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BackgroundThe respiratory toxicity of inhaled polyhexamethylene guanidine (PHMG) has been extensively studied since the humidifier disinfectant incident. However, the impacts of inhalation of PHMG on the immune system are not comprehensively studied yet. ObjectiveTo explore the effects of inhalation of PHMG disinfectant aerosol on major immune organs and immune cells in mice. MethodsThirty male C57BL/6J mice (6-8 weeks old) were randomly divided into three groups: control, low-dose (0.1 mg·m−3 PHMG), and high-dose (1.0 mg·m−3 PHMG), with ten mice in each group. The mice were administered by oral-nasal inhalation of PHMG aerosol for 4 h per day, 5 d per week for 4 weeks consecutively. After designed treatment, venous blood was collected from the inner canthus of the eyes of mice and peripheral hematological indicators were measured with a blood analyzer. Then the mice were sacrificed by cervical dislocation and the lung, thymus, spleen, and femur were isolated. Lung, thymus, and spleen were weighed and organ coefficients were calculated, and single cell suspensions of thymus, spleen, and bone marrow were prepared to analyze lymphocytes phenotypes and proportions by flow cytometry. ResultsThe body weight of mice in the high-dose group was lower than that of mice in the control group (P0.05). Leukocyte count [(1.49±0.22)×109·L−1], lymphocyte count [(0.96±0.36)×109·L−1] and its proportion [(63.13±14.96)%] in the peripheral blood of mice in the high-dose group were lower than those in the control group [(2.69±0.25)×109·L−1, (2.33±0.28)×109·L−1, and (86.23±3.40)%, respectively] (P

Sourdough flavors were closely related to microbial metabolism. The microbial diversity of foxtail millet dough during fermentation has never been studied. Here, the metabolic potential and diversity of the bacterial community were analyzed by metagenomic during dough fermentation. Firmicutes was the dominant phylum in the dough, within heterofermentative lactic acid bacteria (e.g., Companilactobacillus, Limosilactobacillus, Pediococcus and Lactobacillus) as the most abundant bacteria. Proteobacteria was gradually inhibited after fermentation. Companilactobacillus_crustorum was notably found abundant during dough leavening. Limosilactobacillus_fermentum increased markedly during fermentation, while Companilactobacillus_crustorum decreased significantly. For further exploration, genes associated with metabolism were annotated through metagenomics. Limosilactobacillus, Companilactobacillus and Pediococcus were actively engaged in glycolysis (ko00010), starch and sucrose metabolism (ko00500), and pyruvate metabolism (ko00620), leading in part to lactic and acetic acid accumulations and dough acidification. Limosilactobacillus and Lactiplantibacillus were the main contributors to key aminopeptidases or/and transaminases involved in amino acid metabolism, which was responsible for flavor metabolite formation. This study will provide an enhanced understanding of the predominance and diversity of dough bacterial communities, and contribute to future strain screening in the dough for better flavor.

Abstract Background Targeting ferroptosis has been identified as a promising approach for the development of cancer therapies. Monounsaturated fatty acid (MUFA) is a type of lipid that plays a crucial role in inhibiting ferroptosis. Ficolin 3 (FCN3) is a component of the complement system, serving as a recognition molecule against pathogens in the lectin pathway. Recent studies have reported that FCN3 demonstrates inhibitory effects on the progression of certain tumors. However, whether FCN3 can modulate lipid metabolism and ferroptosis remains largely unknown. Methods Cell viability, BODIPY-C11 staining, and MDA assay were carried out to detect ferroptosis. Primary hepatocellular carcinoma (HCC) and xenograft models were utilized to investigate the effect of FCN3 on the development of HCC in vivo. A metabonomic analysis was conducted to assess alterations in intracellular and HCC intrahepatic lipid levels. Results Our study elucidates a substantial decrease in the expression of FCN3, a component of the complement system, leads to MUFA accumulation in human HCC specimens and thereby significantly promotes ferroptosis resistance. Overexpression of FCN3 efficiently sensitizes HCC cells to ferroptosis, resulting in the inhibition of the oncogenesis and progression of both primary HCC and subcutaneous HCC xenograft. Mechanistically, FCN3 directly binds to the insulin receptor β (IR-β) and its pro-form (pro-IR), inhibiting pro-IR cleavage and IR-β phosphorylation, ultimately resulting in IR-β inactivation. This inactivation of IR-β suppresses the expression of sterol regulatory element binding protein-1c (SREBP1c), which subsequently suppresses the transcription of genes related to de novo lipogenesis (DNL) and lipid desaturation, and consequently downregulates intracellular MUFA levels. Conclusions These findings uncover a novel regulatory mechanism by which FCN3 enhances the sensitivity of HCC cells to ferroptosis, indicating that targeting FCN3-induced ferroptosis is a promising strategy for HCC treatment.

In order to increase the utilization rate of foxtail millet resources, the brewing conditions of fermented foxtail millet alcoholic beverage were optimized by single-factor experiment and response surface methodology. For the fermentation of the liquor koji, foxtail millet was used as the primary ingredient. As part of the comprehensive evaluation index, which included the soluble solid, total acid, and sensory score, the nutritional value, antioxidant potential, and volatile flavoring compounds were also identified. Results showed that the optimal fermentation conditions of foxtail millet alcoholic beverage were as follows: addition amount of liqueur koji 1%, fermentation time 3 d, fermentation temperature 32 ℃. The soluble solids of the beverage were 22.05%, total acid was 19.33 g/L, sensory score was 89.37, alcohol level of 0.7%vol, flavone was 66.78 mg/L, and polyphenol was 65.13 mg/L. In the beverage, potassium was the most abundant mineral and nicotinamide was the most abundant vitamin. The clearance rates for DPPH radical, ABTS+ radical, and hydroxyl radical were 73.19%, 34.29% and 53.72%, respectively. In addition, a total of 46 volatile flavor compounds were found in the beverage, with esters and alcohols being the most prevalent ones. These molecules were recognized as flavor compounds giving the fermented foxtail millet alcoholic beverage a distinct scent. As a result, the product serves as a theoretical guide for the creation of functional foods using foxtail millet as a raw ingredient. It is nutrient-dense and has a pleasing aroma and flavor.

The utilization of byproducts from foxtail millet polishing can reduce food loss and waste. Thus, it is necessary to know the chemical compounds from the millet and the segregation of the layers. The nutrients including minerals were compared among the husk, bran, and millet, and a LC-MS metabolomics analysis was also performed among them. The results showed that the protein, crude fat and 4 fatty acids, seven minerals, the nitrogen-containing compounds and phenolic acids were at much higher levels in the bran part than the husk and millet, whereas the husk only contained higher levels of dietary fibre, and some minerals. The millet section, as the edible part, contained the lowest level of chemical constituents. It illustrated that the bran part contained more functional and nutritional components than the millet and husk part. Therefore, the bran of the foxtail millet should be a food resources instead of wasting.

Abstract Obstructive sleep apnea syndrome (OSAS), characterized by chronic intermittent hypoxia (CIH), is an independent risk factor for aggravating non‐alcoholic steatohepatitis (NASH). The prevailing mouse model employed in CIH research is inadequate for the comprehensive exploration of the impact of CIH on NASH development due to reduced food intake observed in CIH‐exposed mice, which deviates from human responses. To address this issue, a pair‐feeding investigation with CIH‐exposed and normoxia‐exposed mice is conducted. It is revealed that CIH exposure aggravates DNA damage, leading to hepatic fibrosis and inflammation. The analysis of genome‐wide association study (GWAS) data also discloses the association between Eepd1, a DNA repair enzyme, and OSAS. Furthermore, it is revealed that CIH triggered selective autophagy, leading to the autophagic degradation of Eepd1, thereby exacerbating DNA damage in hepatocytes. Notably, Eepd1 liver‐specific knockout mice exhibit aggravated hepatic DNA damage and further progression of NASH. To identify a therapeutic approach for CIH‐induced NASH, a drug screening is conducted and it is found that Retigabine dihydrochloride suppresses CIH‐mediated Eepd1 degradation, leading to alleviated DNA damage in hepatocytes. These findings imply that targeting CIH‐mediated Eepd1 degradation can be an adjunctive approach in the treatment of NASH exacerbated by OSAS.

During liver regeneration, especially after a hepatectomy, hepatocytes experience significant lipid accumulation. These transiently accumulated lipids are generally believed to provide substrates for energy supply or membrane biomaterials for newly generated hepatocytes. Remarkably, a recent study found that acute lipid accumulation during regeneration can act as a signal for chromatin remodeling to regulate regeneration. Chen, Y.H., et al. identified MIER1 (mesoderm induction early response protein 1) as a crucial inhibitor of liver regeneration through in vivo CRISPR screening. MIER1 binds to and restrains cell cycle genes’ expression. During liver regeneration, acute lipid accumulation suppresses MIER1 translation via the EIF2S pathway, resulting in transient down-regulation of MIER1 protein, which promotes cell cycle gene expression and liver regeneration. Interestingly, the researchers also found that the dynamic regulation of MIER1 was impaired in fatty and aging livers with chronic steatosis, while of knockout of MIER1 in these animals improved their regenerative capacity. In conclusion, this study provides valuable insights into the complex mechanisms underlying liver regeneration and highlights the potential therapeutic applications of targeting MIER1 for improving liver regeneration in disease states associated with impaired lipid homeostasis.

Background The benchmark dose (BMD) method calculates the dose associated with a specific change in response based on a specific dose-response relationship. Compared with the traditional no observed adverse effect level (NOAEL) method, the BMD method has many advantages, and the 95% lower confidence limit of benchmark dose lower limit (BMDL) is recommended to replace NOAEL in deriving biological exposure limits. No authority has yet published any health-based guideline for rare earth elements. Objective To evaluate genotoxicity threshold induced by acute exposure to neodymium nitrate in mice using BMD modeling through micronucleus test and comet assay. Methods SPF grade mice (n=90) were randomly divided into nine groups, including seven neodymium nitrate exposure groups, one control group (distilled water), and one positive control group (200 mg·kg−1 ethyl methanesulfonate), 10 mice in each group, half male and half female. The seven dose groups were fed by gavage with different concentrations of neodymium nitrate solution (male: 14, 27, 39, 55, 77, 109, and 219 mg·kg−1; female: 24, 49, 69, 97, 138, 195, and 389 mg·kg−1) twice at an interval of 21 h. Three hours after the last exposure, the animals were neutralized by cervical dislocation. The bone marrow of mice femur was taken to calculate the micronucleus rate of bone marrow cells, and the liver and stomach were taken for comet test. Results The best fitting models for the increase of polychromatophil micronucleus rate in bone marrow of female and male mice induced by neodymium nitrate were the exponential 4 model and the hill model, respectively. The BMD and the BMDL of female mice were calculated to be 31.37 mg·kg−1 and 21.90 mg·kg−1, and those of male mice were calculated to be 58.62 mg·kg−1 and 54.31 mg·kg−1, respectively. The best fitting models for DNA damage induced by neodymium nitrate in female and male mouse hepatocytes were the exponential 5 model and the exponential 4 model, respectively, and the calculated BMD and BMDL were 27.15 mg·kg−1 and 11.99 mg·kg−1 for female mice, and 16.28 mg·kg−1 and 10.47 mg·kg−1 for male mice, respectively. The hill model was the best fitting model for DNA damage of gastric adenocytes in both female and male mice, and the calculated BMD and BMDL were 36.73 mg·kg−1 and 19.92 mg·kg−1 for female mice, and 24.74 mg·kg−1 and 14.08 mg·kg−1 for male mice, respectively. Conclusion Taken the micronucleus rate of bone marrow cells, DNA damage of liver cells and gastric gland cells as the end points of genotoxicity, the BMDL of neodymium nitrate is 10.47 mg·kg−1, which can be used as the threshold of genotoxic effects induced by acute exposure to neodymium nitrate in mice.

Abstract Objectives we performed this meta- analysis to investigate the impact of insulin receptor substrate 1 (IRS1) gene rs1801278 on susceptibility to gestational diabetes mellitus (GDM). Methods The pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated, and p value is used to determine statistical significance. Sensitivity analysis was performed under three models (dominant, recessive and allele model), and the pooled ORs and 95%CI were calculated. Funnel plots and Begger’s regression test were employed to test the publication bias. Results The meta-analysis included 4777 participants (2116 cases and 2661 controls). The IRS1 rs1801278 (C/T) were not significant associated with GDM risk under the dominant and allele models, OR (95%CI) = 1.22 (0.88–1.70) and 1.24 (0.91–1.68), respectively (both p values were more than 0.05). But we also found the IRS1 rs1801278 (C/T) were significant associated with GDM risk under the recessive model, OR (95%CI) = 0.37 (0.16–0.86), p = 0.030. Our results showed that none of the studies affected the quality of the pooled OR. We also found no significant publication bias existed in this meta study for three genetic models, P TT + CT vs. CC = 0.445; P CC+CT vs. TT= 0.095; P C vs. T = 0.697. Conclusion this meta-analysis indicated that IRS1 rs1801278 (C/T) was associated with the GDM risk under the recessive model but was not associated with the GDM risk under dominant and allele models.

The application of ultrasonic atomization on aqueous ethanol dewatering/dehydration was investigated using a single transducer device. This study predicted the ultrasonic properties in the aqueous ethanol solutions according to temperature and bulk solution composition. The predicted ultrasonic properties include speed, near-field length, last minimum length, impedance, reflection, transmission, and attenuation. The effects of solution thickness, solution temperature, and carrier gas flow rate on the ethanol ultrasonic separation were studied. Both ultrasonic separation efficiency and collection rates increased with solution temperatures. The collection rates increased with carrier gas flow rates while the ultrasonic separation efficiency decreased. Solution thickness below the last minimum length or above the near-field length can result in decreased ultrasonic separation efficiency. Additionally, based on the surface enrichment with the atomization droplet sizes, a thermodynamic model was developed to predict the mist composition. This model is more accurate than previous models because of considering the effects of temperatures and composition on the droplet size and using a more accurate model, modified Myers-Scott model, to predict the surface tension precisely. The role of carrier gas flow rate on the selectivity of droplet/bubble was analyzed through force analysis. The force analysis indicated the coexistence of pure ethanol nanodroplets and solution microdroplets during the ultrasonic separation. An instability characteristic time was applied to evaluate the atomization threshold related to wavelength, density, surface tension, and viscosity. The optimal operations prefer high temperature, low carrier gas flow rate, maximum thickness between near field length and last minimum length, and atmospheric pressure. Since ultrasonic separation uses electricity, replacing the current bioethanol refining process can result in the potential CO2 reduction up to 2.3 kg CO2 equivalent/kg ethanol if renewable electricity is used. The future replacement of bioethanol refining in the United States can cut over 100 million metric tons of CO2 yearly.

Adipose tissue is a crucial metabolic organ in the human body. It stores and exerts distinct physiological functions in different body regions. Fat not only serves as a cushion and insulator but also stores energy and conveys endocrine signals within the body. There is a growing recognition that adipose tissue is an organ that is misunderstood and underestimated in contribution to human health and disease progression by regulating its size and functionality. In mammals, the adipose tissue reservoir consists of three functionally distinct types of fat: white adipose tissue (WAT), brown adipose tissue (BAT), and beige or inducible brown adipose tissue (iWAT), which exhibits thermogenic capabilities intermediate between the other two. Fat in different depots exhibits considerable differences in origin, characteristics, and functions. They vary not only in adipocyte lineage, properties, thermogenesis, and endocrine functions but also in their immunological functions. In a recent study published in Nature Metabolism, Zhang et al. investigated the role of JunB in the thermogenic capacity of adipocytes and its significance in obesity and metabolic disorders. The study revealed that JunB expression in BAT coexists with both low and high thermogenic adipocytes, indicating a fundamental feature of heterogeneity and plasticity within BAT. In summary, this article demonstrates that research targeting JunB holds promise for improving diet-induced obesity and insulin resistance, offering new avenues for treating metabolic disorders.

Abstract. Introduction:. Postoperative rebound pain after peripheral nerve block increases patient suffering and delays recovery after surgery. Objectives:. We tested whether the 5HT-3 receptor antagonist and α7nAChR agonist tropisetron could prevent postoperative rebound pain. Methods:. A total of 115 patients were randomized to receive 5-mg/5-mL tropisetron or the same volume of normal saline. Pain intensity was measured with the numerical rating scale of pain (NRS). Rebound pain was defined as a change from mild pain (NRS ≤ 3) measured in the postanesthesia care unit to severe pain (NRS ≥ 7) within 24 hours after peripheral nerve blockade. Logistic regression was used to identify relevant factors associated with postoperative rebound pain. Results:. Tropisetron did not affect the NRS score or the incidence of rebound pain after peripheral nerve block. Logistic regression revealed that preoperative pain, bone surgery, and length of incision were risk factors for postoperative rebound pain, and patient-controlled analgesia was protective against postoperative rebound pain. Conclusion:. Tropisetron does not affect the incidence of rebound pain after peripheral nerve block. Patients at high risk of postoperative rebound pain should be identified for appropriate management. Registration site: www.chictr.org.cn (ChiCTR2300069994).

Silver nanoparticles (AgNPs) are extensively utilized in industrial, biotechnological and medical fields because of their specific physical and chemical properties, which shown small size effects, surface and interface effects, quantum scale effects. Inevitably, wastewater containing AgNPs is leached into the soil. AgNPs in soil may be absorbed by plant roots and they affect plant growth. Understanding the complex interactions between AgNPs and plants is of crucial significance since plants are essential to the ecological environment as key players in ecosystems. Most previous reports have focused on AgNP phytotoxicity rather than positive effects in the plant field. This article reviews recent studies on the important aspects about nanoparticles including the green synthesis, absorption, migration, accumulation, biotransformation, biological effects, and the underlying molecular mechanisms of AgNPs affecting plants. We provide insights into the interactions between AgNPs and plants, helping to further understand AgNP-related effects and biosafety in agricultural production, as well as the practical application of various nanomaterials in agriculture.

Abstract Ottonia anisum (O. anisum), belonging to the family Piperaceae, is renowned for its medicinal properties. The plant is rich in alkaloids, terpenoids and flavonoids with recorded bioactivities. The stems, roots, and leaves, of the O. anisum have been extensively used in the folk medicine. Therefore, the present study was conducted to examine the pharmacological activities of O. anisum root extract. Methanolic root extract of O. anisum was assessed for local anesthetic, analgesic, anti-inflammatory and HCl-induced acute lung injury activities in animal models. Local anesthetic activity assessed in frog and guinea pigs through foot withdrawal reflex and intradermal wheal method, respectively, revealed the dose-dependent onset time of anesthesia response. In the case of HCl-induced ALI, the mice group orally administered with O. anisum extract were assessed for bronchoalveolar lavage fluid (BLF) contents, oxidative stress, and proinflammatory molecules. The analysis revealed the reduction in inflammatory molecules, neutrophils, and oxidative stress in the extract treated mice group. In addition, the redox homeostasis, reduced GSH and the catalase activity was found to be restored in the treated groups. Intriguingly, the genes associated with the NFkB expression was found to be downregulated in O. anisum extract treated groups. Moreover, the extract unveiled the significant analgesic and anti-inflammatory activities. Overall, the findings emphasize the clinical applicability of O. anisum extract in the treatment of ALI as well as the potential usage in local anesthetic, analgesic, and anti-inflammatory agents during the treatments. Graphical Abstract

Agent-based models have gained traction in exploring the intricate processes governing the spread of infectious diseases, particularly due to their proficiency in capturing nonlinear interaction dynamics. The fidelity of agent-based models in replicating real-world epidemic scenarios hinges on the accurate portrayal of both population-wide and individual-level interactions. In situations where comprehensive population data are lacking, synthetic populations serve as a vital input to agent-based models, approximating real-world demographic structures. While some current population synthesizers consider the structural relationships among agents from the same household, there remains room for refinement in this domain, which could potentially introduce biases in subsequent disease transmission simulations. In response, this study unveils a novel methodology for generating synthetic populations tailored for infectious disease transmission simulations. By integrating insights from microsample-derived household structures, we employ a heuristic combinatorial optimizer to recalibrate these structures, subsequently yielding synthetic populations that faithfully represent agent structural relationships. Implementing this technique, we successfully generated a spatially-explicit synthetic population encompassing over 17 million agents for Shenzhen, China. The findings affirm the method's efficacy in delineating the inherent statistical structural relationship patterns, aligning well with demographic benchmarks at both city and subzone tiers. Moreover, when assessed against a stochastic agent-based Susceptible-Exposed-Infectious-Recovered model, our results pinpointed that variations in population synthesizers can notably alter epidemic projections, influencing both the peak incidence rate and its onset.

The odor of the foxtail millet is one of the most important indexes to evaluate the foxtail millet quality. Different sowing time results in different quality of the foxtail millet, and the volatiles can be used as fingerprint for distinguish them. The odor components of foxtail millets from spring sowing area and summer sowing area were investigated by means of gas chromatography-mass spectrometry (GC-MS) combined with simultaneous distillation extraction (SDE). A total of 53 volatile compounds were identified in all the samples containing 19 aldehydes, 4 alcohols, 7 ketones, 7 benzene derivatives, 12 hydrocarbons, 3 heterocycles and 1 acid. Aldehydes were the predominant odor components in foxtail millet. Compared with summer sowing area, there were abundant variety and high content of odor components in spring sowing area. Twenty-one volatiles were found to be odor-active compounds. The components with the highest OAVs in most sowing area were (E,E)-2,4-decadienal, (E)-2-nonenal, (E,E)-2,4-nonadienal and nonanal. Finally, 20 volatiles were screened out to distinguish the foxtail millet from spring-sowing area and summer-sowing area by multivariate statistical analysis. The results will be helpful to identify the foxtail millet from different sowing seasons and provide evidence that the spring-sowing foxtail millet shows more active odors.

Abstract The structural reconstruction mechanism of lignin and cellulose-derived biochars during direct graphitization under ultra-high temperatures was intensively investigated. It was demonstrated that cellulose-derived char was almost composed of carbon microcrystallites, whereas lignin-derived char reserved some of its skeleton structures, and such structural difference played a vital role in the morphology of formed graphitic layers. The results illustrated that the graphitized lignin-derived sample under 2800 ℃ had graphitic degree of 89.53%, interlayer spacing of 0.3363 nm and electronic conductivity of 104.6 S cm−1, while cellulose-derived sample had graphitic degree of 76.74%, layer distance of 0.3374 nm, and electronic conductivity of only 48.8 S cm−1. Combined with the results of structural analysis of the chars derived from lignin and cellulose, it was inferred that the stable and aromatic ring containing skeleton structure in lignin was beneficial to the ring-enlarging reconstruction and the formation of large areas of continuous graphitic layers during graphitizing process, leading to high electronic conductivity. Meanwhile, the interwoven microcrystallites in cellulose-derived char strongly restricted the expanding of continuous lamellar graphitic areas even at such ultra-high temperature, causing the formation of turbostratic structure with numerous structural defects as well, and finally resulting in relatively lower electronic conductivity. This work is expected to provide theoretical guidance for preparing high-performance functional carbon materials from lignocellulosic biomass. Graphical Abstract

Arbuscular mycorrhizal (AM) fungi are well known for enhancing phosphorus uptake in plants; however, their regulating roles in cation transporting gene family, such as natural resistance-associated macrophage protein (NRAMP), are still limited. Here, we performed bioinformatics analysis and quantitative expression assays of tomato SlNRAMP 1 to 5 genes under nutrient deficiency and cadmium (Cd) stress in response to AM symbiosis. These five SlNRAMP members are mainly located in the plasma or vacuolar membrane and can be divided into two subfamilies. Cis-element analysis revealed several motifs involved in phytohormonal and abiotic regulation in their promoters. SlNRAMP2 was downregulated by iron deficiency, while SlNRAMP1, SlNRAMP3, SlNRAMP4, and SlNRAMP5 responded positively to copper-, zinc-, and manganese-deficient conditions. AM colonization reduced Cd accumulation and expression of SlNRAMP3 but enhanced SlNRAMP1, SlNRAMP2, and SlNRMAP4 in plants under Cd stress. These findings provide valuable genetic information for improving tomato resilience to nutrient deficiency and heavy metal stress by developing AM symbiosis.

Abstract Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that is becoming increasingly prevalent, and it ranges from simple steatosis to cirrhosis. However, there is still a lack of pharmacotherapeutic strategies approved by the Food and Drug Administration, which results in a higher risk of death related to carcinoma and cardiovascular complications. Of note, it is well established that the pathogenesis of NAFLD is tightly associated with whole metabolic dysfunction. Thus, targeting interconnected metabolic conditions could present promising benefits to NAFLD, according to a number of clinical studies. Here, we summarize the metabolic characteristics of the development of NAFLD, including glucose metabolism, lipid metabolism and intestinal metabolism, and provide insight into pharmacological targets. In addition, we present updates on the progresses in the development of pharmacotherapeutic strategies based on metabolic intervention globally, which could lead to new opportunities for NAFLD drug development.

Due to excess energy intake and a sedentary lifestyle, the prevalence of obesity is rising steadily and has emerged as a global public health problem. Adipose tissue undergoes structural remodeling and dysfunction in the obese state. Secreted proteins derived from the liver, also termed as hepatokines, exert multiple effects on adipose tissue remodeling and the development of obesity, and has drawn extensive attention for their therapeutic potential in the treatment of obesity and related diseases. Several novel hepatokines and their functions on systemic metabolism have been interrogated recently as well. The drug development programs targeting hepatokines also have shown inspiring benefits in obesity treatment. In this review, we outline how adipose tissue changes during obesity. Then, we summarize and critically analyze the novel findings on the effects of metabolic “beneficial” and metabolic “harmful” hepatokines to adipose tissue. We also discuss the in-depth molecular mechanism that hepatokines may mediate the liver-adipose tissue crosstalk, the novel technologies targeting hepatokines and their receptors in vivo to explore their functions, and the potential application of these interventions in clinical practice.

Graphene oxide (GO) sheet as a nanomaterial has been incorporated into cement-based composites to improve mechanical properties. This study investigates the effectiveness of GO sheets in enhancing the compressive strength of 3D-printed cementitious mortar. Two dosages of GO are investigated, including the GO-to-binder weight ratio of 0.015% (GO-0.015) and 0.03% (GO-0.03). Experiment results showed that adding GO at both dosages improved the compressive strengths of printed specimens in different loading directions. However, the strength improvement in GO-0.015 (∼10%) was more significant than GO-0.03 (∼5%). Although the scanning electron microscopy analysis demonstrated the cement matrix shared similar levels of microstructure densification in GO-0.015 and GO-0.03, the material underfill in 3D-printed GO-0.03 specimen due to its lower flowability generated large voids between filaments. Consequently, large voids acting as additional weakness offset the positive effects of GO on strength improvement in the 3D-printed specimen of GO-0.03.

It is difficult to separate fluorene and phenanthene by conventional separation method owing to their similar properties. The reaction-separation coupling technique was adopted to solve the problem, in which fluorene is first converted into 9-fluorenylmethanol. The factors affecting the yield and selectivity of 9-fluorenylmethanol by one-step synthesis with potassium carbonate as catalyst were investigated for the separation of phenanthrene from anthracene residue further. The results showed that with DMSO+10% ethanol as solvent, n(fluorene)∶n(formaldehyde)∶n(potassium carbonate)=1∶1∶0.2, and reaction at 13 ℃ for 15 min, the yield of 9-fluorenemethanol is about 25% and the selectivity is higher than 84%. Ethanol can inhibit the formation of 9-fluorenyl anion, and the inorganic salt affects the mass transfer and slows down the dehydration reaction. Using the mixture of fluorene and phenanthrene with mass ratio of 1∶4 as raw material, the yield and purity of phenanthrene reaches 97.6% and 93.2% after five reaction-separation cycles, respectively; the total yield of 9-fluorenylmethanol is 66.5%, and the average purity is 95.0%.

Abstract Background Abnormal biogenesis and ribosome free function of ribosomal proteins (RPs) is important for tumorgenesis and development. Ribosomal protein L11 (RPL11) is a component of ribosomal 60 S large subunit with different roles in different cancers. Here, we aimed to unravel the role of RPL11 in non-small cell lung cancer (NSCLC), especially those affecting cell proliferation. Methods RPL11 expression in NCI-H1650, NCI-H1299, A549 and HCC827 and normal lung bronchial epithelial cells HBE was detected using western blotting. The function of RPL11 in NSCLC cells were determined by investigating cell viablity, colony formation and cell migration. Mechanism expoloration of RPL11 effect on NSCLC cells proliferation was explored using flow cytometry, and the effect on autophagy was investigated by the additon of autophagy inhibitor chloroquine (CQ) and endoplasmic reticulum stress (ERS) inhibitor tauroursodeoxycholic acid (TUDCA). Results RPL11 was highly expressed in NSCLC cells. Extopic expression of RPL11 promoted NCI-H1299 and A549 cells proliferation, and migration, and promoted the transition from the G1 phase to the S phase of the cell cycle. Small RNA interference of RPL11 (siRNA) suppressed NCI-H1299 and A549 cells proliferation and migration and arrested the cell cycle in G0/G1 phase. Moreover, RPL11 promoted NSCLC cell proliferation by modulating autophagy and ERS. Expression levels of autophagy and ERS markers were induced by RPL11 overexpression and inhibited by siRPL11. CQ partially suppressed RPL11-induced A549 and NCI-H1299 proliferation: CQ addition reduced RPL11-induced cells viability and clone numbers and reversed the cell cycle process. ERS inhibitor (TUDCA) partially reversed RPL11-induced autophagy. Conclusion Taken together, RPL11 has a tumor-promoting role in NSCLC. It promotes the cell proliferation of NSCLC cells by regulating ERS and autophagy.

With the increasing demand for road traffic safety assessment, global concerns about road safety have been rising. This is particularly evident with the widespread adoption of V2X (Vehicle-to-Everything) technology, where people are more intensively focused on how to leverage advanced technological means to effectively address challenges in traffic safety. Through the research of driving style recognition technology, accurate assessment of driving behavior and the provision of personalized safety prompts and warnings have become crucial for preventing traffic accidents. This paper proposes a risk field construction technique based on environmental data collected by in-vehicle sensors. This paper introduces a driving style recognition algorithm utilizing risk field visualization and mask learning technologies. The research results indicate that, compared to traditional classical models, the improved algorithm performs excellently in terms of accuracy, stability, and robustness, enhancing the accuracy of driving style recognition and enabling a more effective evaluation of road safety.

Research on the comprehensive utilization of sour jujube and its beneficial properties to human health has attracted extensive attention. This study aims to conduct a bibliometric analysis of the bioactive profile of sour jujube and future trends in applications. The research advancements within this field from 2000 to 2023 were addressed using the Web of Science database and VOSviewer. Among the 322 results, the most frequent keywords of bioactivity are flavonoids, antioxidants, saponins, insomnia, polyphenols, terpenoids and anti-inflammatory; the most studied parts of sour jujube are seeds, fruits and leaves; the published articles with high citations mainly focus on identification, biological effects and different parts distribution of bioactive compounds. The bioactivity of various parts of sour jujube was reviewed considering their application potential. The seeds, rich in flavonoids, saponins and alkaloids, exhibit strong effects on central nervous system diseases and have been well-developed in pharmacology, healthcare products and functional foods. The pulp has antioxidant properties and is used to develop added-value foods (e.g., juice, vinegar, wine). The leaves can be used to make tea and flowers are good sources of honey; their extracts are rich sources of flavonoids and saponins, which show promising medicinal effects. The branches, roots and bark have healing properties in traditional folk medicine. Overall, this study provides a reference for future applications of sour jujube in food and medicine fields.

The advancement of autonomous driving technology has urgently necessitated enhanced safety testing measures. Traditional road testing methods face significant challenges due to their high costs and prolonged durations. In response to the inefficiencies of manual scenario construction and the difficulties in selecting effective scenarios using common scenario generation methods in autonomous driving safety testing, this study proposes an innovative automatic SG system based on PreScan2021.1.0. The SG process is significantly simplified by this system’s capability to swiftly and accurately generate a vast array of specific scenarios through the input of scene parameters. The results indicate that this system achieves SG at a rate 2.5-fold faster than manual methods, alongside substantial improvements in accuracy. This system introduces a novel approach to virtual simulation, which is vital for the progress of autonomous driving safety. It offers a new paradigm for quickly and precisely generating test scenarios for autonomous driving.

Abstract Background Inhibition of hepatic lipogenesis is widely regarded as an effective treatment for metabolic-associated fatty liver disease (MAFLD), although numerous related drugs have failed to reach clinical application. The goal of this study is to identify a novel small compound that can effectively treat MAFLD. Methods Primary hepatocytes were first exposed to palmitic acid and oleic acid, then treated with compounds prior to high through screening for cellular lipid content. The efficacy of these compounds was measured by Nile Red staining and triglyceride analysis. The potential cellular toxicity caused by these compounds was evaluated by CCK8 assay. qPCR and Western blot were used to determine expression of RNAs and proteins, respectively. The compound was intraperitoneally injected into diet-induced obese (DIO) mice to examine its efficacy in vivo. Results We identified the dimethyl 1-methyl-2-thioxoindoline-3,3-dicarboxylate (TOIDC) as a powerful chemical to reduce cellular lipid with minimal cellular toxicity. When injected intraperitoneally, TOIDC effectively ameliorates MAFLD in DIO mice. Mechanically, TOIDC suppresses de novo lipogenesis through inhibiting sterol regulatory element-binding protein 1 (SREBP1). Conclusions Our findings indicate that TOIDC could be a promising lead compound to develop new drugs to treat MAFLD. Graphical Abstract

Abstract Background Abnormal expression of ribosomal proteins has an important regulatory effect on the progression of cancer. RPL5 is involved in the progression of various malignancies, however, the role of RPL5 in colon cancer remains is still unclear. Methods Data from TCGA and GTEx databases were used to analyze the RPL5 expression in pan-cancer. The expression level of RPL5 in clinical colon cancer tissue samples and human colon cancer cell lines was detected by western blotting; siRNA targeting RPL5 was designed, and its interference efficiency was verified by western blotting and RT-qPCR; CCK8 assay, clone formation assay, cell cycle assay, and cell scratch assay were used to observe the effect of RPL5 on colon cancer cell proliferation and migration; the changes of proteins related to MAPK/ERK signaling pathway were also detected using western blotting. Results The expression level of RPL5 in colon cancer tissues and cell lines was significantly higher than that in adjacent tissues and NCM460 cells, respectively, and its expression level was higher in HCT116 cells and RKO cells. Knockdown of RPL5 significantly inhibited the proliferation and migration of HCT16 and RKO cells, and arrested the cell cycle in G0/G1 phase. Mechanistic studies revealed that the expression of p-MEK1/2, p-ERK, c-Myc were down-regulated, and the expression of FOXO3 was up-regulated after down-regulation of RPL5, ERK activator (TBHQ) could partially reverse the above-mentioned effects caused by siRPL5. Moreover, TBHQ could partially reverse the inhibitory effect of siRPL5 on the proliferation and migration of colon cancer cells. Collectively, RPL5 promoted colon cell proliferation and migration, at least in part, by activating the MAPK/ERK signaling pathway. Conclusion RPL5 promoted colon cell proliferation and migration, at least in part, by activating the MAPK/ERK signaling pathway, which may serve as a novel therapeutic target for cancers in which MAPK/ERK signaling is a dominant feature.

Abstract Excessive inflammatory responses contribute to the pathogenesis and lethality of highly pathogenic human coronaviruses, but the underlying mechanism remains unclear. In this study, the N proteins of highly pathogenic human coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), middle east respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), were found to bind MASP-2, a key serine protease in the lectin pathway of complement activation, resulting in excessive complement activation by potentiating MBL-dependent MASP-2 activation, and the deposition of MASP-2, C4b, activated C3 and C5b-9. Aggravated inflammatory lung injury was observed in mice infected with adenovirus expressing the N protein. Complement hyperactivation was also observed in SARS-CoV-2-infected patients. Either blocking the N protein:MASP-2 interaction, MASP-2 depletion or suppressing complement activation can significantly alleviate N protein-induced complement hyperactivation and lung injury in vitro and in vivo. Altogether, these data suggested that complement suppression may represent a novel therapeutic approach for pneumonia induced by these highly pathogenic coronaviruses.

ObjectiveThe study investigated the correlation and predictive value between the severity of cerebral microbleeds (CMBs) and the level of serum High Mobility Group Protein B1 (HMGB1) and the occurrence of cognitive impairment in patients with cerebral small vessel disease (CSVD).MethodsA total of 139 patients with CSVD admitted to the Department of Neurology of the First Affiliated Hospital of Xinxiang Medical University from December 2020 to December 2022 were selected as study subjects. The Montreal Cognitive Assessment (MoCA) scale was used to assess the cognitive function and was divided into the cognitive impairment group and the cognitive normal group. Magnetic Resonance Imaging (MRI) and Susceptibility Weighted Imaging (SWI) were used to screen and assess the severity of CMBs. Serum HMGB1 levels of CSVD patients were measured by enzyme linked immunosorbent assay (ELISA). Multivariable logistic regression analysis was used to explore risk factors for cognitive impairment and CMBs. Pearson correlation analysis was used to investigate the correlation between HMGB1 and cognitive function. Receiver Operating Characteristics (ROC) curves were used to assess the predictive value of HMGB1 for the occurrence of cognitive impairment in patients with CMBs.ResultsHigh Mobility Group Protein B1, uric acid (UA), glycosylated hemoglobin (HbA1c), CMBs, lacunar cerebral infarction (LI), years of education, and history of hypertension were risk factors for cognitive impairment (P < 0.05); HMGB1 was significantly and negatively associated with total MoCA score, visuospatial/executive ability, and delayed recall ability (P < 0.05). HMGB1 was significantly and positively correlated with the number of CMBs (P < 0.05). The area under the ROC curve for HMGB1 predicting cognitive impairment in patients with CMBs was 0.807 (P < 0.001).ConclusionSerum HMGB1 levels are associated with the development of cognitive impairment in CSVD patients, and serum HMGB1 levels have a high predictive value for the development of cognitive impairment in CSVD patients with combined CMBs, which can be used for early clinical identification and intervention of vascular cognitive impairment.

BackgroundGut microbiome plays an indispensable role in the occurrence and progression in various diseases. The incidence of pancreatic cancer (PC) and liver metastasis (PCLM) are high, most of them are found in advanced stage. Therefore, it is particularly necessary to search for predictive biomarkers, which are helpful for early detection and treatment, and thus improve the survival rate and quality of life of PC patients.MethodsWe retrospectively analyzed 44 pancreatic cancer patients (P group, n = 44) and 50 healthy people (N group, n = 50) from March 21, 2021 and August 2, 2022. Among all PC patients, we divided them into liver metastasis group (LM group, n = 27) and non-liver metastasis group (non-LM group, n = 17). DNA was extracted and 16S ribosomal RNA (16S rRNA) gene sequencing was performed. SPSS was used for statistical analyses and all bioinformatics analyses were based on QIIME2, p

Biodiesel is viewed as the alternative to petroleum diesel, but its poor low-temperature performance constrains its utilization. Cloud point (CP), the onset temperature of thermal crystallization, appropriately shows the low-temperature performance. The effective way to reduce CP is to remove saturated fatty acid methyl esters (FAMEs). Compared to current methods, this work describes an extraordinary approach to fractionating FAMEs by forming solid urea inclusion compounds (UICs). Urea inclusion fractionation reduces the CPs by removing high melting-point linear saturated FAME components. Urea inclusion fractionation in this study was performed under various processing conditions: mass ratios of urea to FAMEs to solvents, various solvents, FAMEs from various feedstocks, and processing temperatures. Supersaturation of urea in the solution is the driving force, and it significantly affects yield, composition, CP, separation efficiency, and selectivity. Through a single urea inclusion fractionation process, FAMEs, except palm oil FAMEs, resulted in CP reduction ranging from 20 to 42 oC with a yield of 77–80% depending on the compositions. CP of palm oil FAMEs could reach as low as -17 oC with a yield of 46% after twice urea inclusion fractionation. According to the model prediction, the cetane number after urea inclusion fractionation decreased about 0.7–2 but was still higher than the minimum biodiesel requirement. Oxidation stability after urea inclusion decreased according to the proposed model, but this can be mitigated by adding antioxidants. Emission evaluation after urea inclusion fractionation indicated decreased hydrocarbons, carbon monoxide, and particulate matter. However, it resulted in the increasing emission of nitrogen oxides.

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease (AD). The pathologic hallmarks of the disease are the loss of dopaminergic neurons of substantia nigra pars compacta and the presence of intraneuronal alpha synuclein (a-syn) aggregates. Clinical features of PD include motor symptoms such as bradykinesia, rigidity, tremors, postural instability, and gait impairment, and non-motor symptoms such as constipation, orthostatic hypotension, REM sleep disorder, depression and dementia. Currently, there is no disease-modifying therapy for PD. Several human studies have shown that exercise reduces progression of motor symptoms, improves performance on cognitive tasks, and slows functional deterioration. However, regular exercise may not always be feasible in PD patients. Irisin is an exercise-induced myokine involved in metabolism modulation and body fat reduction, but it also crosses the blood-brain barrier and may mediate some of the benefits of exercise in brain function. Recent evidence has shown that irisin could be therapeutically promising in PD as an “exercise-mimicking” intervention. Exogenous irisin administration decreases brain a-syn pathology and loss of dopaminergic neurons, while it improves motor outcomes in preclinical models. Several other neurodegenerative disorders such as AD share common underlying pathogenetic mechanisms with PD such as protein misfolding and aggregation, neuroinflammation, brain metabolic abnormalities, and neuronal loss. Therefore, investigation of irisin as a disease-modifying therapy could be promising for PD and other neurodegenerative disorders including AD.

Intraspecific recurrent selection in V. vinifera is an effective method for grape breeding with high quality and disease resistance. The core theory of this method is the substitution accumulation of multi-genes with low disease resistance. The discovery of multi-genes for disease resistance in V. vinifera may provide a molecular basis for breeding for disease resistance in V. vinifera. In this study, resistance to downy mildew was identified, and genetic analysis was carried out in the intraspecific crossing population of V. vinifera (Ecolly × Dunkelfelder) to screen immune, highly resistant and disease-resistant plant samples; transcriptome sequencing and differential expression analysis were performed using high-throughput sequencing. The results showed that there were 546 differential genes (194 up-regulated and 352 down-regulated) in the immune group compared to the highly resistant group, and 199 differential genes (50 up-regulated and 149 down-regulated) in the highly resistant group compared to the resistant group, there were 103 differential genes (54 up-regulated and 49 down-regulated) in the immune group compared to the resistant group. KEGG analysis of differentially expressed genes in the immune versus high-resistance group. The pathway is mainly concentrated in phenylpropanoid biosynthesis, starch and sucrose metabolism, MAPK signaling pathway–plant, carotenoid biosyn-thesis and isoquinoline alkaloid biosynthesis. The differential gene functions of immune and resistant, high-resistant and resistant combinations were mainly enriched in plant–pathogen interaction pathway. Through the analysis of disease resistance-related genes in each pathway, the potential minor resistance genes in V. vinifera were mined, and the accumulation of minor resistance genes was analyzed from the molecular level.

The stability of a predator-prey model with two-stage structure and fear effect was studied. This model incorporated maturation time delay of the prey, and a delay differential equation model was established. By using the theory of the ordinary differential equations, the comparison theorem, the theory of the delay differential equations and the persistence theory of the infinite dimensional dynamical systems, the nonnegativity and boundedness of the solution of the model were proved, the conditions for the existence of the equilibria were given, the local asymptotic stability and the global asymptotic stability of the equilibria and the uniform persistence of the model were discussed. Numerical simulation was used to verify the correctness of the theoretical results, and it is concluded that the stability of the model changes when the fear effect and time delay are different.

The ever-increasing burden of obesity, type 2 diabetes mellitus (T2DM) and related comorbidities is demanding a better pathophysiological understanding as well as new treatment options. Incretin based therapies are already available while the recent Food and Drug Administration (FDA) approval of the dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide appears to revolutionize the treatment of T2DM and obesity. GLP-1 and GIP exert pleiotropic physiological actions, including enhancement of insulin secretion, glycemic and appetite control, cardioprotection, and adipose tissue improved function among others. Evidence from recent clinical trials has shown that tirzepatide is at least or more effective compared to classic metabolic therapeutic agents, including insulin, when it comes to glycemic control in T2DM. Of importance, it also exerts remarkable weight-lowering actions, emerging as an alternative to bariatric surgery for obesity treatment. Overall, current data show that tirzepatide is a highly effective therapeutic option for T2DM. Numerous ongoing randomized controlled clinical trials are further examining its potential as a treatment for obesity.

Non-alcoholic fatty liver disease represents the most common liver disease worldwide and the prevailing cause of liver-related morbidity and mortality. It encompasses a broad clinical spectrum ranging from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis, and finally hepatocellular carcinoma. There have been many studies about the underlying mechanisms of NASH progression, fueling a solid therapeutic pipeline across a variety of potential targets to resolve steatohepatitis or fibrosis. Unfortunately, no therapeutic agent has been approved so far for NASH. In an interesting study, Wei et al. highlighted the role of MRG15 as a targetable epigenetic remodeller in the rhythmic regulation of hepatic lipid metabolism. Remarkably, a recent study from the same group uncovered a chromatin-binding independent working mechanism of MRG15 in regulating the progression from early liver steatosis to the advanced NASH stage with fibrosis and inflammation. Collectively, these studies have shown that MRG15 constitutes a key factor during different stages of NAFLD development. Nuclear MRG15 is recruited to promoter regions of liver lipogenesis genes by LRH-1, where it activates the rhythmic expression of lipid synthesis genes, leading to liver steatosis; while in mitochondria, MRG15 accelerates TUFM degradation, resulting in the aggravation of inflammation and fibrosis, and NASH progression. Blocking of MRG15 by CRISPR targeting or by the FDA-approved drug argatroban, which is an antagonist to MRG15, may attenuate liver steatosis. Further studies regarding the functional aspects of MRG15 in different cell types and its regulatory signals will shed light on the intriguing functions of MRG15 in lipid metabolism and tissue fibrogenesis.

The interplay between the environment and the immune cells is linked to metabolic homeostasis under physiologic and pathophysiologic conditions. Diabetes mellitus type 2 (T2D) is considered an immune-related inflammatory disorder, in which the adipose tissue macrophages (ATMs) are key players orchestrating metabolic chronic meta-inflammation and contributing to the pathogenesis of metabolic disease. However, the molecular regulators that integrate the environmental signals to control ATM activation and adipose inflammation during obesity and T2D remain unclear. Epigenetic mechanisms constitute important parameters in metabolic homeostasis, obesity and T2D via the integration of the environmental factors to the transcriptional regulation of gene programs. In a very recent study published in Diabetes by Kong et al., BAF60a has been identified as a key chromatin remodeling checkpoint factor that associates obesity-associated stress signals with meta-inflammation and systemic homeostasis. Furthermore, this work uncovers Atf3 as an important downstream effector in BAF60a-mediated chromatin remodeling and transcriptional reprogramming of macrophage activation in adipose tissue. The findings of this research may contribute to the development of new therapeutic approaches for obesity-induced metabolic inflammation and associated metabolic disorders.