduced after mutation. Therefore, it demonstrated that Phe186 and Lys238 of PlaA1 provided non-covalent bonds conducive to the enzymatic activity and stability in the interaction between PlaA1 and PlaS, which would provide some theoretical basis for further rational design and modification of phospholipase A1 subsequently.

Antibiotics used as growth promoters in livestock and animal husbandry can be detected in animal-derived food. Epidemiological studies have implicated that exposure to these antibiotic residues in food may be associated to childhood obesity. Herein, the effect of exposure to residual dose of tylosin—an antibiotic growth promoter—on host metabolism and gut microbiota was explored in vivo. Theoretical maximal daily intake (TMDI) doses of tylosin were found to facilitate high-fat diet-induced obesity, induce insulin resistance, and perturb the composition of gut microbiota in mice. The obesity-related phenotypes were transferrable to germ-free recipient mice, indicating that the effects of TMDI dose of tylosin on obesity and insulin resistance occurred mainly via alteration of the gut microbiota. Tylosin TMDI exposure restricted to early life, which is the critical period of gut microbiota development, altered the abundance of specific bacteria related to host metabolic homeostasis later in life. Moreover, early-life exposure to tylosin TMDI was sufficient to modify the ratio of primary to secondary bile acids, thereby inducing lasting metabolic consequences via the downstream FGF15 signaling pathway. Altogether, these findings demonstrate that exposure to very low dose of antibiotic residues, whether continuously or in early life, can exert long-lasting effects on host metabolism by altering gut microbiota and its metabolites.ImportanceEvidence has indicated that chronic exposure to antibiotic residues in food could contribute to obesity. However, few studies have investigated the effect of chronic exposure to very low-dose antibiotic residue in food (~1000-fold lower than the therapeutic dose) on gut microbiota and host metabolism. Our study demonstrates that even with limited exposure in early life, a residual dose of tylosin causes lasting metabolic disturbances through altering gut microbiota and its metabolites. Our findings reveal that the gut microbiota is susceptible to previously ignored environmental factors.

Animal models of non-alcoholic steatohepatitis (NASH) and liver fibrosis are essential for preclinical research of novel drugs. A high-fat diet (HFD) animal model has an indispensable role in the research of gut-liver axis by generating an imbalance of gut microbiota and intestinal leakage, resulting in translocation of harmful bacterial metabolites and lipopolysaccharides (LPSs) to the liver, triggering hepatic immune responses, and stimulating NASH and liver fibrosis. Replacing trans-fat with palm oil in HFDs is an emerging animal model with human translatability in terms of liver biopsy phenotype and transcriptome changes. We developed the NASH and fibrosis C57BL/6J mouse model using a palm oil-containing high-fat diet (P-HFD) combined with LPS to simulate gut dysbiosis and endotoxemia and examined the role of carbon tetrachloride (CCl4) on the gut-liver axis. We developed the mouse models, and the mice were fed P-HFD with or without intraperitoneal LPS/CCl4 injections. NASH/fibrosis progression and gut microbiota shift were examined at 4, 8, 12, 16, 20, and 24 weeks (n=192). The animal model showed obesogenic and metabolic changes, hepatomegaly, increased hepatic lipid levels, NASH phenotype, increased gut dysbiosis, changes in gut microbiota and its function, reduced beneficial bacteria, increased pathogenic related microbiome, intestinal leakage, and endotoxemia. P-HFD with LPS supplementation resulted in comparable NASH, intestinal leakage, and endotoxemia phenotypes compared with the P-HFD group, but worsened the degree of intestinal microbiota dysbiosis by increasing the occurrence of pathogenic bacteria and reducing beneficial microbiota. P-HFD with CCl4 resulted in a liver fibrosis phenotype and produced a more severe gut microbiota shift. These mouse models could be informative for a researcher focused on the gut-liver axis and could be used as valuable tool for preclinical drug testing.

IntroductionMushroom-forming fungi comprise diverse species that develop complex multicellular structures. In cultivated species, both ecological adaptation and artificial selection have driven genome evolution. However, little is known about the connections among genotype, phenotype and adaptation in mushroom-forming fungi.ObjectivesThis study aimed to (1) uncover the population structure and demographic history of Lentinula edodes, (2) dissect the genetic basis of adaptive evolution in L. edodes, and (3) determine if genes related to fruiting body development are involved in adaptive evolution.MethodsWe analyzed genomes and fruiting body-related traits (FBRTs) in 133 L. edodes strains and conducted RNA-seq analysis of fruiting body development in the YS69 strain. Combined methods of genomic scan for divergence, genome-wide association studies (GWAS), and RNA-seq were used to dissect the genetic basis of adaptive evolution.ResultsWe detected three distinct subgroups of L. edodes via single nucleotide polymorphisms, which showed robust phenotypic and temperature response differentiation and correlation with geographical distribution. Demographic history inference suggests that the subgroups diverged 36,871 generations ago. Moreover, L. edodes cultivars in China may have originated from the vicinity of Northeast China. A total of 942 genes were found to be related to genetic divergence by genomic scan, and 719 genes were identified to be candidates underlying FBRTs by GWAS. Integrating results of genomic scan and GWAS, 80 genes were detected to be related to phenotypic differentiation. A total of 364 genes related to fruiting body development were involved in genetic divergence and phenotypic differentiation.ConclusionAdaptation to the local environment, especially temperature, triggered genetic divergence and phenotypic differentiation of L. edodes. A general model for genetic divergence and phenotypic differentiation during adaptive evolution in L. edodes, which involves in signal perception and transduction, transcriptional regulation, and fruiting body morphogenesis, was also integrated here.

We investigated the structural, vibrational, and electrical transport properties for natural barite under the conditions of 298–873 K and 1.5–35.0 GPa using a diamond anvil cell by virtue of Raman spectroscopy and electrical conductivity measurements. Upon compression, natural barite transformed into post-barite at 18.9 GPa and atmospheric temperature, which was evidenced by the emergence of υ5 Raman peak, the discontinuities in the pressure-dependent Raman shifts, FWHM of υ1 Raman peak and electrical conductivity under non-hydrostatic condition. The phase transition is of good reversibility, whereas a considerable pressure hysteresis was detected during the process of decompression. Under quasi-hydrostatic condition, the structural transition of natural barite occurred at a higher pressure of 21.4 GPa, which is possibly related to the influence of deviatoric stress. Furthermore, our high-temperature and high-pressure Raman spectra and electrical conductivity results for natural barite revealed that the phase transformation pressures decreased as temperatures enhanced and further, the phase boundary between barite and post-barite was described as P (GPa) = 24.00–0.0166 T (K). Our obtained phase diagram of natural barite can improve the knowledge about the structural and electrical properties for other barite-group minerals MSO4 (M = Sr and Pb) under high temperature and high pressure conditions.

Anhedonia is the core symptom of depression, which largely reflects the therapeutic effect of depression. Hypericum perforatum is one of the most important antidepressant herb that has fewer side effects than traditional antidepressants. Considering the antibacterial effect of Hypericum perforatum, we verified whether this antidepressant activity was related to intestinal microbiomics. So we established anhedonia mouse model to explore the underlying treatment mechanism of hyperforin, the key antidepressant ingredient of Hypericum perforatum and to screen new psychobiotics based on hyperforin. It was found that hyperforin prevented anhedonia induced by chronic restraint stress in mice and altered the richness and evenness of bacteria populations compared with stressed mice. Metastat analysis showed that Akkermansia muciniphila and Muribaculum intestinale were the bacterial species obviously affected by hyperforin, and their abundance in hyperforin-treated group significantly increased. The results suggest that the effect of hyperforin on anhedonia may be partly assisted by Akkermansia muciniphila. These also indicate that Muribaculum intestinale may be another important intestinal bacteria involved in the pathogenesis of anhedonia symptom and depression.

In the recent work~\cite{Wang:2021p2}, the author proposed the expanded Maxwell's equations for moving charged media system, which seems subtle. Considering a very short time, we can approximately define the inertial frame of reference. If we assume all the physical quantities are defined in the same reference frame by default, Maxwell's equations for the static media system and moving media system are definitely the traditional Maxwell's equations, which are covariant and consistent with the two fundamental postulates of special relativity. We even prove the covariance of Maxwell's equations explicitly by considering the Lorentz transformation under the ${\cal O} (v)$ order approximation and the Galileo approximation, respectively. Therefore, it seems to us that the fields in the expanded Maxwell's equations cannot be in the same reference frame. Defining the fields in the lab and co-moving frames explicitly, we derive the expanded Maxwell's equations for moving media system. Furthermore, we discuss another possible variant of Maxwell's equations, which has an additional coefficient $\alpha$ related to the media. However, it is still subtle from theoretical point of view., Comment: 14 pages

Bacteroides fragilis (BF) plays a critical role in developing and maintaining the mammalian immune system. We previously found that BF colonization could prevent inflammation and tumor formation in a germ-free (GF) colitis-associated colorectal cancer (CAC) mouse model. The role of Toll-like receptor 4 (TLR4) in CAC development has not been clearly elucidated in BF mono-colonized gnotobiotic mice. The wild-type (WT) and TLR4 knockout (T4K) germ-free mice were raised with or without BF colonization for 28 days (GF/WT, GF/T4K, BF/WT, and BF/T4K) and then CAC was induced under azoxymethane (AOM)/dextran sulfate sodium (DSS) administration. The results showed that tumor formation and tumor incidence were significantly inhibited in the BF/WT group compared to those observed in the GF/WT group. However, the tumor prevention effect was not observed in the BF/T4K group unlike in the BF/WT group. Moreover, the CAC histological severity of the BF/WT group was ameliorated, but more severe lesions were found in the GF/WT, GF/T4K, and BF/T4K groups. Immunohistochemistry showed decreased cell proliferation (PCNA, β-catenin) and inflammatory markers (iNOS) in the BF/WT group compared to those in the BF/T4K group. Taken together, BF mono-colonization of GF mice might prevent CAC via the TLR4 signal pathway.

N-Alkenoxypyridinium salts were found to be highly active electrophilic reagents that could be used to activate the C-N bond of amides. Both aromatic amides and aliphatic amides could be transformed into the corresponding β-oxo esters with good yields via the combined use of N-alkenoxypyridinium salts and water. The methodology proceeds under mild reaction conditions and is tolerant of various functional groups in both reaction partners.

In this study, a Petri-dish-based double-layer high-throughput screening method was established to improve glucose tolerance of β-glucosidase Bgl15. Two beneficial mutations were identified, and the joint mutant 2R1 improved the half-maximal inhibitory concentration of glucose from 0.04 to 2.1 M. The crystal structure of 2R1 was subsequently determined at 2.7 Å. Structure analysis revealed that enhancement of glucose tolerance may be due to improved transglycosylation activity made possible by a hydrophobic binding site for glucose as an acceptor and more stringent control of a putative water channel. To further ameliorate the application potential of the enzyme, it was engineered to increase the half-life at 50 °C from 0.8 h (Bgl15) to 180 h (mutant 5R1). Furthermore, supplementation of 5R1 to the cellulase cocktail significantly improved glucose production from pretreated sugar cane bagasse by 38%. Consequently, this study provided an efficient approach to enhance glucose tolerance and generated a promising catalyst for cellulose saccharification.

A mathematical model of optimization for cargo hold structure of small and medium-sized duplex stainless steel (DSS) chemical tankers based on the rule is described. The weight of DSS is defined as the objective function. The explicit formulas of the relevant rules, the explicit geometric relations formed by the structural arrangement and the implicit constraints such as layout, lines, expert experience, workmanship and so on are taken as the constraints. The design variables and the algorithm are determined by analyzing the logical relations among the factors. Besides, the efficiency of the optimum algorithm is improved by utilizing the distribution law of the optimal corrugations. Finally, the comprehensive optimization of the cargo hold DSS is accomplished by C++ programming. The weight of the optimized scheme of the example is 4.93% lower than that of the original scheme. The finite element analysis results show that the optimized scheme is satisfied with the requirements of the rules and has a good structure performance. The optimization method based on the rules and accomplished by the programming is practical for structural preliminary design.

Graphical abstract, Towards clinical translation of cancer nanomedicine, it is important to systematically investigate the various parameters related to nanoparticle (NP) physicochemical properties, tumor characteristics, and inter-individual variability that affect the tumor delivery efficiency of therapeutic nanomaterials. Comprehensive investigation of these parameters using traditional experimental approaches is impractical due to the vast parameter space; mathematical models provide a more tractable approach to navigate through such a multidimensional space. To this end, we have developed a predictive mathematical model of whole-body NP pharmacokinetics and their tumor delivery in vivo, and have conducted local and global sensitivity analyses to identify the factors that result in low tumor delivery efficiency and high off-target accumulation of NPs. Our analyses reveal that NP degradation rate, tumor blood viscosity, NP size, tumor vascular fraction, and tumor vascular porosity are the key parameters in governing NP kinetics in the tumor interstitium. The impact of these parameters on tumor delivery efficiency of NPs is discussed, and optimal values for maximizing NP delivery are presented.

In a parallel distributed generation system, the conventional droop control strategy makes it difficult for the inverter to output reactive power precisely due to the line impedance uncertainty and load fluctuation, which leads to a voltage deviation of the microgrid system. In order to precisely distribute reactive power, this paper advances an adaptive compensation strategy based on fuzzy control. The fuzzy controller detects the load power of AC bus terminal and output adaptive power coefficient to adjust amplitude voltage to generate compensation voltage. The compensation voltage is fed back to the d-axis voltage of the power loop for reactive power redistribution. Because the fuzzy control membership function value is difficult to determine accurately, this paper puts forward a method which combines neural network with fuzzy control to determine membership function values and fuzzy rules. Simulations and experimental results show that the adaptive compensation control strategy can share power accurately with good dynamic characteristics and robustness.

Antibiotics used as growth promoters in livestock and animal husbandry can be detected in animal-derived food. Epidemiological studies have implicated that exposure to these antibiotic residues in food may be associated to childhood obesity. Herein, the effect of exposure to residual dose of tylosin—an antibiotic growth promoter—on host metabolism and gut microbiota was explored in vivo. Theoretical maximal daily intake (TMDI) doses of tylosin were found to facilitate high-fat diet-induced obesity, induce insulin resistance, and perturb the composition of gut microbiota in mice. The obesity-related phenotypes were transferrable to germ-free recipient mice, indicating that the effects of TMDI dose of tylosin on obesity and insulin resistance occurred mainly via alteration of the gut microbiota. Tylosin TMDI exposure restricted to early life, which is the critical period of gut microbiota development, altered the abundance of specific bacteria related to host metabolic homeostasis later in life. Moreover, early-life exposure to tylosin TMDI was sufficient to modify the ratio of primary to secondary bile acids, thereby inducing lasting metabolic consequences via the downstream FGF15 signaling pathway. Altogether, these findings demonstrate that exposure to very low dose of antibiotic residues, whether continuously or in early life, can exert long-lasting effects on host metabolism by altering gut microbiota and its metabolites. Importance Evidence has indicated that chronic exposure to antibiotic residues in food could contribute to obesity. However, few studies have investigated the effect of chronic exposure to very low-dose antibiotic residue in food (~1000-fold lower than the therapeutic dose) on gut microbiota and host metabolism. Our study demonstrates that even with limited exposure in early life, a residual dose of tylosin causes lasting metabolic disturbances through altering gut microbiota and its metabolites. Our findings reveal that the gut microbiota is susceptible to previously ignored environmental factors.

Background: Atrial fibrillation (AF) is the most common type of arrhythmia. AF is more common in the elderly population than in the young population. Radiofrequency ablation (RA) is the treatment option for drug-naïve AF; however, previous studies have focused on the young population. Therefore, it would be clinically valuable to compare the efficacy and safety of RA in both elderly and young patients with AF. Objective: This study intended to compare the efficacy and safety of RA in elderly and young patients with AF. Methods: Forty patients with drug-naïve AF who underwent RA at our hospital were retrospectively evaluated, of whom 20 were < 65 years old (group 1) and 20 were ≥ 65 years old (group 2). The treatment efficacy was evaluated by comparing the durations of the surgical procedures, the postoperative platelet activation, and the inflammatory factor levels. Results: The total operation times for RA (160.64 ± 7.25 vs. 160.64 ± 7.25 min, P = 0.341) and the fluoroscopy times (40.82 ± 5.93 vs. 39.89 ± 6.35 min, P = 0.636) did not differ between the elderly (74.1 ± 6.7 years) and the young (54.6 ± 7.9 years) groups. The postoperative platelet activation levels (6.90% ± 0.64% vs. 6.90% ± 0.70%, P = 0.991), the P-selectin expression levels (4.5 ± 1.3 vs. 4.9 ± 1.3, P = 0.333) and the activated glycoprotein IIb/IIIa (0.5 ± 1.0 vs. 0.4 ± 1.1, P = 0.649), and the inflammatory factor levels (C-reactive protein: 26.45 ± 6.66 vs. 25.72 ± 7.78 mg/L, P = 0.750) were elevated in both groups but did not differ between the two groups. Conclusion: RA is a safe and effective procedure in elderly and young patients with medically refractory AF.

Cardiovascular disease (CVD) is strongly associated with the gut microbiota and its metabolites, including trimethylamine-N-oxide (TMAO), formed from metaorganismal metabolism of ʟ-carnitine. Raw garlic juice, with allicin as its primary compound, exhibits considerable effects on the gut microbiota. This study validated the benefits of raw garlic juice against CVD risk via modulation of the gut microbiota and its metabolites. Allicin supplementation significantly decreased serum TMAO in ʟ-carnitine-fed C57BL/6 J mice, reduced aortic lesions, and altered the fecal microbiota in carnitine-induced, atherosclerosis-prone, apolipoprotein E-deficient (ApoE−/−) mice. In human subjects exhibiting high-TMAO production, raw garlic juice intake for a week reduced TMAO formation, improved gut microbial diversity, and increased the relative abundances of beneficial bacteria. In in vitro and ex vivo studies, raw garlic juice and allicin inhibited γ-butyrobetaine (γBB) and trimethylamine production by the gut microbiota. Thus, raw garlic juice and allicin can potentially prevent cardiovascular disease by decreasing TMAO production via gut microbiota modulation.

Stropharia rugosoannulata is a popular edible mushroom. In October 2020, white mold disease was found on substrates of S. rugosoannulata in a heliogreenhouse in Huai’an city, Jiangsu province, China. The cultivation materials included rice straw (30%), wheat straw (30%), saw dust (30%), and a small amount of wheat bran (5%) and rice bran (5%). In the diseased substrates, a large amount of thick white fungal mycelia was observed with yellow ooze on the surface, which prevented the growth of the mycelia and fruiting bodies of S. rugosoannulata. Disease incidence was calculated as ∼30%. The fungus was identified morphologically and through DNA as Mucor irregularis, and pathogenicity was confirmed. In order to ensure the safe production of S. rugosoannulata, once white mold disease is found, the infected tissue should be removed. This is the first report that M. irregularis causes white mold disease on S. rugosoannulata in China.

Atherosclerosis is the main cause of cardiac and peripheral vessel infarction in developed countries. Recent studies have established that gut microbiota and their metabolites play important roles in the development and progression of cardiovascular disease; however, the underlying mechanisms remain unclear. The present study aimed to investigate endothelium plaque lesion formation in ApoE-deficient rats fed a normal chow diet under germ-free (GF) and specific-pathogen-free (SPF) conditions at various time points. There was no difference in serum cholesterol and triglyceride levels between SPF-rats and GF-rats. Histological studies revealed that the GF-rats developed endothelium plaques in the aorta from 26 to 52 weeks, but this was not observed in SPF-rats. GF-rat coronary arteries had moderate-to-severe endothelium lesions during this time period, but SPF-rat coronary arteries had only mild lesion formation. Immunohistochemical staining showed higher accumulation of CD68-positive and arginase-negative foamy-like macrophages on the arterial walls of GF-rats, and expression of TNF-α and IL-6 in foam cells was only observed in GF-rats. In addition, microbial metabolites, including equol derivatives, enterolactone derivatives, indole-3-propionate, indole-3-acrylic acid, cholic acid, hippuric acid, and isoquinolone, were significantly higher in the SPF group than in the GF group. In conclusion, our results indicate that gut microbiota may attenuate atherosclerosis development.

Simple Summary ALDH2, mitochondrial aldehyde dehydrogenase 2, is a critical enzyme involved in ethanol clearance in acetaldehyde metabolism. The prevalence of the ALDH2*2 variant is 45% in the Taiwanese population. ALDH2 reportedly has protective properties on myocardial damage, stroke, and diabetic retina damage. However, the effects of ALDH2 in modulation of metabolic syndromes remain unclear. The study evaluated the roles of ALDH2 in a high-fat-diet-induced metabolic syndrome in mice. We explored the effects of ALDH2 gene on NAFLD and potential association with gut microbiota. Abstract Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a critical enzyme involved in ethanol clearance in acetaldehyde metabolism and plays a key role in protecting the liver. The ALDH2*2 mutation causes a significant decrease in acetaldehyde scavenging capacity, leading to the accumulation of acetaldehyde after consuming alcohol. The prevalence of the ALDH2*2 variant is in 45% of Taiwanese individuals. ALDH2 reportedly has protective properties on myocardial damage, stroke, and diabetic retina damage. However, the effects of ALDH2 in the modulation of metabolic syndromes remain unclear. This study evaluates the roles of ALDH2 in a high-fat-diet-induced metabolic syndrome in mice. Male (M) and female (F) wild-type (WT) and ALDH2 knock-in C57BL/6J mice (4–5 weeks old) were fed a high-fat diet for 16 weeks. Results showed that the body and white-adipose-tissue weights were significantly increased in ALDH2-M compared to those in the other groups. We observed markedly elevated serum levels of alanine transaminase and glucose. Oral glucose-tolerance test and homeostasis-model assessment of insulin resistance (HOMA-IR) values were significantly higher in ALDH2-M mice than those in WT-M mice, with no observable differences in female mice. Abundant steatosis and inflammatory cells were observed in ALDH2-M, with significantly decreased expression of hepatic genes IRS2, GLUT4, and PGC-1α compared to that in WT-M. ALDH2 gene mutation also affected the β-diversity of gut microbiota in ALDH2-M resulting in the decreased abundance of Actinobacteria and an increase in Deferribacteres. Our results suggest that potential changes in gut microbiota may be associated with the defective ALDH2 exacerbation of high-fat-diet-induced liver diseases in male mice. However, female mice were not affected, and sex hormones may be an important factor that requires further investigation.

The progression of metabolic dysfunction associated fatty liver disease (MAFLD) leads to steatohepatitis, liver fibrosis and hepatocellular carcinoma. Thus far, there have been no FDA-approved medications for MAFLD. Bariatric surgery (BS) has been found to improve insulin resistance, steatohepatitis and liver fibrosis but is not recommended for treating MAFLD due to its invasiveness. Recent studies suggest the improved glucose metabolism after BS is a result of, at least partly, alterations to the gut microbiota and its associated metabolites, including short chain fatty acids and bile acids. It makes sense the improved steatohepatitis and fibrosis after BS are also induced by the gut microbiota that involves in host metabolic modulation, for example, through altering bile acids composition. Given that the gut–liver axis is a path that may harbor unexplored mechanisms behind MAFLD, we review current literatures about disentangling the metabolic benefits of MAFLD after BS, with a focus on gut microbiota. Some useful research tools including the rodent BS model, the multiomics approach, and the human microbiota associated (HMA) mice are presented and discussed. We believe, by taking advantage of these modern translational tools, researchers will uncover microbiota related pathways to serve as potential therapeutic targets for treating MAFLD.

There are ongoing interests in improving the galactooligosaccharide (GOS) synthesis efficiency of β-galactosidase by protein engineering. In this study, an intelligent double-hydrophobic amino acid scanning strategy was proposed and employed to target nine residues forming the glycon-binding site (-1 subsite) of β-galactosidase Bgal1-3. Two mutants C510V and H512I with significantly improved GOS synthesis efficiency were obtained. When 40% (w/v) lactose was used as a substrate, Bgal1-3 reached a maximum GOS yield of 45.3% at 16 h, while the mutants reached higher yields in a much shorter time (59.1% at 10 h for C510V, 51.5% at 2 h for H512I). When skim milk was treated with these enzymes, more GOS was produced (19.9 g/L for C510V, 12.7 g/L for H512I) than that for Bgal1-3 (10.3 g/L) at a lactose conversion of 90%. These results validated hydrophobicity scanning as an efficient method to engineer β-galactosidases into promising catalysts for the preparation of GOS and GOS-enriched milk.

Myocardial hypertrophy is an important cause of heart failure and sudden death. Studies have shown that Mitofusin-2 (MFN2) is downregulated in myocardial hypertrophy, but the upstream regulation mechanism underlying its downexpression in cardiomyocytes is still unclear. This study aims to identify the expression profile of microRNAs (miRNAs) in hypertrophic cardiomyopathy (HCM) and explore the function of miRNA-20 in inducing cardiomyocyte hypertrophy through regulating MFN2. Through miRNA + mRNA microarray analysis, 1451 miRNAs were identified, 367 miRNAs expressed differently between groups. Meanwhile, a number of 24,718 mRNAs were identified, among which 5850 mRNAs were upregulated and 3005 mRNAs were downregulated in HCM group compared with the control group. Expression of hsa-miRNA-20a-5p was 2.26 times higher in the HCM group compared with the control group and 7 target gene prediction programs predicted MFN2 as a target of miRNA-20. In vitro model of hypertrophic cardiomyocytes displayed high expression level of miRNA-20, atrial natriuretic peptide (ANP) mRNA, and protein, accompanying low expression level of Mfn2 mRNA and protein, which meant miRNA-20 played a role in cardiomyocyte hypertrophy and might interact with MFN2 to function. Thereafter, overexpression of miRNA-20 led to cell hypertrophy accompanied with lowly expressed Mfn2 mRNA and protein. When transfected with miRNA-20 inhibitors, the expression of miRNA-20 and ANP gene was attenuated and MFN2 was the other way around. The cell surface area of Ang II group and mimic group was significantly larger compared with the control group, and in the inhibitor+Ang II group, the area was significantly decreased compared with the Ang II group. Dual-luciferase assays showed that miRNA-20 bound to 3' untranslated region of MFN2 and inhibited its expression. In conclusion, hypertrophic myocardium and normal myocardium have different miRNA expression profiles and the effect of miRNA-20 reducing the expression of MFN2 plays a role in promoting cardiomyocyte hypertrophy.

LiFePO4/C cathode material was prepared via high-temperature ball-milling route with ultrasonic dispersion as mixing process using eutectic molten salt (0.76 LiOH·H2O-0.24 Li2CO3) as lithium source. Box-Behnken design was used to study the combined effects of ultrasonic time, ball-milling temperature, and ball-milling time on the discharge capacity to obtain the optimum predicted conditions. The optimum conditions were as follows: ultrasonic time was 63 min, ball-milling temperature was 638 °C, and ball-milling time was 7 h. LiFePO4/C prepared from the optimized experimental conditions exhibited a well electrochemical performance; its discharge capacity was 161.3 mAh g−1 at a 0.1 C-rate which was in consistence with the predicted discharge capacity of 160.2 mAh g−1. Moreover, its capacity retention rate achieved 93.6% at a 10 C-rate over 100 cycles.

The human adaptive immune response is known to weaken in advanced age, resulting in increased severity of pathogen-born illness, poor vaccine efficacy, and a higher prevalence of cancer in the elderly. Age-related erosion of the T cell compartment has been implicated as a likely cause, but the underlying mechanisms driving this immunosenescence have not been quantitatively modeled and systematically analyzed. T cell receptor diversity, or the extent of pathogen-derived antigen responsiveness of the T cell pool, is known to diminish with age, but inherent experimental difficulties preclude accurate analysis on the full organismal level. In this paper, we formulate a mechanistic mathematical model of T cell population dynamics on the immunoclonal subpopulation level, which provides quantitative estimates of diversity. We define different estimates for diversity that depend on the individual number of cells in a specific immunoclone. We show that diversity decreases with age primarily due to diminished thymic output of new T cells and the resulting overall loss of small immunoclones.

Background: Essential hypertension (EH) is a chronic disease of universal high prevalence and a well-established independent risk factor for cardiovascular and cerebrovascular events. The regulation of blood pressure is crucial for improving life quality and prognoses in patients with EH. Therefore, it is of important clinical significance to develop prediction models to recognize individuals with high risk for EH. Methods: In total, 965 subjects were recruited. Clinical parameters and genetic information, namely EH related SNPs were collected for each individual. Traditional statistic methods such as t-test, chi-square test and multi-variable logistic regression were applied to analyze baseline information. A machine learning method, mainly support vector machine (SVM), was adopted for the development of the present prediction models for EH. Results: Two models were constructed for prediction of systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively. The model for SBP consists of 6 environmental factors (age, BMI, waist circumference, exercise [times per week], parental history of hypertension [either or both]) and 1 SNP (rs7305099); model for DBP consists of 6 environmental factors (weight, drinking, exercise [times per week], TG, parental history of hypertension [either and both]) and 3 SNPs (rs5193, rs7305099, rs3889728). AUC are 0.673 and 0.817 for SBP and DBP model, respectively. Conclusions: The present study identified environmental and genetic risk factors for EH in northern Han Chinese population and constructed prediction models for SBP and DBP.

Yao-Wang Zhao,1 Da Guo,2 Chuang-Ye Li,1 Jian-Ming Ouyang21Department of Urology, Hunan Children’s Hospital, Changsha 410007, People’s Republic of China; 2Institute of Biomineralization and Lithiasis Research, Jinan University, Guangzhou 510632, People’s Republic of ChinaBackground: Kidney stone formation is closely related to renal epithelial cell damage and the adhesion of calcium oxalate crystals to cells.Methods: In this research, the adhesion of human kidney proximal tubular epithelial cells (HK-2) to calcium oxalate monohydrate crystals with a size of approximately 100 nm was studied. In addition, the inhibition of crystal adhesion by four tea polysaccharides (TPS0, TPS1, TPS2, and TPS3) with the molecular weights of 10.88, 8.16, 4.82, and 2.31 kDa, respectively were compared.Results: When oxalic acid-damaged HK-2 cells were repaired, cell viability increased. By contrast, reactive oxygen species level, phosphatidylserine eversion, and osteopontin expression decreased, thus indicating that tea polysaccharides have a repairing effect on damaged HK-2 cells. Moreover, after repairing the damaged cells, the amount of adherent crystals was reduced. The repair effect of tea polysaccharides is closely related to molecular weight, and TPS2 with the moderate molecular weight displayed the best repair effect.Conclusion: These results suggest that tea polysaccharides, especially TPS2, may inhibit the formation and recurrence of calcium oxalate kidney stones.Keywords: tea polysaccharide, kidney stone, crystal adhesion, molecular weight &nbsp

Background Sphingosine kinase 1 (SPHK1) is an enzyme that converts pro-apoptotic ceramide and sphingosine into anti-apoptotic sphingosine-1-phosphate. There is growing evidence that SPHK1 activation promotes oncogenic transformation, tumor growth, chemotherapy resistance, and metastatic spread. High SPHK1 expression has been associated with a poor prognosis in several human cancers. Results In the present study, the expression level of SPHK1 was examined in feline mammary tumor (FMT) specimens, and the IHC expression level of SPHK1 was associated with the histological grade of FMTs. IHC analysis of 88 FMT cases revealed that the expression level of SPHK1 was upregulated in 53 tumor tissues (60.2%) compared to adjacent mammary tissues. SPHK1 expression in FMTs was significantly associated with histological grade, presence of lymphovascular invasion, and estrogen receptor negativity. Treatment of primary FMT cells with SPHK1 inhibitors reduced cell viability, indicating that SPHK1 acts to promote FMT cell survival. These results indicate that SPHK1 may play an important role in FMTs and may be a therapeutic target in cats with FMT. Conclusions SPHK1 over-expression in breast cancer tissues is associated with a poor prognosis in humans. SPHK1 over-expression in more aggressive FMTs provides support for a potential role of SPHK1 inhibitors for the treatment of FMTs. Targeting SPHK1 has potent cytotoxic effects in primary FMT cells. These findings suggest that further examination of the role SPHK1 plays in FMTs will pave the way for the investigation of SPHK1 inhibitors in future clinical applications. Electronic supplementary material The online version of this article (10.1186/s12917-019-1883-z) contains supplementary material, which is available to authorized users.

Objective: The objective of the study was to evaluate computed tomography (CT)-guided 125I implantation for the treatment of recurrent and malignant pelvic tumors. Materials and Methods: Fifteen cases of pelvic malignant tumors were studied. Tumor length/diameter was 4–10 cm (average: 6.8 ± 2.3 cm). In patients with pelvic recurrence or metastasis of malignant tumors, comprehensive treatment, including surgery, chemotherapy, or radiotherapy, was performed alongside CT-guided 125I implantation. The follow-up clinical benefit rate, rate of pain relief, quality of life score, and status of any complications were analyzed. Results: The patients were followed up for 6 months after the operation, and evaluation of lesions revealed complete response (CR) in 3/15 cases, partial response (PR) in 8/15 cases, stable disease in 3/15 cases, and progressive disease in 1/15 cases. The total effective rate (CR + PR) was 73.3% (11/15), and the pain relief rate was 86.6% (13/15). No bleeding, pelvic abscesses, intestinal fistulas, intestinal perforations, or other complications were reported. Conclusions: When using CT-guided 125I implantation, patients with malignant abdominal tumors undergo a convenient operation, sustain little trauma, and have an improved quality of life.

Maleic anhydride was used to functionalize the graphene oxide (GO). The prepared functionalized GO was used to modify the bismaleimide (BMI) resin and the carbon fiber/BMI composites. The structure and properties of the composites were characterized. The results indicate that the maleic anhydride molecules are successfully grafted onto the GO surfaces. Due to the introduction of functionalized GO, the tensile strength, elastic modulus, blending strength, impact strength and glass transition temperature of the BMI resin were substantially improved. The impact fracture morphologies show that brittle fracture is transformed into ductile fracture after modification; moreover, the interfacial adhesions of carbon fiber/BMI composites were also enhanced obviously. The ILSS of composites increased from 84.0MPa to 104.6MPa after modification.

A high-performance β-glucosidase for efficient cellulose hydrolysis needs to excel in thermostability, catalytic efficiency, and resistance to glucose inhibition. However, it is challenging to achieve superb properties in all three aspects in a single enzyme. In this study, a hyperactive and glucose-tolerant β-glucosidase Ks5A7 was employed as the starting point. Four rounds of random mutagenesis were then performed, giving rise to a thermostable mutant 4R1 with five amino acid substitutions. The half-life of 4R1 at 50 °C is 8640-fold that of Ks5A7 (144 h vs 1 min). Meanwhile, 4R1 had a higher specific activity (374.26 vs 243.18 units·mg–1) than the wild type with a similar glucose tolerance. When supplemented to Celluclast 1.5L, the mutant significantly enhanced the hydrolysis of pretreated sugar cane bagasse, improving the released glucose concentration by 44%. With excellent performance in thermostability, activity, and glucose tolerance, 4R1 will serve as an exceptional catalyst for industrial applica...

Widespread utilization of polyethylene terephthalate (PET) has caused critical environmental pollution. The enzymatic degradation of PET is a promising solution to this problem. In this study, PETase, which exhibits much higher PET-hydrolytic activity than other enzymes, was successfully secreted into extracellular milieu from Bacillus subtilis 168 under the direction of its native signal peptide (named SPPETase). SPPETase is predicted to be a twin-arginine signal peptide. Intriguingly, inactivation of twin-arginine translocation (Tat) complexes improved the secretion amount by 3.8-fold, indicating that PETase was exported via Tat-independent pathway. To the best of our knowledge, this is the first report on the improvement of Tat-independent secretion by inactivating Tat components of B. subtilis 168 in LB medium. Furthermore, PET film degradation assay showed that the secreted PETase was fully active. This study paves the first step to construct an efficient engineered strain for PET degradation.

The emerging food additive, xylo-oligosaccharide (XOSs), was prepared through enzymatic hydrolysis of hemicelluloses isolated from press lye. Two of the three experimental enzyme preparations presented favourable effects, while the other one consisting of the nominal enzyme preparations with high enzyme activity was found to have poor catalytic effects. The conversion of xylan exceeded 40% and the selectivity for XOSs reached 90% when the temperature, hemicellulose concentration, dosage of enzymes, and hydrolysis time were 40 °C, 100 g/L, 1 ku/g, and 4 h, respectively. Xylo-oligosaccharide preparation through enzymatic hydrolysis of hemicelluloses isolated from press lye was proved to be a feasible process to utilize the by-product of the lye regeneration, which will substantially improve the economy of the lye regeneration and recycling.Supported by Science and Education Integration Program of Henan University of Technology. Keywords:: Xylo-oligosaccharide, Hemicelluloses, Enzyme, Hydrolysis, Press lye