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Abstract The effects of neurotoxicant cadmium (Cd) exposure on brain development have not been well elucidated. To investigate this, we have herein subjected pregnant mice to low-dose Cd throughout gestation. Using single-cell RNA sequencing (scRNA-seq), we explored the cellular responses in the embryonic brain to Cd exposure, and identified 18 distinct cell subpopulations that exhibited varied responses to Cd. Typically, Cd exposure impeded the development and maturation of cells in the brain, especially progenitor cells such as neural progenitor cells (NPCs) and oligodendrocyte progenitor cells (OPCs). It also caused significant cell subpopulation shifts in almost all the types of cells in the brain. Additionally, Cd exposure reduced the dendritic sophistication of cortical neurons in the offspring. Importantly, these changes led to aberrant Ca2+ activity in the cortex and neural behavior changes in mature offspring. These data contribute to our understanding of the effects and mechanisms of Cd exposure on brain development and highlight the importance of controlling environmental neurotoxicant exposure at the population level.

Abstract Cadmium (Cd) is a neurotoxic contaminant that induces cognitive decline similar to that observed in Alzheimer's disease (AD). Autophagic flux dysfunction is attributed to the pathogenesis of AD, and this study aimed to investigate the effect of autophagy on environmental Cd‐induced AD progression and the underlying mechanism. Here, Cd exposure inhibited autophagosome‐lysosome fusion and impaired lysosomal function, leading to defects in autophagic clearance and then to APP accumulation and nerve cell death. Proteomic analysis coupled with Ingenuity Pathway Analysis (IPA) identified SIRT5 as an essential molecular target in Cd‐impaired autophagic flux. Mechanistically, Cd exposure hampered the expression of SIRT5, thus increasing the succinylation of RAB7A at lysine 31 and inhibiting RAB7A activity, which contributed to autophagic flux blockade. Importantly, SIRT5 overexpression led to the restoration of autophagic flux blockade, the alleviation of Aβ deposition and memory deficits, and the desuccinylation of RAB7A in Cd‐exposed FAD4T mice. Additionally, SIRT5 levels decrease mainly in neurons but not in other cell clusters in the brains of AD patients according to single‐nucleus RNA sequencing data from the public dataset GSE188545. This study reveals that SIRT5‐catalysed RAB7A desuccinylation is an essential adaptive mechanism for the amelioration of Cd‐induced autophagic flux blockade and AD‐like pathogenesis.

AbstractEpigallocatechin gallate (EGCG) is a main component in green tea extract, which possesses multiple bioactivities. The present research studied the effects of EGCG on the laying performance, egg quality, immune status, antioxidant capacity, and hepatic metabolome of Linwu laying ducks reared under high temperature. A total of 180 42-w-old healthy Linwu laying ducks were allocated into control or EGCG-treated groups. Each treatment had 6 replicates with 15 ducks in each replicate. Diets for the two groups were basal diets supplemented with 0 or 300 mg/kg EGCG, respectively. All ducks were raised in the high temperature condition (35 ± 2 °C for 6 h from 10:00 to 16:00, and 28 ± 2 °C for the other 18 h from 16:00 to 10:00 the next day) for 21 days. Results showed that EGCG increased the egg production rate (p = 0.014) and enhanced the immunocompetence by improving serum levels of immunoglobulin A (p = 0.008) and immunoglobulin G (p = 0.006). EGCG also fortified the antioxidant capacity by activating superoxide dismutase (p = 0.012), catalase (p = 0.009), and glutathione peroxidase (p = 0.021), and increasing the level of heat-shock protein 70 (p = 0.003) in laying ducks’ liver. At the same time, hepatic metabolomics result suggested that EGCG increased the concentration of several key metabolites, such as spermidine (p = 0.031), tetramethylenediamine (p = 0.009), hyoscyamine (p = 0.026), β-nicotinamide adenine dinucleotide phosphate (p = 0.038), and pantothenic acid (p = 0.010), which were involved in the metabolic pathways of glutathione metabolism, arginine and proline metabolism, β-alanine metabolism, and tropane, piperidine, and pyridine alkaloid biosynthesis. In conclusion, 300 mg/kg dietary EGCG showed protection effects on the laying ducks reared in high temperature by improving the immune and antioxidant capacities, which contributed to the increase of laying performance of ducks. The potential mechanism could be that EGCG modulate the synthesis of key metabolites and associated metabolic pathways.

Alveolar epithelial cell (AEC) senescence is considered to be a universal pathological feature of many chronic pulmonary diseases. Our previous study found that epoxyeicosatrienoic acids (EETs), produced from arachidonic acid (ARA) through the cytochrome P450 cyclooxygenase (CYP) pathway, have significant negative regulatory effects on cellular senescence in AECs. However, the exact mechanisms by which EETs alleviate the senescence of AECs still need to be further explored. In the present study, we observed that bleomycin (BLM) induced enhanced mitophagy accompanied by increased mitochondrial ROS (mito-ROS) content in the murine alveolar epithelial cell line MLE12. While EETs reduced BLM-induced mitophagy and mito-ROS content in MLE12 cells, and the mechanism was related to the regulation of NOX4/Nrf2-mediated redox imbalance. Furthermore, we found that inhibition of EETs degradation could significantly inhibit mitophagy and regulate NOX4/Nrf2 balance to exert anti-oxidant effects in D-galactose-induced premature aging mice. Collectively, these findings may provide new ideas for treating age-related pulmonary diseases by targeting EETs to improve mitochondrial dysfunction and reduce oxidative stress.

Polycystic Ovary Syndrome (PCOS) is a multifaceted endocrine disorder that implicates a spectrum of clinical manifestations, including hormonal imbalance, metabolic dysfunction, and even compromised ovarian granulosa cell (GC) activity. The underlying molecular mechanisms of PCOS remain elusive, presenting a significant barrier to effective diagnosis and treatment. This review delves into the emerging role of long non-coding RNAs (lncRNAs) in the pathophysiology of PCOS, articulating their intricate interactions with mRNAs, microRNAs, and other epigenetic regulators that collectively influence the hormonal and metabolic milieu of PCOS. We examine the dynamic regulatory networks orchestrated by lncRNAs that impact GC function, steroidogenesis, insulin resistance, and inflammatory pathways. By integrating findings from recent studies, we illuminate the potential of lncRNAs as biomarkers for PCOS and highlight their contribution to the disorder, offering a detailed perspective on the lncRNA-mediated modulation of gene expression and pathogenic pathways. Understanding targeted lncRNA interactions with PCOS proposes novel avenues for therapeutic intervention to ameliorate the reproductive and metabolic disturbances characteristic of the syndrome.

In pressurized water reactors, LiOH may be concentrated in some areas, leading to the accelerated corrosion of fuel claddings. Injecting boric acid into primary coolants can mitigate the accelerated corrosion effect of LiOH on Zircaloys, but the effects of boron content on the corrosion behavior of the Zr-Sn-Nb alloy are still unknown. This work focused on the corrosion and hydrogen absorption behavior at 360 °C/18.6 MPa in 100 mg/kg LiOH solutions with 0 mg/kg, 50 mg/kg, and 200 mg/kg boron contents for up to 510 days, aiming to study the effect of boron content on corrosion resistance in LiOH solutions. Corrosion kinetics, microstructures of oxide films, hydrogen absorption concentrations and hydride morphology were obtained after the test. The results show that injecting boron in LiOH solutions can significantly reduce the corrosion weight gain, hydrogen concentration, and hydrogen length of Zr-Sn-Nb alloys, that is, improving corrosion resistance effectively. During the oxidation of the Zr-Sn-Nb alloy, B3+ and Li+ incorporate in oxide films. The incorporation of Li+ may lead to the generation of oxygen vacancies, which can carry oxygen from the solutions to O/M interface, accelerating corrosion. The incorporation of B3+ in oxide films will slow down the oxidation of Zr-Sn-Nb alloys by reducing the oxygen vacancies caused by Li+ aggregation.

Lead (Pb) and arsenic (As) are commonly occurring heavy metals in the environment and produce detrimental impacts on the central nervous system. Although they have both been indicated to exhibit neurotoxic properties, it is not known if they have joint effects, and their mechanisms of action are likewise unknown. In this study, zebrafish were exposed to different concentrations of Pb (40 μg/L, 4 mg/L), As (32 μg/L, 3.2 mg/L) and their combinations (40 μg/L + 32 μg/L, 4 mg/L + 3.2 mg/L) for 30 days. The histopathological analyses showed significant brain damage characterized by glial scar formation and ventricular enlargement in all exposed groups. In addition, either Pb or As staining inhibited the swimming speed of zebrafish, which was enhanced by their high concentrations in a mixture. To elucidate the underlying mechanisms, we examined changes in acetylcholinesterase (AChE) activity, neurotransmitter (dopamine, 5-hydroxytryptamine) levels, HPI axis-related hormone (cortisol and epinephrine) contents and neurodevelopment-related gene expression in zebrafish brain. The observations suggest that combined exposure to Pb and As can cause abnormalities in swimming behavior and ultimately exacerbate neurotoxicity in zebrafish by interfering with the cholinergic system, dopamine and 5-hydroxytryptamine signaling, HPI axis function as well as neuronal development. This study provides an important theoretical basis for the mixed exposure of heavy metals and their toxicity to aquatic organisms.

Cadmium is a highly ubiquitous environmental pollutant that poses a serious threat to human health. In this study, we assessed the cardiotoxicity of Cd exposure and explored the possible mechanisms by which Cd exerts its toxic effects. The results demonstrated that exposure to Cd via drinking water containing CdCl2 10 mg/dL for eight consecutive weeks induced cardiac injury in C57BL/6J mice. The histopathological changes of myocardial hemolysis, widening of myocardial space, and fracture of myocardial fiber were observed. Meanwhile, elevated levels of cardiac enzyme markers and up-regulation of pro-apoptotic genes also indicated cardiac injury after Cd exposure. Non-targeted lipidomic analysis demonstrated that Cd exposure altered cardiac lipid metabolism, resulted in an increase in pro-inflammatory lipids, and changed lipid distribution abundance. In addition, Cd exposure affected the secretion of inflammatory cytokines by activating the NF-κB signaling pathway, leading to cardiac inflammation in mice. Taken together, results of our present study expand our understanding of Cd cardiotoxicity at the lipidomic level and provide new experimental evidence for uncovering the association of Cd exposure with cardiovascular diseases.

Although adequate intake of manganese (Mn) is essential to humans, Mn in excess is neurotoxic. Exposure to extremely high doses of Mn results in “manganism”, a condition that exhibits Parkinson-like symptoms. However, the mechanisms underlying its neurotoxic effects in Mn-induced parkinsonism pathogenesis are unclear. In this study, 8-week-old male C57BL/6 J mice were injected intraperitoneally with saline and 50 mg/kg MnCl2 respectively once daily for 14 days to produce an acute Mn neurotoxicity model. Accumulation of Mn in the midbrain, motor dysfunction and loss of dopaminergic neurons in the substantia nigra evidenced Mn neurotoxicity. Untargeted lipidomic analysis demonstrated that Mn overexposure altered lipidome profiles. A significant modulation of 12 lipid subclasses belonging to 5 different categories were found in the midbrain and among the most abundant lipids were sphingolipids, glycerophospholipids, and glycerides. The levels of sphingomyelin (SM) were significantly decreased after Mn treatment. The expression of SM biosynthesis genes was decreased dramatically while sphingomyelinase was up-regulated. In addition, we observed oxidative stress in both the midbrain of mice and MN9D cells, indicated by the increase of MDA level, the decrease of reduced GSH level and the inhibition of SOD and GPx enzyme activities. There was a correlation between these changes and motor dysfunctions. Overall, our study is the first to use lipidomics techniques to explore the pathogenesis of Mn-induced parkinsonism in C57BL/6 J mice. Mn induced molecular events in the midbrain, such as lipid metabolism disorders, oxidative stress and dopaminergic neurons injury, may mechanistically play important roles in the pathogenesis of Parkinson-like symptoms. Moreover, these findings emphasize the necessity for reducing the health risk of environmental neurotoxic pollutants in relation to parkinsonism.

Simultaneous inhibition of histone deacetylases (HDACs) and anaplastic lymphoma kinase (ALK) could enhance therapeutic activity against ALK addicted cancer cells. Herein, a new series of 2,4-pyrimidinediamine derivatives as ALK and HDACs dual inhibitors were designed, synthesised and evaluated. Compound 12a which possessed good inhibitory potency against ALKwt and HDAC1, exhibited stronger antiproliferative activity than Ceritinib on ALK positive cancer cell lines though inducing cell apoptosis and cell cycle arrest in vitro and in vivo. In addition, the mechanism is further verified by the down-regulation of p-ALK protein, and up-regulation of Acetylated histone 3 (Ac-H3) protein in cancer cells. These results suggested that 12a would be a potential candidate for the ALK addicted cancer treatment.

All-polymer solar cells (all-PSCs) have attracted enormous attention and achieved significant progress in recent years due to their long-term stability and excellent film stretchability. However, the problem of morphology control in bulk-heterojunction (BHJ) films due to highly entangled polymeric chains hinders the further improvement of device performance. In this work, we obtained fine-tuned photoactive layer morphology through reconstructed microstructure induced by steric effects to realize an improved device performance in ternary all-PSCs. The large tetrahexylphenyl substituents on the backbone of naphthalene diimide–indacenodithienothiophene based copolymer acceptor BL-102 bring forth the steric-hindrance effect and influence intermolecular interactions. Therefore, the copolymer BL-102 delivers the property of suppressed self-aggregation, causing reconstructed crystalline features and morphology in blending films. The ternary devices tended to reduce the excessive phase separation by suppressing the aggregation of original polymers but to promote intermixing behaviors. Therefore, the optimal BHJ film manifested a well-formed bi-continuous interpenetrating nanoscale network with a larger π–π stacking coherence length and ordered face-on molecular orientation. Hence, a faster electron transfer (ET) and hole transfer (HT) process combined with balanced charge carrier mobilities can be achieved to enhance the overall device performance. This work provides an effective method to regulate the photoactive layer morphology of all-PSCs through structurally steric hindrance effects and demonstrate the significance of ternary-blending strategy induced nanoscale morphology modulation for fabricating highly efficient all-PSCs.

Using technology in education facilitates knowledge dissemination expediently while broadening and deepening learning modes and content diversity. As an information technological innovation, E-learning platform is widely used to learn college English. However, few studies have explored the motivations for students’ e-satisfaction and continued intention towards using it for college English study. Based on the extended Unified Theory of Acceptance and Use of Technology (UTAUT2), this study identifies the influencing factors for the continued usage intention and tests the mediating role of e-satisfaction and habit. Six hundred and twenty-six usable responses from Guangxi were analyzed with partial least squares structural equation modelling. Results show that performance expectancy, learning value, hedonic motivation and habit positively affects students’ continued usage intention, e-satisfaction positively mediates the relationship between the antecedents and continued usage intention, and habit positively mediates the relationship between e-satisfaction and continued usage intention. The research provides guidelines for the successful implementation of e-learning platform for college English study and key references for improvement of students’ engagement and satisfaction experience with using e-learning platform for college English study.

Doxorubicin (DOX) is an anthracycline antineoplastic agent that has limited clinical utility due to its dose-dependent cardiotoxicity. Although the exact mechanism remains unknown, inflammatory responses have been implicated in DOX-induced cardiotoxicity (DIC). In this study, we analyzed the transcriptomic, metabolomic as well as lipidomic changes in the DOX-treated mice to explore the underlying mechanisms of DIC. We found that continuous intraperitoneal DOX injections (3 mg/kg/d) for a period of five days significantly induced cardiac dysfunction and cardiac injury in male C57BL/6 J mice (8 weeks old). This corresponded to a significant increase in the myocardial levels of IL-4, IL-6, IL-10, IL-17 and IL-12p70. Furthermore, inflammation-related genes such as Ptgs2, Il1b, Cxcl5, Cxcl1, Cxcl2, Mmp3, Ccl2, Ccl12, Nfkbia, Fos, Mapk11 and Tnf were differentially expressed in the DOX-treated group, and enriched in the IL-17 and TNF signaling pathways. Besides, amino acids, peptides, imidazoles, toluenes, hybrid peptides, fatty acids and lipids such as Hex1Cer, Cer, SM, PG and ACCa were significantly associated with the expression pattern of inflammation-related genes. In conclusion, the integration of transcriptomic, metabolomic and lipidomic data identified potential new targets and biomarkers of DIC.

Abstract Aging causes astrocyte morphological degeneration and functional deficiency, which impairs neuronal functions. Until now, whether age-induced neuronal deficiency could be alleviated by engraftment of glial progenitor cell (GPC) derived astrocytes remained unknown. In the current study, GPCs were generated from embryonic cortical neural stem cells in vitro and transplanted into the brains of aged mice. Their integration and intervention effects in the aged brain were examined 12 months after transplantation. Results indicated that these in-vitro-generated GPC-derived astrocytes possessed normal functional properties. After transplantation they could migrate, differentiate, achieve long-term integration, and maintain much younger morphology in the aged brain. Additionally, these GPC-derived astrocytes established endfeet expressing aquaporin-4 (AQP4) and ameliorate AQP4 polarization in the aged neocortex. More importantly, age-dependent sensory response degeneration was reversed by GPC transplantation. This work demonstrates that rejuvenation of the astrocyte niche is a promising treatment to prevent age-induced degradation of neuronal and behavioral functions.

BackgroundHallux valgus (HV) is a common foot and ankle surgery disease. The correction of HV deformity relies on a highly challenging surgical treatment. Thus, widely adopted evidence-based clinical guidelines are still needed to guide the selection of the most appropriate interventions. Recently, the study of HV has been growing and scholars are increasingly paying particular attention to this area. However, bibliometric literature remains lacking. Therefore, this study aims to reveal the hotspots and future research trends in HV via bibliometric analysis to fill this knowledge gap.MethodsLiterature related to HV from 2004 to 2021 was retrieved from the Science Citation Index Expanded (SCI-expanded) of the Web of Science Core Collection (WoSCC). Quantitative and qualitative analyses of scientific data are performed using software such as CiteSpace, R-bibliometrix, and VOSviewer.ResultsA total of 1,904 records were identified for analysis. The United States had the most number of published articles and total citations. Thus, the United States has made an essential contribution to the field of HV. Meanwhile, La Trobe University in Australia was the most productive institution. Menz HB and Foot & Ankle International were the most influential authors and the most popular journals among researchers, respectively. In addition, “older people,” “chevron osteotomy,” “Lapidus,” and “hallux rigidus” have always been the hotspots of attention. Changes and developments in the surgery of HV have gained researchers' interest. Future research trends are more focused on “radiographic measurement,” “recurrence,” “outcome,” “rotation,” “pronation,” and “minimally invasive surgery.” Thus, focusing on these subject directions can facilitate academic progress and provide the possibility of better treatments for HV.ConclusionThis study summarizes the hotspots and trends in the field of HV from 2004 to 2021, which will provide researchers with an updated view of essential information and somehow guide future research.

Abstract Oral squamous cell carcinoma (OSCC) is the most common type of oral malignancy, and metastasis accounts for the poor prognosis of OSCC. Autophagy is considered to facilitate OSCC development by mitigating various cellular stresses; nevertheless, the mechanisms of autophagy in OSCC cell proliferation and metastasis remain unknown. In our study, high-sensitivity label-free quantitative proteomics analysis revealed nuclear protein 1 (NUPR1) as the most significantly upregulated protein in formalin-fixed paraffin-embedded tumour samples derived from OSCC patients with or without lymphatic metastasis. Moreover, NUPR1 is aberrantly expressed in the OSCC tissues and predicts low overall survival rates for OSCC patients. Notably, based on tandem mass tag-based quantitative proteomic analysis between stable NUPR1 knockdown OSCC cells and scrambled control OSCC cells, we confirmed that NUPR1 maintained autophagic flux and lysosomal functions by directly increasing transcription factor E3 (TFE3) activity, which promoted OSCC cell proliferation and metastasis in vitro and in vivo. Collectively, our data revealed that the NUPR1–TFE3 axis is a critical regulator of the autophagic machinery in OSCC progression, and this study may provide a potential therapeutic target for the treatment of OSCC.

It is generally considered that stress causes decreased immune function and render fish vulnerable to infection and diseases. However, the molecular mechanisms between stress responses and susceptibility to infections, especially viral diseases, in fish remain unknown. Understanding and monitoring the biological consequences and mechanisms underlying stress responses in fish may contribute to the improvement of animal welfare and production efficiency. In this study, long-term exposure to a variety of stressors, including chasing, overcrowding, restraint stress, and air exposure mimicking chronic stresses, in aquaculture practices was conducted in Carassius gibel to investigate the consequences of chronic stress on inflammation and antiviral capability. With the continuation of stimulation, experimental fish gradually became insensitive to the stress of net chasing and feeding with the accompaniment of upregulated gene expressed in the HPI axis and elevated levels of stress hormones. As expected, stress-induced hyperglycaemia with a decrease in the insulin signaling pathway and altered gene expression in glycolysis and gluconeogenesis, suggesting the disturbance of glycometabolism. Importantly, a link between intestinal homoeostasis and systemic low-grade inflammation in stressed C. gibel was observed, implying crosstalk among the brain, intestine, and other organs. Furthermore, the compromised antiviral capability with impaired antiviral innate immunity in stressed fish was confirmed by RNA sequencing and infection with Cyprinid herpesvirus 2 (CyHV-2), promoting the understanding of enhanced susceptibility to viral infection in stressed fish.

ABSTRACT: This study aimed to investigate the effects of diets supplemented with different levels of rosemary extract (RE) on the growth performance, meat quality, serum biochemistry, antioxidative capacity, and immunological capacity of Cherry Valley meat ducks. A total of 525 healthy Cherry Valley female meat ducks at 1 d of age were selected for this study. Ducks were randomly divided into 5 treatments with 7 replicates per treatment, and each replicate had 15 ducks. All replicates were randomly assigned to treatments. The study was designed as a dose response experiment. Treatment 1 (CON) was fed with the basal diet, and Treatment 2 to 5 (RE250, RE500, RE750, RE1000) were fed with the basal diet supplemented with 250, 500, 750, and 1,000 g/t RE, respectively. The whole experiment lasted 42 days with early stage (1–21 d) and late stage (22–42 d). Results showed that during 22 to 42 d, ducks that were fed over 500 g/t RE had significantly lower feed gain ratio than the ones in CON (P = 0.006). In addition, ducks in RE750 had significantly lower L* and a* in leg muscle compared with the ones in CON (P < 0.05). Besides, ducks that were fed between 250 and 750 g/t RE had significantly lower total protein level in serum compared with the ones in CON (P = 0.005). Ducks in RE250 and RE750 had significantly lower albumin, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels in serum compared with the ones in CON and RE1000 (P < 0.05), and significant quadratic relationships were noticed between albumin, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol and dietary RE level (P < 0.05). Moreover, ducks that were fed between 500 and 750 g/t RE had significantly higher levels of interleukin-2 in serum compared to the ones in CON and RE1000 (P = 0.003). Ducks in RE250 and RE750 had significantly higher levels of immunoglobulin G in serum compared to the ones in CON and RE1000 (P < 0.001). Ducks that were fed over 500 g/t RE had significantly higher levels of immunoglobulin A in serum compared to the ones in CON (P = 0.001). Finally, ducks that were fed between 500 and 750 g/t RE had significantly higher serum levels of glutathione peroxidase, superoxide dismutase, catalase, and total antioxidant capacity (P < 0.05) compared to the ones in CON. Ducks that were fed over 250 g/t RE had significantly lower serum level of malondialdehyde compared to the ones in CON (P = 0.020). Collectively, dietary supplementation of RE improved the growth performance and meat qualities of meat ducks during 22 to 42 d, which were possibly associated with the antioxidative and anti-inflammatory effects of RE. Based on the serum antioxidative and immunological parameters, we suggested that 500 to 750 g/t was the optimal supplementation rate for RE in diets for meat ducks aged 22 to 42 d.

Cadmium (Cd), which is considered an endocrine disruptor, has been linked to the onset of breast cancer (BC). Our recent study demonstrated that Cd-induced BC progression has a strong correlation with miR-374c-5p dysregulation. The aim of our work was to investigate other potential miRNAs involved in Cd-induced BC cell proliferation and metastasis. In our study, the miRNA profiles of Cd-treated T-47D cells (10 μM, 72 h) were analyzed by miRNA-seq, and our results confirmed that miR-3614–5p was the top downregulated miRNA. Moreover, miR-3614–5p mimic transfection significantly decreased the proliferative ability, migration and invasive ability of BC cell lines (T-47D and MCF-7). Furthermore, we analyzed the overlapping genes from our RNA-seq data and predicted targets from the mirDIP database, and twelve genes (ALDH1A3, FBN1, GRIA3, NOS1, PLD5, PTGER4, RASGRF2, RELN, RNF150, SLC17A4, TG, and TXNRD1) were identified as potential binding targets of miR-3614–5p in the current model. Nonetheless, only miR-3614–5p inhibition caused an increase in TXNRD1 expression upon Cd exposure in T-47D and MCF-7 cell lines. Importantly, luciferase reporter assays further verified that miR-3614–5p suppressed the expression of TXNRD1 by directly binding to the 3′-untranslated region (UTR), and TXNRD1 inhibition significantly repressed the proliferation and metastasis capacity of BC cells upon Cd exposure. Together, our findings demonstrated that Cd exposure repressed the expression of miR-3614–5p, thus activating TXNRD1 expression, which promoted the abnormal proliferation and metastasis of BC cells.

The immunoglobulin (Ig) is a crucial component of adaptive immune system in vertebrates including teleost fish. Here complete cDNA sequence of IgD heavy chain gene from common carp (Cyprinus carpio) was cloned and analyzed. The full-length cDNA of IgD heavy chain gene contained an open reading frame (ORF) of 2460 bp encoding 813 amino acids. According to amino acids sequence, multiple alignment and phylogenetic analysis showed that carp Igs are closely related to those of Cyprinidae fish. Transcriptional expression of IgD as well as IgM, IgZ1 and IgZ2 showed similar expression patterns in different organs, this is, high expression level in systemic immune tissues (ie, head kidney, heart and spleen) and low expression in mucosal tissues (ie, gill, skin and gut). Following viral infection with spring viraemia of carp virus (SVCV), obvious pathological changes in skin, gill and gut mucosa and up-regulated expression of antiviral related genes in skin, gill, gut and spleen were observed, indicating that SVCV successfully infected common carp and activated the systemic and mucosal immune system. Interestingly, IgM showed a significant up-regulation only in systemic tissue (spleen), but not in mucosal tissues (gut, gills and skin), while increased expression of IgZ1 and IgZ2 was found in gut. In contrast, the expression of IgD increased significantly in spleen, gills and skin. These strongly suggest that fish Ig isotypes play different roles in mucosal and systemic immunity during viral infection.Common carp (Cyprinus carpio); Igs; Spring viraemia of carp virus (SVCV)

IntroductionThis study aimed to investigate the effects of organic trace elements chelated with hydroxy methionine (OTE-HM) in diets, which substituted inorganic trace elements, on laying performance, egg quality, blood microelement content, antioxidant capacity and immune function of laying ducks.MethodsA total of 300 healthy laying ducks at age of 30 wk were randomly divided into 5 treatments and 10 ducks per replicate. The treatments included a control group (CON) which was served with basal diet supplemented with 20 mg/kg Cu, 50 mg/kg Fe, 70 mg/kg Mn, and 70 mg/kg Zn in inorganic form, and 4 OTE-HM treated groups (OTE-HM25, OTE-HM50, OTE-HM75, OTE-HM100) which were served with basal diets supplemented with OTE-HM providing trace elements (combination of Cu, Fe, Mn, Zn) at 25%, 50%, 75% and 100% of the commercial levels, respectively.ResultsResults showed that substitution of inorganic trace elements with OTE-HM did not affect egg production, qualified egg rate, average egg weight, average daily egg mass, average daily feed intake, or feed per kg egg of laying ducks (P > 0.05). Dietary with OTE-HM did not influence eggshell strength, eggshell thickness, egg shape index, eggshell ratio, yolk ratio, albumen ratio, albumen height, and Haugh unit of the sampled eggs of ducks (P > 0.05), but increased the yolk color, compared with dietary with inorganic trace elements (P< 0.01). Moreover, the blood content of Cu of the laying ducks was significantly increased by OTE-HM compared with that in CON (P< 0.001), but the other elements in laying duck blood were not different among treatments (P > 0.05). OTE-HM (75% and 100%) significantly increased serum activities of glutathione peroxidase and Cu-Zn superoxide dismutase, and decreased serum content of malonaldehyde of laying ducks compared with those in CON (P< 0.05). OTE-HM (50%, 75%, and 100%) significantly increased the serum contents of immunoglobulin G and immunoglobulin A of laying ducks compared with those in CON (P< 0.05).DiscussionCollectively, replacing inorganic trace elements with 50% and 75% OTE-HM in diets did not influence the laying performance or egg quality, but improved trace element efficacy, antioxidant capacity and immune function of the laying ducks.

Paraquat (PQ) is the most widely used herbicide in the world and a well-known potent neurotoxin for humans. PQ exposure has been linked to increase the risk of Parkinson's disease (PD). However, the mechanism underlying its neurotoxic effects in PD pathogenesis is unclear. In our present study, C57BL/6J mice treated with PQ manifested severe motor deficits indicated by the significant reductions in suspension score, latency to fall from rotarod, and grip strength at 8 weeks after PQ exposure. Pathological hallmarks of Parkinsonism in the midbrain such as dopaminergic neuron loss, increased α-synuclein protein, and dysregulated PD-related genes were observed. Non-targeted lipidome analysis demonstrated that PQ exposure alters lipid profile and abundance, increases pro-inflammatory lipids.27 significantly altered subclasses of lipids belonged to 6 different lipid categories. Glycerophospholipids, sphingolipids, and glycerides were the most abundant lipids. Abundance of pro-inflammatory lipids such as Cer, LPC, LPS, and LPI was significantly increased in the midbrain. mRNA expressions of genes regulating ceramide biosynthesis in the midbrain were markedly up-regulated. Moreover, PQ exposure increased serum pro-inflammatory cytokines and provoked neuroinflammation in the midbrain. Pro-inflammatory lipids and cytokines in the midbrain were positively correlated with motor deficits. PQ poisoning in humans significantly also elevated serum pro-inflammatory cytokines and induced an intense systemic inflammation. In summary, we presented initial investigations of PQ induced molecular events related to the PD pathogenesis, capturing aspects of disturbed lipid metabolism, neuroinflammation, impairment of dopaminergic neurons in the midbrain, and an intense systemic inflammation. These neurotoxic effects of PQ exposure may mechanistically contribute to the pathogenesis of PQ induced Parkinsonism. Results of this study also strongly support the hypothesis that ever-increasing prevalence of Parkinson’s disease is etiologically linked to the health risk of exposure to neurotoxic environmental pollutants.

After the legislative ban on the utilization of antibiotics in animal feed, phytochemical substances gained increasing attention as alternatives to antibiotics because of their bioactivities and safety for animals. The present study aimed to investigate the influence of dietary rosemary extract (RE) on growth performance, meat quality, serum biochemistry, antioxidant and immune capacities, and gut microbiota composition of broilers. By exploring connections among RE, physiological characteristics of broilers, and key microbiota, we sought to provide evidence for the utilization of RE in poultry feed. A total of 280 1-d-old female AA broilers were randomly separated into five groups, and were fed a basal diet supplemented with 0, 250, 500, 750, and 1,000 mg/kg of RE, respectively. Results showed that with regard to growth performance, both 500 and 750 mg/kg RE reduced the broiler feed-to-gain ratio from 1 to 21 d (P = 0.018). Regarding meat quality, all compositions of dietary RE reduced cooking loss of breast muscle (P < 0.01), and 500 and 1,000 mg/kg RE reduced the cooking loss of thigh muscle (P = 0.045). Regarding serum biochemical indexes, 500 mg/kg RE reduced ALB, TCHO, HDL-C, and LDL-C, and 750 mg/kg RE reduced GLU, TP, ALB, UA, TG, TCHO, HDL-C, and LDL-C (P < 0.01). Regarding antioxidant and immune capacities, 250, 500, 750, and 1,000 mg/kg RE increased T-AOC, GSH-Px, SOD, CAT, IL-2, IgA, IgG, and IgM levels (P < 0.01), and decreased serum MDA level (P < 0.01). RE at 750 mg/kg showed similar effects on growth performance, meat quality, and antioxidative and immune capacities, but a better influence on serum biochemical indexes of broilers compared with 500 mg/kg. Further analysis was conducted to investigate the effect of 750 mg/kg dietary RE on the gut microbial composition of broilers, and the results showed that 750 mg/kg RE reduced the relative abundance of g_Lachnoclostridium, g_Escherichia_Shigella, and g_Marvinbryantia (P 2), which were negatively correlated to antioxidative and immune-associated parameters (P < 0.05). In conclusion, 750 mg/kg dietary RE was shown to have certain beneficial effects on growth performance and meat quality, and hypolipidemic and hypoglycemic effects on broilers. Furthermore, dietary RE improved antioxidant and immune capacities, which was partially attributed to the reduced abundance of certain pathogenic bacteria in broilers.

Fluoride has received much attention for its predominant bone toxicity in the human body. However, the toxic mechanism of bone injury caused by fluoride exposure remains largely unclear. Bone marrow mesenchymal stem cells (BMSCs) are widely used as model cells for evaluating bone toxicity after environmental toxicant exposure. In this study, BMSCs were exposed to fluoride at 1, 2, and 4 mM for 24 h, and fluoride significantly inhibited cell viability at 2 and 4 mM. A multiomics analysis combining transcriptomics with metabolomics was employed to detect alterations in genes and metabolites in BMSCs treated with 2 mM fluoride. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of transcriptomics profiles identified “lysosomes” as the top enriched pathway, which was severely damaged by fluoride exposure. Lysosomal damage was indicated by decreases in the expression of lysosomal associated membrane protein 2 (LAMP 2) and cathepsin B (CTSB) as well as an increase in pH. Upregulation of the lysosome-related genes Atp6v0b and Gla was observed, which may be attributed to a compensatory lysosomal biogenesis transcriptional response. Interestingly, inhibition of glutathione metabolism was observed in fluoride-treated BMSCs at the metabolomic level. Moreover, an integrative analysis between altered genes, metabolites and lysosome signaling pathways was conducted. Palmitic acid, prostaglandin C2, and prostaglandin B2 metabolites were positively associated with Atp6v0b, a lysosome-related gene. Overall, our results provide novel insights into the mechanism responsible for fluoride-induced bone toxicity.

Difenoconazole is a type of triazole fungicide that is widely used in the treatment of plant diseases. Triazole fungicides have been shown in several studies to impair the development of the nervous system in zebrafish embryos. There is still little known about difenoconazole-induced neurotoxicity in fish. In this study, zebrafish embryos were exposed to 0.25, 0.5, and 1 mg/L of difenoconazole solution until 120 h post-fertilization (hpf). The difenoconazole-exposed groups showed concentration-dependent inhibitory tendencies in heart rate and body length. Malformation rate and spontaneous movement of zebrafish embryos increased, and the locomotor activity decreased in the highest exposure group. The content of dopamine and acetylcholine was reduced significantly in difenoconazole treatment groups. The activity of acetylcholinesterase (AChE) was also increased after treatment with difenoconazole. Furthermore, the expression of genes involved in neurodevelopment was remarkably altered, which corresponded with the alterations of neurotransmitter content and AChE activity. These results indicated that difenoconazole might affect the development of the nervous system through influencing neurotransmitter levels, enzyme activity, and the expression of neural-related genes, ultimately leading to abnormal locomotor activity in the early stages of zebrafish.

Abstract Backgrounds The dried rhizome of Ligusticum sinense Oliv.cv. Chaxiong has been used to treat cardiovascular and cerebrovascular diseases, atherosclerosis, anemia and stroke. A high purity extract from chaxiong (VOC, brownish yellow oil) was extracted and separated. Its main components were senkyunolide A (SA, 33.81%), N-butylphthalide (NBP, 1.38%), Neocnidilide (NOL, 16.53%), Z-ligustilide (ZL, 38.36%), and butenyl phthalide (BP, 2.48%), respectively. Little is known about the pharmacokinetics of these phthalides in Chaxiong, and different preparations to improve the physicochemistry and pharmacokinetics of VOC have not been investigated. Methods At different predetermined time points after oral administration or intravenous administration, the concentrations of SA, NBP, NOL, ZL and BP in the rat plasma were determined using LC-MS/MS, and the main PK parameters were investigated. VOC-P188 solid dispersion and VOC-β-CD inclusion compound were prepared by melting solvent method and grinding method, respectively. Moreover, the physicochemical properties, dissolution and pharmacokinetics of VOC-P188 solid dispersion and VOC-β-CD inclusion compound in rats were assessed in comparison to VOC. Results The absorptions of SA, NBP, NOL, ZL and BP in VOC were rapid after oral administration, and the absolute bioavailability was less than 25%. After the two preparations were prepared, dissolution rate was improved at pH 5.8 phosphate buffer solution. Comparing VOC and physical mixture with the solid dispersion and inclusion compound, it was observed differences occurred in the chemical composition, thermal stability, and morphology. Both VOC-P188 solid dispersion and VOC-β-CD inclusion compound had a significantly higher AUC and longer MRT in comparison with VOC. Conclusion SA, NBP, NOL, ZL and BP in VOC from chaxiong possessed poor absolute oral bioavailability. Both VOC-P188 solid dispersion and VOC-β-CD inclusion compound could be prospective means for improving oral bioavailability of SA, NBP, NOL, ZL and BP in VOC.

Cd exposure has been demonstrated to induce a variety of metabolic disorders accompanied with imbalance of glucose and lipid homeostasis. The metabolic toxicity of Cd exposure at metabolome-wide level remains elusive. In our study, we demonstrated that Cd exposure via drinking water increased blood glucose levels, decreased serum insulin levels, led to glucose intolerance and suppressed insulin expression in the pancreas of C57/6J mice. Cd exposure significantly inhibited cell viability and suppressed insulin secretion in MIN6 cells in vitro. Since pancreatic β-cells are the only source of insulin production in the body and play a pivotal role in modulating glucose and lipid metabolisms, we further delineated the metabolomic signatures of Cd exposure in insulin-secreting MIN6 cells by using non-target metabolomics. PCA and OPLS-DA analysis clearly suggested that Cd exposure led to a marked metabolic alteration in MIN6 cells. 76 perturbed metabolites were identified after Cd exposure. Classification of metabolites suggested that Cd perturbed metabolites belong to nucleosides, nucleotides and analogues, organic acids and derivatives, and lipids and lipid-like molecules. 28 perturbed metabolites existed in mitochondrion, suggesting mitochondrion as the major target organelle in metabolic toxicity of Cd exposure. KEGG pathway analysis revealed that 20 metabolic pathways were disturbed by Cd exposure. Mitochondrial TCA cycle and glycerophospholipid metabolism were remarkably disturbed. The mRNA expressions of genes in mitochondrial TCA cycle and fatty acid oxidation in pancreas and MIN6 cells were significantly dysregulated by Cd exposure. Disturbances in mitochondrial TCA cycle and glycerophospholipid metabolism result in producing perturbed metabolites in pancreatic β-cells. Moreover, 14 perturbed metabolites identified in MIN6 cells co-existed in the urine of Cd exposed workers. 11 biomarkers of diabetes mellitus were also found to be significantly altered in the urine of Cd exposed workers. In conclusion, findings of this study greatly extend our understanding of metabolic toxicity of Cd exposure in pancreatic β-cells at metabolome-wide level and offer some new clues for linking Cd exposure to development of diabetes mellitus. Results of this study also support the notion that Cd induced metabolic toxicity could be monitored by examining perturbed urinary metabolites in humans and highlight the significance of reducing Cd exposure via drinking water at population level.

Abstract Background Circular RNAs (circRNAs) are a class of endogenous single-strand RNA transcripts with crucial regulation in human cancers. The objective of this study is to investigate the role of circ_0082182 in CRC and its specific functional mechanism. Methods The quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure the levels of circ_0082182, microRNA-411 (miR-411) and microRNA-1205 (miR-1205). Cell proliferation was detected by Cell counting Kit-8 (CCK-8) and colony formation assays. Flow cytometry was used for determining cell cycle and cell apoptosis. Cell apoptosis was also assessed by caspase3 and caspase9 activities. Cell migration and invasion were examined using scratch assay and transwell assay. The interaction between circ_0082182 and miRNA was validated by the dual-luciferase reporter and biotinylated RNA pull-down assays. Wnt/β-catenin pathway and epithelial-mesenchymal transition (EMT)-associated proteins were quantified by Western blot. Xenograft model was established for the research of circ_0082182 in vivo. Results Circ_0082182 was upregulated in CRC and could predict the poor prognosis of CRC patients. Functionally, circ_0082182 promoted CRC cell proliferation, cell cycle progression, and metastasis while inhibited apoptosis. Subsequently, circ_0082182 was shown to act as the sponges of miR-411 and miR-1205. MiR-411 and miR-1205 were identified as tumor inhibitors in CRC. Furthermore, circ_0082182 promoted the CRC progression via sponging miR-411 and miR-1205. Moreover, circ_0082182 facilitated the Wnt/β-catenin pathway and EMT process by targeting miR-411 and miR-1205. In vivo, circ_0082182 accelerated the CRC tumorigenesis and EMT process by activating the Wnt/β-catenin pathway by downregulating the expression of miR-411 or miR-1205. Conclusion This study showed that circ_0082182 functioned as an oncogene in the developing process of CRC by sponging miR-411 or miR-1205 to activate the Wnt/β-catenin pathway. Circ_0082182 might be a molecular target in the diagnosis and treatment of CRC.

Abstract Grain boundary (GB) oxidation of proton-irradiated 304 nuclear grade stainless steel in primary water of pressurized water reactor was investigated. The investigation was conducted by studying microstructure of the oxide and oxide precursor formed at GB on an "atom-by-atom" basis by a combination of atom-probe tomography and transmission electron microscope. The results revealed that increasing irradiation dose promoted the GB oxidation, in correspondence with a different oxide and oxide precursor formed at the GB. Correlation of the oxide and oxide precursor with the GB oxidation behavior has been discussed in detail.

As a γ-aminobutyric acid A receptor (GABAAR) inhibitor, etomidate fulfills several characteristics of an ideal anesthetic agent, such as rapid onset with rapid clearance and high potency, along with cardiovascular stability. Unfortunately, etomidate has been reported to inhibit CYP11B1 at hypnotic doses, which is associated with a marked increase in patient deaths due to this unexpected off-target effect. In this study, molecular docking was used to simulate the binding mode of etomidate with GABAAR and CYP11B1. Based on the in-depth analysis of the binding mode, strong electron-withdrawing group on the C4 position of the imidazole ring was introduced to reduce the charge density of the nitrogen, which is beneficial in reducing the coordination bond between the imidazole nitrogen and heme iron in CYP11B1, as well as in reducing the adrenocortical suppression. Based on the results of ADMET property prediction, MEP analysis, and molecular docking simulation, 4-fluoroetomidate (EL-0052) was designed and synthesized. In vivo studies in rats and mice confirmed that EL-0052 had the efficacy similar to etomidate, but without adrenocortical suppression. These findings suggested that EL-0052 was superior to etomidate and support the continued development of EL-0052 as a preclinical candidate as an anesthetic.

To gain insight into the differences in the composition and volatile components content in ancient Platycladus orientalis leaves with different tree ages in Huangdi Mausoleum, the volatile components were identified by headspace solid-phase microextraction combined with gas chromatography-mass spectrometry (HS–SPME–GC–MS) method. The volatile components were statistically analyzed by orthogonal partial least squares discriminant analysis and hierarchical cluster analysis, and the characteristic volatile components were screened. The results exhibited that a total of 72 volatile components were isolated and identified in 19 ancient Platycladus orientalis leaves with different tree ages, and 14 common volatile components were screened. Among them, the contents of α-pinene (6.40–16.76%), sabinene (1.11–7.29%), 3-carene (1.14–15.12%), terpinolene (2.17–4.95%), caryophyllene (8.04–13.53%), α-caryophyllene (7.34–14.41%), germacrene D (5.27–12.13%), (+)-Cedrol (2.34–11.30%) and α-terpinyl acetate (1.29–25.68%) were relatively higher (>1%), accounting for 83.40–87.61% of the total volatile components. Nineteen ancient Platycladus orientalis trees were clustered into three groups through the HCA method based on the 14 common volatile components content. Combined with the results of OPLS–DA analysis, (+)-cedrol, germacrene D, α-caryophyllene, α-terpinyl acetate, caryophyllene, β-myrcene, β-elemene and epiglobulol were the differential volatile components to distinguish ancient Platycladus orientalis with different tree ages. The results revealed that the composition of the volatile components in ancient Platycladus orientalis leaves with different tree ages was different, showing different aroma characteristics, which provided a theoretical reference for the differential development and application of volatile components in ancient Platycladus orientalis leaves.

Target localization has been a popular research topic in recent years since it is the basis of all kinds of location-based applications. For GNSS-denied urban or indoor environments, the localization method based on time-of-arrival (TOA) is one of the most popular localization methods due to its high accuracy and simplicity. However, the Non-line-of-sight (NLOS) error is the major cause that degrades the accuracy of the TOA-based localization method. Identifying whether a received signal at a base station (BS) is due to a line-of-sight (LOS) transmission or NLOS is the key to TOA-based localization methods. In the popular LOS signal identification methods, compared with statistic signal methods and machine learning methods, the geometric constraint method has the advantages of simplicity and without requiring priori knowledge of signals and large amounts of training datasets. In this paper, we propose a geometric constraint two-step LOS signal identification method based on common chord intersection point position deviation from mobile stations (MS). In the first step, all BSs are divided into multiple BS combinations with every three BSs, the TOA distance error of each BS combination is estimated based on common chord intersection point position deviation from MS, the BS combinations whose TOA distance error satisfy Gaussian distribution are roughly identified as LOS BS combination and enter the second step, the other BS combinations are discarded as NLOS BS combination. In the second step, based on mutual distance threshold and discrimination result matrix, common chord intersection points of LOS BS combination, and corresponding LOS BS combinations are identified. The BSs of LOS BS combinations are identified as LOS BS and the signals received at LOS BS are identified as LOS signal ultimately. Compared with the other two geometric constraint methods, the proposed algorithm has better identification accuracy, and the setting of the identification threshold value has a theoretical basis, which facilitates the application of the proposed algorithm.

Utilization of infrared light in photocatalytic water splitting is highly important yet challenging given its large proportion in sunlight. Although upconversion material may photogenerate electrons with sufficient energy, the electron transfer between upconversion material and semiconductor is inefficient limiting overall photocatalytic performance. In this work, a TiO2/graphene quantum dot (GQD) hybrid system has been designed with intimate interface, which enables highly efficient transfer of photogenerated electrons from GQDs to TiO2. The designed hybrid material with high photogenerated electron density displays photocatalytic activity under infrared light (20 mW cm-2) for overall water splitting (H2: 60.4 μmol gcat.-1 h-1 and O2: 30.0 μmol gcat.-1 h-1). With infrared light well harnessed, the system offers a solar-to-hydrogen (STH) efficiency of 0.80% in full solar spectrum. This work provides new insight into harnessing charge transfer between upconversion materials and semiconductor photocatalysts and opens a new avenue for designing photocatalysts toward working under infrared light.

Cadmium (Cd) is a toxic heavy metal that can facilitate the development and progression of breast cancer (BC). Emerging evidence has indicated that the progression of Cd-exposed BC is related to the dysregulation of microRNAs (miRNAs). The purpose of our study was to investigate the expression pattern and underlying mechanisms of miR-374c-5p in Cd-mediated BC progression. In this study, T-47D cells and MCF-7 cells were treated with different concentrations of Cd (0.1, 1 and 10 μM) for 72 h. MiR-374c-5p expression was downregulated, and transfection of miR-374c-5p mimics significantly decreased BC cell proliferation, migration and invasion induced by 10 μM Cd. Importantly, we used the Cytoscape software plugin cytoHubba to analyse the intersected genes between our RNA-Seq results and the mirDIP database, and six hub genes (CNR1, CXCR4, GRM3, RTN1, SLC1A6 and ZEB1) were identified as potential direct targets of miR-374c-5p in our model; however, luciferase reporter assays indicated that miR-374c-5p only repressed GRM3 by directly binding to its 3′-untranslated region (UTR). Of note, we verified that suppression of N6-methyladenosine (m6A) modification led to miR-374c-5p downregulation by decreasing its RNA transcript stability. Together, these findings demonstrated that m6A modification of pri-miRNA-374c blocks miRNA-374c-5p maturation and then activates GRM3 expression, which drives BC cell metastasis after Cd exposure.

In this paper, we proposed a model of how corporate acquisition influences industrial performance by exploring industry-level and firm-level ownership characteristics in emerging markets. Based on a database of 1,934 acquisitions of listed firms in China, we examined the relationship between corporate acquisition type and industrial performance and the moderating effects of industrial and firm ownership characteristics. The study generated three major findings: 1) compared with cross-industry acquisitions, intra-industry acquisitions of firms have a stronger positive effect on industrial performance; 2) corporate ownership and industrial ownership variables exert different moderating impact on the relationship between acquisition type and industrial performance; and 3) firm ownership and industrial ownership have a joint moderating effect on the relationship between acquisition type and industrial performance. By conceptually arguing and empirically verifying how multi-level factors influence industrial performance in the context of emerging economies, we contributed to the study of the relationship between the micro-level firm acquisition and the macro-level industrial development in several distinct ways.

Abstract To improve the reliability of virtual screening for transforming growth factor-beta type 1 receptor (TβR1) inhibitors, 2 docking methods and 11 scoring functions in Discovery Studio software were evaluated and validated in this study. LibDock and CDOCKER protocols were performed on a test set of 24 TβR1 protein–ligand complexes. Based on the root-mean-square deviation (RMSD) values (in Å) between the docking poses and co-crystal conformations, the CDOCKER protocol can be efficiently applied to obtain more accurate dockings in medium-size virtual screening experiments of TβR1, with a successful docking rate of 95%. A dataset including 281 known active and 8677 inactive ligands was used to determine the best scoring function. The receiver operating characteristic (ROC) curves were used to compare the performance of scoring functions in attributing best scores to active than inactive ligands. The results show that Ludi 1, PMF, Ludi 2, Ludi 3, PMF04, PLP1, PLP2, LigScore2, Jain and LigScore1 are better scoring functions than the random distribution model, with AUC of 0.864, 0.856, 0.842, 0.812, 0.776, 0.774, 0.769, 0.762, 0.697 and 0.660, respectively. Based on the pairwise comparison of ROC curves, Ludi 1 and PMF were chosen as the best scoring functions for virtual screening of TβR1 inhibitors. Further enrichment factors (EF) analysis also supports PMF and Ludi 1 as the top two scoring functions.

Cadmium (Cd) is a carcinogen that stimulates breast cancer (BC) progression. Rapamycin is a macrolide antibiotic produced by Streptomyces hygroscopicus that possesses a wide array of pharmacological activities, including anti-BC activity. However, the effects of rapamycin on Cd-increased BC progression and the underlying mechanism have not been fully elucidated. Here, we hypothesize that rapamycin antagonizes Cd-induced BC cell proliferation and metastasis by directly modulating ACSS2. In this study, we found that rapamycin efficiently inhibited Cd-induced proliferation, invasion and migration in MCF-7 and T47-D cells. Moreover, a surface plasmon resonance (SPR) assay confirmed that rapamycin directly binds to the ACSS2 protein with a calculated equilibrium dissociation constant (KD) of 18.3 μM. Molecular docking showed that there are three binding sites in the ACSS2 protein and that rapamycin binds at the coenzyme A (COA) binding site with a docking score of − 12.26 and a binding free energy of − 26.34 kcal/mol. More importantly, rapamycin suppresses Cd-induced BC progression by activating ACSS2. After cells were cotreated with an ACSS2 inhibitor, the effects of rapamycin were abolished. In conclusion, our findings suggest that rapamycin suppresses Cd-augmented BC progression by upregulating ACSS2, and ACSS2 may serve as a direct target of rapamycin for inhibiting xenobiotic (e.g., Cd)-mediated BC progression.

Background: With the global popularity of communication devices such as mobile phones, there are increasing concerns regarding the effect of radiofrequency electromagnetic radiation (RF-EMR) on the brain, one of the most important organs sensitive to RF-EMR exposure at 1,800 MHz. However, the effects of RF-EMR exposure on neuronal cells are unclear. Neurite outgrowth plays a critical role in brain development, therefore, determining the effects of 1,800 MHz RF-EMR exposure on neurite outgrowth is important for exploring its effects on brain development.Objectives: We aimed to investigate the effects of 1,800 MHz RF-EMR exposure for 48 h on neurite outgrowth in neuronal cells and to explore the associated role of the Rap1 signaling pathway.Material and Methods: Primary hippocampal neurons from C57BL/6 mice and Neuro2a cells were exposed to 1,800 MHz RF-EMR at a specific absorption rate (SAR) value of 4 W/kg for 48 h. CCK-8 assays were used to determine the cell viability after 24, 48, and 72 h of irradiation. Neurite outgrowth of primary hippocampal neurons (DIV 2) and Neuro2a cells was observed with a 20 × optical microscope and recognized by ImageJ software. Rap1a and Rap1b gene expressions were detected by real-time quantitative PCR. Rap1, Rap1a, Rap1b, Rap1GAP, and p-MEK1/2 protein expressions were detected by western blot. Rap1-GTP expression was detected by immunoprecipitation. The role of Rap1-GTP was assessed by transfecting a constitutively active mutant plasmid (Rap1-Gly_Val-GFP) into Neuro2a cells.Results: Exposure to 1,800 MHz RF-EMR for 24, 48, and 72 h at 4 W/kg did not influence cell viability. The neurite length, primary and secondary neurite numbers, and branch points of primary mouse hippocampal neurons were significantly impaired by 48-h RF-EMR exposure. The neurite-bearing cell percentage and neurite length of Neuro2a cells were also inhibited by 48-h RF-EMR exposure. Rap1 activity was inhibited by 48-h RF-EMR with no detectable alteration in either gene or protein expression of Rap1. The protein expression of Rap1GAP increased after 48-h RF-EMR exposure, while the expression of p-MEK1/2 protein decreased. Overexpression of constitutively active Rap1 reversed the decrease in Rap1-GTP and the neurite outgrowth impairment in Neuro2a cells induced by 1,800 MHz RF-EMR exposure for 48 h.Conclusion: Rap1 activity and related signaling pathways are involved in the disturbance of neurite outgrowth induced by 48-h 1,800 MHz RF-EMR exposure. The effects of RF-EMR exposure on neuronal development in infants and children deserve greater focus.

Seafood consumption provides essential elements to humans while also posing risks to human health. A total of 2610 individuals of five edible marine bivalve species (Ruditapes philippinarum, Paphia undulata, Meretrix meretrix, Sinonovacula constricta and Meretrix lyrata) were randomly sampled from six farmer markets in three cities (Beihai, Qinzhou and Fangchenggang) in the southernmost coastal region of China. The concentrations of heavy metals (Cu, Pb, Zn, Cd, Cr, Hg and As) were determined by inductively coupled plasma mass spectrometry (ICP-MS). The estimated daily intake (EDI), target hazard quotient (THQ), total hazard index (HI), and target cancer risk (TR) were calculated to evaluate potential human health risks from bivalve consumption. The mean concentrations of metals in the tissues of bivalves descended in the order Zn > Cu > As > Cd > Cr >Pb > Hg in descending order, and the concentrations varied substantially among the five bivalves. Heavy metal concentrations in edible tissues of most bivalve samples were below the safety limits set by national and international regulations, and there were significant correlations between certain metal concentrations. The EDI values for each metal in each bivalve were significantly lower than the corresponding PTDI (provisional tolerable daily intake) values. Health risk assessment showed that although there is no noncarcinogenic health risk for local residents exposed to individual or combined metals from these bivalves, there is a carcinogenic risk from Cd and Cr exposure. Thus, in the long term, monitoring and controlling bivalve consumption will be important. Although current accumulation levels of bivalves are safe, continued and excessive lifetime consumption over 70 years may pose a target cancer risk.

Arsenic is one of the most common environmental pollutants. Neurotoxicity induced by arsenic has become a major public health concern. However, the effects of arsenic-induced neurotoxicity in the brain and the underlying molecular mechanisms are not well understood. N-acetyl-cysteine (NAC) is a thiol-based antioxidant that can antagonize heavy metal-induced neurotoxicity by scavenging reactive oxygen species (ROS). Here, we used the mouse oligodendrocyte precursor cell (OPC) line Oli-neu to explore the neurotoxic effects of arsenic and the protective effects of NAC. We found that arsenic exposure decreased cell viability, increased oxidative stress, caused mitochondrial dysfunction, and led to apoptosis of Oli-neu cells. Furthermore, we revealed that NAC treatment reversed these neurotoxic effects of arsenic. TMEM179, a key membrane protein, was found highly expressed in OPCs and to be an important factor in maintaining mitochondrial functions. We found that TMEM179 played a critical role in mediating the neurotoxic effects of arsenic and the protective role of NAC. PKCβ is a downstream factor through which TMEM179 regulates the expression of apoptosis-related proteins. This study improves our understanding of the neurotoxic effects and mechanisms of arsenic exposure and the protective effects of NAC. It also identifies a potential molecular target, TMEM179, for the treatment of arsenic-induced neurotoxicity.

Accurate localization is the premise of many technologies and applications, such as navigation, emergency assistance and wireless sensor network. For Global Navigation Satellite System (GNSS)-denied urban or indoor environments, various localization technologies based on mobile communication networks or other wireless technologies have been designed and developed. The main challenge for these localization technologies is the presence of a non-line-of-sight (NLOS) propagation environment due to dense obstacles or buildings. The virtual station method is a promising high-accuracy target localization technique in NLOS environments, and the localization of the scatterer is key to the virtual station method. Once one-bounce scattering signals from the same scatterer are identified, the localization of the scatterer can be achieved easily with the existing localization algorithm of line-of-sight (LOS) scenario, and then the localization of NLOS scenarios is converted into a problem of LOS easily. In this paper, a hybrid time of arrival (TOA)/angle of arrival (AOA) virtual station localization algorithm based on scattering signal identification is proposed. Firstly, one-bounce scattering signals from the same scatterer are identified based on TOA/AOA measurements. Next, scatterers are located based on one-bounce scattering signals with the LOS localization algorithm, and then scatterers are regarded as virtual stations and used for mobile station (MS) localization. Compared with the existing research on the virtual station method, the proposed algorithm relies only on TOA/AOA measurements and does not require any assumption or prior knowledge about the scatterer, base station (BS) or MS, which provides a solid foundation for feasible target localization. Simulation results demonstrate, as far as we know, the proposed algorithm outperforms the state-of-the-art hybrid TOA/AOA algorithm in localization accuracy.

The realization of efficient water electrolysis is still blocked by the requirement for a high and stable driving potential above thermodynamic requirements. An Ni-based electrocatalyst, is a promising alternative for noble-metal-free electrocatalysts but tuning its surface electronic structure and exposing more active sites are the critical challenges to improving its intrinsic catalytic activity. Here, we tackle the challenge by tuning surface electronic structures synergistically with interfacial chemistry and crystal facet engineering, successfully designing and synthesizing the carbon-encapsulated Ni (111)/Ni3C (113) heterojunction electrocatalyst, demonstrating superior hydrogen evolution reaction (HER) activities, good stabilities with a small overpotential of −29 mV at 10 mA/cm2, and a low Tafel slope of 59.96 mV/dec in alkaline surroundings, approximating a commercial Pt/C catalyst and outperforming other reported Ni-based catalysts. The heterostructure electrocatalyst operates at 1.55 V and 1.26 V to reach 10 and 1 mA cm−2 in two-electrode measurements for overall alkaline water splitting, corresponding to 79% and 98% electricity-to-fuel conversion efficiency with respect to the lower heating value of hydrogen.

Among all types of TGFβ signal blockers, small molecule kinase inhibitors (SMKIs) have attracted wide attention due to their economical production, obvious stability, and ease of oral administration. Nevertheless, SMKIs of TGFβRItypically have low druggability so there are none on the market. In this study, structure-based drug design (SBDD) was performed focusing on the pyrrolopyrimidin scaffold of BMS22 to find TGFβRIinhibitors with excellent medical potential. The binding mode, druggability, and target affinity were assessed by molecular docking, ADMET predictions, and molecular dynamics (MD) simulations for the designed TGFβRIinhibitors. Finally, the highly druggable compound W8 was discovered and then synthesized, which inhibited TGFβRIwith an IC50 value of about 10 μM. In addition, the binding free energies (ΔGbind) of W8 (−42.330 ± 3.341 kcal/mol) and BMS22 (−30.560 ± 6.076 kcal/mol) indicate that the high binding affinity is not necessarily accompanied by high inhibitory activity. Last but not least, the per-residue interaction analysis revealed that the contribution energy of ASP351 to binding was the most significant difference between BMS22 and W8, −2.195 kcal/mol and 1.707 kcal/mol, respectively. As a result, increasing the affinity between SMKIs and ASP351 of TGFβRImay effectively improve the inhibitory activity. The insights gained from this study could help with structure-guided optimization in searching for better SMKIs of TGFβRI.

Doxorubicin (DOX) is a widely used antitumor drug that causes severe cardiotoxicity in patients; no effective strategy yet exists to address this problem. We previously reported that 8-formylophiopogonanone B (8-FOB), a natural isoflavone in Ophiopogon japonicas, antagonizes paraquat-induced hepatotoxicity. Here, we explored the mechanisms underlying DOX-induced cardiotoxicity as well as whether 8-FOB can alleviate DOX-induced cardiotoxicity. Acute cardiotoxicity was established by injecting C57BL/6J mice with a single dose of DOX (20 mg/kg, intraperitoneal). To elucidate the mechanisms underlying DOX-induced cardiotoxicity, differentially expressed genes between hearts from DOX-treated and control mice were identified from the Gene Expression Omnibus (GEO) database via GEO2R. Using the Cytoscape software plugin cytoHubba, five hub genes associated with DOX-induced cardiotoxicity were identified: CD68, PTEN, SERPINE1, AIF1, and HMOX1. However, of these, only HMOX1 protein expression levels were significantly increased after DOX treatment. We also confirmed that HMOX1-dependent myocardial inflammation and fibrosis were closely associated with DOX-induced cardiotoxicity. More importantly, 8-FOB protected against DOX-cardiotoxicity by ameliorating cardiac injury and dysfunction, reducing cardiac fibrosis and inflammatory cytokine release, and inhibiting HMOX1 expression. In conclusion, our results suggest that inhibition of HMOX1-dependent myocardial inflammatory insults and fibrosis is essential for 8-FOB to ameliorate DOX-caused cardiotoxicity.

The increasing intensity of environmental radiofrequency electromagnetic fields (RF-EMF) has increased public concern about its health effects. Of particular concern are the influences of RF-EMF exposure on the development of the brain. The mechanisms of how RF-EMF acts on the developing brain are not fully understood. Here, based on high-throughput RNA sequencing techniques, we revealed that transcripts related to neurite development were significantly influenced by 1800 MHz RF-EMF exposure during neuronal differentiation. Exposure to RF-EMF remarkably decreased the total length of neurite and the number of branch points in neural stem cells-derived neurons and retinoic acid-induced Neuro-2A cells. The expression of Eph receptors 5 (EPHA5), which is required for neurite outgrowth, was inhibited remarkably after RF-EMF exposure. Enhancing EPHA5 signaling rescued the inhibitory effects of RF-EMF on neurite outgrowth. Besides, we identified that cAMP-response element-binding protein (CREB) and RhoA were critical downstream factors of EPHA5 signaling in mediating the inhibitory effects of RF-EMF on neurite outgrowth. Together, our finding revealed that RF-EMF exposure impaired neurite outgrowth through EPHA5 signaling. This finding explored the effects and key mechanisms of how RF-EMF exposure impaired neurite outgrowth and also provided a new clue to understanding the influences of RF-EMF on brain development.

Abstract This letter investigated a device-to-device (D2D) communication underlaying cellular system, where one wireless device (WD) can directly transmit information to two inner users under non-orthogonal multiple access (NOMA) protocol with low latency. Considering the user fairness and reliability, both users can adopt successive interference cancellation (SIC) to decode information by the given decoding order. Subject to predefined quality-of-service (QoS) requirement and the constraint of WD’s transmit power, the maximal rate of latter decoded information and the corresponding precoding vectors are obtained by applying the technique of semidefinite relaxation (SDR) and the Langrangian duality method. Then, the suboptimal scheme based on singular value decomposition (SVD) is also proposed with a lower computational complexity. Numerical simulation shows that with the design of proper precoding vectors D2D communication system assisted by NOMA has a better performance than orthogonal multiple access (OMA).

This paper studies the application of simultaneous wireless information and power transfer (SWIPT) to downlink non-orthogonal multiple access (NOMA) system. A novel cooperative NOMA protocol for high communication reliability and user fairness is proposed, where a near NOMA user acts as a full-duplex (FD) energy-harvesting relay to help transmission from the source node S to the far NOMA user. The power splitting (PS) architecture is adopted at the relay to perform the SWIPT. The aim is to maximize the data rate of the near NOMA user while satisfying the QoS requirement of the far NOMA user and the energy causality condition of the near NOMA user. The formulated problem is a non-convex fractional programming. By jointly optimizing the power allocation factor, the PS ratio, the receiver filter, and the transmit beamforming, we propose alternative optimization (AO)-based algorithm to obtain an optimal solution. In addition, a low-complexity suboptimal scheme is proposed and the semi-closed form solution is derived to characterize the performance of our proposed design. The simulation results verify the correctness of theoretical analysis and show performance gain of our proposed protocol over the existing transmission protocols.

Broomcorn millet is one of the earliest domesticated plants and has the highest water use efficiency among cereals. Here, the authors report its genome assembly and annotation, which provides a valuable resource for breeders and paves the way for studying plant drought tolerance and C4 photosynthesis.