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Chemotherapy is a difficult treatment for cancer patients because of the low effective accumulation of chemo-drugs and their detrimental side effects. Nanoparticles have shown promise as a solution to these problems. However, the known differences in the porosity and vascularization of tumor vessels, and other factors, including the potential formation of a "protein crown," the short half-life time in circulation, and the low drug distribution, often limit their application. To address these problems, biomimetic nanoparticles coated with cell membranes have been developed and shown to have advantages such as prolonged circulation, high biocompatibility, and enhanced targeting abilities in drugs and nanoparticles, thus exhibiting good application prospects in cancer therapy for liver, lung, and melanoma cancers. Accordingly, we designed a PH-sensitive biomimetic nanodrug delivery system with a delicate "core-shell" structure based on red blood cell membranes. Briefly, core nanoparticles were synthesized by the self-assembly of natural amphoteric polymers, including hydrophilic carboxymethylcellulose sodium and hydrophobic stearic acid. For the shell structure, red blood cell membranes were modified using folic acid by a lipid tether (1,2-distearoyl-sn-glycero-3-phosphoethanolamine) to increase tumor-targeting ability, whereas polyethylene glycol was inserted to decrease lipid tether modification-induced potential sequestration by either the mononuclear phagocyte system or the reticuloendothelial system. Via a series of formulation optimizations, paclitaxel was packaged into the red blood membrane-based core-shell nanoparticles with an average size of 226.9 ± 2.75 nm and a negative Zeta potential of -14.5 ± 0.3 mV. More importantly, the examinations focusing on CD47, a representative red blood cell membrane protein, revealed not only the successful establishment of the membrane shell but also the right-side-out membrane orientation on our core-shell nanoparticles. Our nanodrug delivery system showed good biocompatibility and sensitivity to acidic tumor microenvironments while effectively prolonging the circulation time of paclitaxel and further enhancing its antitumor effects on epithelial malignancies, including liver, lung, and melanoma cancers. In particular, our nanodrug delivery system significantly alleviated paclitaxel-induced renal toxicity. Taken together, our findings highlight that the red blood membrane-based core-shell nanoparticle is a promising biomimetic nanodrug delivery system for functionally delivering chemotherapeutic drugs, and it has promise in clinical applications.

Silica nanoparticles (SiNPs) are among the most abundantly produced nanosized particles in the global market, and their potential toxicity has aroused a great concern. Increasing epidemiological investigations and experimental evidence revealed the threaten of SiNPs exposure to cardiovascular system. The myocardial toxicity caused by SiNPs was gradually demonstrated, nevertheless, the underlying mechanisms remain unclear. In view of mitochondria serving as the centrality in the prominent of cardiovascular disease, we investigated the role of mitochondria and related mechanisms in SiNPs-induced adverse effects on cardiomyocytes. As a result, SiNPs were found in cytoplasm, accompanied with morphological alterations in mitochondria, such as cristae fracture or disappearance, vacuolation. The induction of mitochondrial dysfunction by SiNPs was confirmed, as indicated by the excessive reactive oxygen species (ROS) formation, and blockage of cellular respiratory and ATP production. Concomitantly, SiNPs activated mitochondria-mediated apoptotic signaling in view of the up-regulated BAX, increased Caspase-9 cleavage and declined Bcl-2, ultimately resulting in myocardial apoptosis. It was noteworthy that SiNPs disturbed mitochondrial dynamics toward fission phenotype, which was supported by the dysregulated fission/fusion regulators. Especially, DRP1 and its phosphorylated level at s616 (p-DRP1

Silica nanoparticles (SiNPs) are found in the environmental particulate matter and have been proved to pose an adverse effect on fertility. However, the relationship between miRNA and apoptosis induced by SiNPs in spermatogenesis and its underlying mechanism remains confusing. Therefore, the present study was designed to investigate the toxic effects of SiNPs on spermatogenic cells mediated through miRNAs. Spermatocyte cells were divided into 0 μg/mL and 5 μg/mL SiNPs groups, and the cells were collected and analyzed after passaging for 1, 10, 20, and 30 generations. miRNA profile and mRNA profile of spermatocyte cells were measured after exposure to SiNPs for 30 generations. Further, mimics and inhibitors of miRNA were used to verify the relationship between miRNA and their predicted target genes in the 30th-generation cells. The results showed that the degree of cell apoptosis in the SiNPs group significantly increased in the 30th generation. After exposure to SiNPs for 30 generations, the expression of 15 miRNAs was altered, including 5 upregulated miRNAs and 10 downregulated miRNAs. Of the 15 miRNAs, miR-138 and miR-2861 were related to the death receptor pathway. The miR-2861 mimic could target to regulate the mRNA expression of fas/fasl/ripk1 and increase the protein expression of Fas/FasL/RIPK1/FADD/caspase-8/caspase-3 of spermatogenic cells in the 30th generation, while the miR-138 inhibitor could not. In conclusion, SiNPs could cause apoptosis of spermatocyte cells by inhibiting the expression of miRNA-2861, thereby resulting in the upregulation of mRNA expression of fas/fasl/ripk1 and activating the death receptor pathway of spermatocyte cells. miRNA-2861 could be considered a biomarker of the toxic effect of SiNPs on spermatocyte cells. The main finding: Silica nanoparticles induce apoptosis in spermatocyte cells through microRNA-2861 inhibition, thereby upregulating mRNA expression of fas/fasl/ripk1 and activating the death receptor pathway of spermatocyte cells.

A novel label-free point-of-care quartz crystal microbalance (QCM) aptasensing platform based on metal-organic frameworks (MOFs) and gold nanoparticles (AuNPs) was fabricated for tetracycline (TC) detection. MOFs (HKUST-1) and AuNPs were modified onto the sensing interface of QCM sensor to enhance the sensing performance of the QCM aptasensor. TC aptamer with sulfhydryl group was fixed through Au-S bond. The recognition performance of the aptasensor was predicted and verified by the computer simulation. At the optimal conditions, the frequency change of the sensor was adopted for quantitative detection of TC. The prepared QCM aptasensor exhibited a wide linear range from 1 × 10

Understanding the underlying interactions of nanoparticles (NPs) with cells is crucial to the nanotoxicological research. Evidences suggested lysosomes as a vital target upon the accumulation of internalized NPs, and lysosomal damage and autophagy dysfunction are emerging molecular mechanisms for NPs-elicited toxicity. Nevertheless, the interaction with lysosomes, ensuing adverse effects and the underlying mechanisms are still largely obscure, especially in NPs-induced vascular toxicity. In this study, silica nanoparticles (SiNPs) were utilized to explore the adverse effects on lysosome in vascular endothelial cells by using in vitro cultured human endothelial cells (HUVECs), and in-depth investigated the mechanisms involved. Consequently, the internalized SiNPs accumulated explicitly in the lysosomes, and caused lysosomal dysfunction, which were prominent on the increased lysosomal membrane permeability, decline in lysosomal quantity, destruction of acidic environment of lysosome, and also disruption of lysosomal enzymes activities, resulting in autophagy flux blockage and autophagy dysfunction. More importantly, mechanistic results revealed the SiNPs-caused lysosomal impairments and resultant autophagy dysfunction could promote oxidative stress, DNA damage and the eventual cell apoptosis activated by ROS/PARP1/AIF signaling pathway. These findings improved the understanding of SiNPs-induced vascular injury, and may provide novel information and warnings for SiNPs applications in the fields of nanomedicine.

The pathogenesis of myocardial ischemia/reperfusion (I/R) is poorly understood, but recent evidence suggests that autophagy plays crucial roles in I/R injuries. Soluble receptor for advanced glycation end-products (sRAGE) exerts protective effects during I/R by decreasing cardiac apoptosis, which is mediated via increasing the ubiquitin proteasome system (UPS) and signal transducer and activator of transcription 3 (STAT3). The present study examined the effects and mechanisms of sRAGE on I/R-triggered cardiac autophagy. I/R was performed in mice or primary neonatal cardiomyocytes with or without sRAGE administration or overexpression. Cardiac function and infarct size were detected in mouse hearts. Apoptosis, autophagy and autophagy-related signaling pathways were detected in mouse hearts and cardiomyocytes. The results demonstrated that sRAGE significantly improved cardiac function and reduced infarct size during I/R in mice. sRAGE inhibited I/R-induced apoptosis, which correlated with a reduction in autophagy-associated proteins, including ATG7, Beclin-1 and microtubule-associated protein 1 light chain 3 (LC3). sRAGE reduced autophagosome formation during I/R in vivo and in vitro. sRAGE significantly activated STAT3, but not mammalian target of rapamycin (mTOR), during I/R in vivo and in vitro, and suppression of STAT3 abolished the sRAGE inhibition of autophagy during I/R in vitro. Activation of autophagy using ATG7 overexpression with an adenovirus significantly abolished the sRAGE-induced reduction of cardiac apoptosis during I/R. These results suggest that sRAGE inhibits I/R injuries in the heart via a decrease in autophagy, a process that is dependent on STAT3 activation.

A reasonable overburden thickness is of importance for the stability of underwater shield tunnels. Based on the analysis of existing theoretical methods, this paper presents a modified method for the estimation of the minimum overburden thickness during underwater shield tunnelling. As the existing methods neglect the effects of grouting pressure, the modified method takes into account the grouting pressure and the hardening of grouting mortar. The modified method is compared with existing methods based on a practical underwater tunnelling project of Beijing Subway Line 14. Parametric analysis of the proposed method considering the dimension of the tunnel, the geological condition and the grouting behavior is performed. The results show that tunnel diameter, friction angle and cohesion of soil, and grouting pressure have significant impacts on the results of modified methods. The results of this study can provide a reference for similar projects.

As silica nanoparticles (SiNPs) pervade the global economy, however, the followed emissions during the manufacturing, use, and disposal stages inevitably bring an environmental release, potentially result in harmful impacts. Endothelial dysfunction precedes cardiovascular disease, and is often accompanied by mitochondrial impairment and dysfunction. We had reported endothelial dysfunction induced by SiNPs, however, the related mechanisms by which SiNPs interact with mitochondria are not well understood. In the present study, we examined SiNPs-induced mitochondrial dysfunction, and further demonstrated their adverse effects on mitochondrial dynamics and biogenesis in endothelial cells (HUVECs). Consequently, SiNPs entered mitochondria, caused mitochondrial swelling, cristae disruption and even disappearance. Further analyses revealed SiNPs increased the intracellular level of mitochondrial reactive oxygen species, eventually resulting in the collapse of mitochondrial membrane potential, impairments in ATP synthesis, cellular respiration and the activities of three ATP-dependent enzymes (including Na+/K+-ATPase, Ca2+-ATPase and Ca2+/Mg2+-ATPase), as well as an elevated intracellular calcium level. Furthermore, mitochondria in SiNPs-treated HUVECs displayed a fission phenotype. Accordingly, dysregulation of the key gene expressions (FIS1, DRP1, OPA1, Mfn1 and Mfn2) involved in fission/fusion event further certified the SiNPs-induced perturbation of mitochondrial dynamics. Meanwhile, SiNPs-treated HUVECs displayed declined levels of mitochondrial DNA copy number, PGC-1α, NRF1 and also TFAM, indicating an inhibition of mitochondrial biogenesis triggered by SiNPs via PGC-1α-NRF1-TFAM signaling. Overall, SiNPs triggered endothelial toxicity through mitochondria as target, including the induction of mitochondrial dysfunction, as well as the perturbations of their dynamics and biogenesis.

Large amounts of epidemiological evidence have confirmed the atmospheric particulate matter (PM2.5) exposure was positively correlated with the morbidity and mortality of respiratory diseases. Nevertheless, its pathogenesis remains incompletely understood, probably resulting from the activation of oxidative stress, inflammation, altered genetic and epigenetic modifications in the lung upon PM2.5 exposure. Currently, biomarker investigations have been widely used in epidemiological and toxicological studies, which may help in understanding the biologic mechanisms underlying PM2.5-elicited adverse health outcomes. Here, the emerging biomarkers to indicate PM2.5-respiratory system interactions were summarized, primarily related to oxidative stress (ROS, MDA, GSH, etc.), inflammation (Interleukins, FENO, CC16, etc.), DNA damage (8-OHdG, γH2AX, OGG1) and also epigenetic modulation (DNA methylation, histone modification, microRNAs). The identified biomarkers shed light on PM2.5-elicited inflammation, fibrogenesis and carcinogenesis, thus may favor more precise interventions in public health. It is worth noting that some inconsistent findings may possibly relate to the inter-study differentials in the airborne PM2.5 sample, exposure mode and targeted subjects, as well as methodological issues. Further research, particularly by -omics technique to identify novel, specific biomarkers, is warranted to illuminate the causal relationship between PM2.5 pollution and deleterious lung outcomes.

In order to solve inherent problems of traditional molecularly imprinted electrochemical sensors (MIECS), a novel platform of surface molecularly imprinted magnetic metal-organic frameworks (mMOFs@MIPs) was coupled with magneto electrode to establish magnetic MIECS for the recognition of oxytetracycline (OTC). mMOFs@MIPs were synthesized using layer-by-layer modification method for the recognition of OTC. With the help of magneto electrodes, mMOFs@MIPs can be magnetically modified on the electrode surface, forming the electrochemical sensing interface. The imprinted cavities of mMOFs@MIPs can act as the electron channel of the probe to realize label-free detection of OTC. A linear response was obtained within the OTC concentration range of 1.0 × 10−9 g mL−1-1.0 × 10−4 g mL−1. The applicability of the sensor was estimated using the spiking and recovery method in milk samples with the recoveries ranging from 89.0% to 103.1%. It has potential applications in food safety analysis with high throughput detection capability, high specificity and good stability.

Based on the first-principles calculations, we study the electronic structures and transport properties of cliff-like edge phosphorene nanoribbons (CPNRs), considering different types of edge passivation. The band structures of bare CPNRs possess the metallic features; while hydrogen (H), fluorine (F), chlorine (Cl) and oxygen (O) atoms-passivated CPNRs are semiconductor materials, and the band gap values monotonically decrease when the ribbon width increases. Moreover, the H and F-passivated CPNRs exhibit the direct band gap characteristics, while the Cl and O-passivated cases show the features of indirect band gap. In addition, the edge passivated CPNRs are more energetically stable than bare edge case. Meanwhile, our results also show that the transport properties of the CPNRs can be obviously influenced by the different edge passivation.

The purpose of this study was to investigate the anti-fibrotic effect and possible mechanism of bone marrow mesenchymal stem cells (BMSCs) in silica-induced lung injury and fibrosis in vivo and in vitro. In vivo, rats were exposed to 50mg/ml silica intratracheally. The rats were sacrificed on day 15 or day 30 after intravenous injection of BMSCs. Histopathological examination demonstrated that BMSCs decreased the blue areas of collagen fibers and the number of nodules. Alveolar epithelium was damaged by silica, but it was restored by BMSCs. In vitro, BMSCs co-cultured with RLE-6TN cells in 6-Transwell plates were evaluated to determine the possible mechanism. The results demonstrated that BMSCs downregulated the expression of collagen I and III. BMSCs reversed morphological abnormalities and reduced the proliferation of RLE-6TN cells. These data showed that BMSCs did not give rise to alveolar epithelial cells directly, while the levels of hepatocyte growth factor, keratinocyte growth factor and bone morphogenetic protein -7 increased and expression of tumor necrosis factor-α and transforming growth factor-β1 decreased in the 6TN+Silica+BMSCs group compared with the 6TN+Silica group. Our results revealed that BMSCs exerted anti-fibrotic effects on silica-induced pulmonary fibrosis, which might be associated with paracrine mechanisms rather than differentiation.

Advanced glycation end-products (AGEs) are harmful compounds produced during food processing. This study investigated the effects of frozen storage duration (−18 °C) of raw pork on AGEs generation in meatballs. Meatballs were prepared using frozen raw pork (at 0, 30, 60, 90, and 120 days), and Ne-(carboxymethyl)lysine (CML)/Ne-(carboxyethyl)lysine (CEL) (typical AGEs) levels were determined. With increasing frozen storage times of raw pork, CML levels in meatballs increased from 13.26 (0 day) to 43.30 mg/kg protein (120 days), and CEL levels increased from 12.37 (0 day) to 40.50 mg/kg protein (120 days). Furthermore, oxidative damage to raw pork (carbonyls, total sulfhydryl groups, free amines, surface hydrophobicity, thiobarbituric acid-reactive substances of residual lipids, and intrinsic tryptophan fluorescence intensity) was assessed during storage periods. A significant correlation between myofibrillar protein oxidation and CML/CEL levels was observed, suggesting that oxidative damage to raw pork during frozen storage could promote the generation of CML and CEL in meatballs. Therefore, controlling myofibrillar protein oxidation in raw pork may facilitate reduced AGEs levels in meatballs.

In this work, a molecularly imprinted photoelectrochemical (MIP-PEC) sensor based on a novel PEC composite of metal-organic frameworks (MOFs) and TiO2 (NH2-MIL-125(Ti)–TiO2) was established for the ultrasensitive and selective detection of oxytetracycline (OTC). This is the first attempt of applying MOFs in the construction of MIP-PEC sensor. The NH2-MIL-125(Ti)–TiO2 was synthesized by a simple one-step solvothermal method and modified onto the surface of indium tin oxide (ITO) electrode as the photosensitive layer. Subsequently, molecularly imprinted polymer (MIP) was modified as recognition element by electropolymerization. The NH2-MIL-125(Ti)–TiO2 showed an enhanced photocurrent response due to stronger light absorption capacity and matched energy band. Furthermore, MIP greatly improved the selectivity and sensitivity of the constructed PEC sensor. The photocurrent response of the MIP-PEC sensor was reduced after OTC recognition because the specific binding of OTC to the imprinted cavities blocked the electron transfer of the electrode. Under optimal experimental conditions, the MIP-PEC sensor exhibited a wide detection range from 0.1 nM to 10 μM with a low limit of detection (LOD) of 60 pM, as well as certain reproducibility, stability and good applicability in real samples. The proposed sensor provides ideas for the application of MOFs in the construction of PEC sensors and will offer an alternative method for the detection of other pollutants in the field of food safety.

Optical coherence tomography (OCT) has been considered as the ideal tool for the evaluation of atherosclerotic plaques. Circulating trimethylamine-N-oxide (TMAO), which is a metabolite of the dietary lipid phosphatidylcholine, has recently been linked to elevated coronary artery disease (CAD) risk. The objective of the study was to investigate the relation between circulating TMAO level and coronary plaque vulnerability assessed by OCT in patients with CAD. A total of 26 patients with CAD were recruited to assess coronary plaque using OCT and measure plasma TMAO level. According to plaque rupture status, patients were divided into plaque rupture group (n = 12) and nonplaque rupture group (n = 14). Plasma TMAO level was significantly higher in patients with plaque rupture than in those with nonplaque rupture (8.6 ± 4.8 μmol/L vs 4.2 ± 2.4 μmol/L, p = 0.011). Moreover, positive correlations between plasma TMAO level and lipid arc ( r = 0.43, p = 0.031), lipid volume index ( r = 0.39, p = 0.048) were also observed. In conclusion, circulating TMAO level may reflect coronary plaque vulnerability and progression.

Summary Maintaining homeostasis of Ca 2+ stores in the endoplasmic reticulum (ER) is crucial for proper Ca 2+ signaling and key cellular functions. The Ca 2+ -release-activated Ca 2+ (CRAC) channel is responsible for Ca 2+ influx and refilling after store depletion, but how cells cope with excess Ca 2+ when ER stores are overloaded is unclear. We show that TMCO1 is an ER transmembrane protein that actively prevents Ca 2+ stores from overfilling, acting as what we term a "Ca 2+ load-activated Ca 2+ channel" or "CLAC" channel. TMCO1 undergoes reversible homotetramerization in response to ER Ca 2+ overloading and disassembly upon Ca 2+ depletion and forms a Ca 2+ -selective ion channel on giant liposomes. TMCO1 knockout mice reproduce the main clinical features of human cerebrofaciothoracic (CFT) dysplasia spectrum, a developmental disorder linked to TMCO1 dysfunction, and exhibit severe mishandling of ER Ca 2+ in cells. Our findings indicate that TMCO1 provides a protective mechanism to prevent overfilling of ER stores with Ca 2+ ions.

Nitrogen (N) use and flows in agriculture are largely related to the spatial distributions of crop and animal production systems. However, only limited quantitative information on the spatial variation is available related to nutrient flows, losses, and use efficiencies for crop–animal production systems. In this study, we comprehensively and quantitatively analyzed the N flows, losses, and use efficiencies (NUE) in the crop and animal production systems of Shanxi Province by using the simulation model — Nutrient flows in Food chains, Environment and Resources use (NUFER). Data were coupled with a geographical information system and a large, detailed statistical database collected from 11 municipalities of Shanxi Province in 2012. The results were classified into three production system levels, i.e., crop, animal, and crop–animal production systems. First, crop production systems of Shanxi created a total N input of 953 Gg (equivalent to 240 kg/ha) in 2012, with fertilizer as the largest input source, accounting for 59.2% of the total N input. Overall, southern regions of Shanxi experienced significantly higher N input than northern Shanxi. For example, the crop production N input of Yuncheng and Linfen municipalities was 178 and 143 Gg (equivalent to 320 kg/ha and 289 kg/ha), respectively; however, the N input of Taiyuan and Yangquan municipalities was 27 and 13 Gg, respectively. The harvested N from crop production was 110 Gg in Yuncheng and only 7 Gg in Yangquan. The large and varied N surpluses from the crop production systems across municipalities ranged from 74 to 150 kg/ha, potentially creating the risk of environmental pollution and highlighting an urgent need to improve N management in the crop production system. Second, the total N input in the animal production systems also varied widely across the municipalities, ranging from 65 kg/ha in Xinzhou to 187 kg/ha in Jincheng municipality. The harvested N from animal production was the highest (16 Gg) in Shuozhou and lowest in Yangquan (1 Gg), among all the municipalities. Third, the N input to the crop–animal production system of Shanxi was 1000 Gg in 2012 and among all the municipalities, was highest in Yuncheng (167 Gg), and lowest in Yangquan (12 Gg). Large amounts of N (425 Gg) were released from crop residues and animal excreta, but only 47% of this (200 Gg) was recycled to the cropland. Overall, the NUE of crop production (NUEc), animal production (NUEa), and coupled crop–animal production (NUEc + a) was 36%, 20%, and 15%, respectively. These low NUEs were mainly caused by the excessive N input during crop production and the low recycling rate of N from crop residues and animal excreta. The total N losses from crop–animal production were 610 Gg, accounting for 61% of total N input. Of the total N losses, 41.4%, 30.6%, 26.8%, and 1.2% were lost via NH3 volatilization from cropland and animal manure, the combined effects of runoff, erosion, and leaching from cropland and manure, de-nitrification from cropland, and N2O emissions from cropland, respectively. In addition, N flows varied widely at the regional scale, e.g., N input and loss were significantly higher in the southeast than in the northwest. Large amount of straw residues and animal manure in Jincheng was used as nutrient input to the croplands in Yuncheng and Linfen, which are the two major agricultural regions. In conclusion, a quantitative understanding of the spatial distribution of nutrient flows, losses, and use efficiencies in the crop–animal system is necessary for improving the productivity and sustainability of agriculture while minimizing environmental impacts. N management should be optimized in both crop–animal production systems and at regional levels to significantly improve the NUE of Shanxi Province; this will reduce the risk of environmental pollution and ensure the sustainable development of agriculture.

Many DNA repair proteins can be recruited to DNA damage sites upon genotoxic stress. In order to search potential DNA repair proteins involved in cellular response to mitomycin C treatment, we utilized a quantitative proteome to uncover proteins that manifest differentially enrichment in the chromatin fraction after DNA damage. 397 proteins were identified, among which many factors were shown to be involved in chromatin modification and DNA repair by GO analysis. Specifically, methyl-CpG-binding domain protein 2 (MBD2) is revealed to be recruited to DNA damage sites after laser microirradiation, which was mediated through MBD domain and MBD2 C-terminus. Additionally, the recruitment of MBD2 is dependent on poly (ADP-ribose) and chromodomain helicase DNA-binding protein 4 (CHD4). Moreover, knockdown of MBD2 by CRISPR-Cas9 technique results in MMC sensitivity in mammalian cells.

Epidemiological studies revealed a sharp increase in respiratory diseases attributed to PM2.5. However, the underlying mechanisms remain unclear. Evidence suggested mitochondrion as a sensitive target upon the stimulus of PM2.5, and the centrality in the pathological processes and clinical characterization of lung diseases. To investigate cell fate and related mechanisms caused by PM2.5, we exposed human lung epithelial cells (BEAS-2B) to PM2.5 (0-100 μg/mL). Consequently, PM2.5 components were found in cytoplasm, and morphological and functional alterations in mitochondria occurred, as evidenced by loss of cristae, vacuolization and even the outer mitochondrial membrane rupture, mitochondrial membrane potential collapse, enhanced reactive oxygen species (ROS)/mtROS level, calcium overload, suppressed cellular respiration and ATP production in PM2.5-treated cells. Further, disturbed dynamics toward fission was clearly observed in PM2.5-treated mitochondria, associated with DRP1 mitochondrial translocation and phosphorylation. Besides, PM2.5 induced mitochondria-mediated apoptosis. More importantly, mechanistic results revealed ROS- and DRP1-mediated mitochondrial fission in a reciprocal way, and DRP1 inhibitor (Mdivi-1) significantly alleviated the pro-apoptotic effect of PM2.5 through reversing the activated mitochondrial apoptotic pathway. In summary, our results firstly revealed PM2.5 induced apoptosis in lung epithelial cells through a ROS-DRP1-mitochodrial fission axis-mediated mitochondrial apoptotic pathway, ultimately contributing to the onset and development of pulmonary diseases.

The electronic structures and transport properties of edge-passivated Bi2O2Se nanoribbons have been investigated by combining the density functional theory and non-equilibrium Green’s functions. Compared with the bare Bi2O2Se nanoribbons, the stability of H, F, Cl-passivated Bi2O2Se nanoribbons is greatly improved. The band structures show that the bare Bi2O2Se nanoribbons are metallic whereas H, F, Cl-passivated ones are direct band gap semiconductors, and their band gaps slightly decrease as increasing ribbon width due to the quantum confinement effect. Meanwhile, the current-voltage characteristics of edge-passivated Bi2O2Se nanoribbons have also been obtained. The results show that not only the ribbon width, but also the edge passivation atom can effectively manipulate the electronic transport properties of Bi2O2Se nanoribbons. These findings can help us to make appropriate choices in edge passivation atom and ribbon width to adjust the electronic transport properties of Bi2O2Se nanoribbons.

To demonstrate the combined adverse effect and the mechanism of silica nanoparticles (SiNPs) with 57.66 ± 7.30 nm average diameter and high-fat diet (HFD) on Wistar rats, 60 male Wistar rats were randomly divided into six groups (n = 10): Control group, SiNPs group, HFD group, 2 mg kg−1 SiNPs + HFD group, 5 mg kg−1 SiNPs + HFD group and 10 mg kg−1 SiNPs + HFD group. HFD was administrated for 2 weeks for the rats in advance and SiNPs were supplied every 3 d for 48 d subsequently. The present study illustrated that both HFD and SiNPs could decrease sperm concentration, mobility rates, increase abnormality rates, damage testicular structure, reduce spermatogonium numbers and spermatoblast numbers, reduce ATP levels, and affect expression of regulatory factors for meiosis in testis. HFD and SiNPs further damaged the sperm and lowered the ATP level and expression of factors associated with meiotic signaling pathway compared with the HFD without SiNPs in testicular tissue of Wistar rats. These results suggested that SiNPs significantly promoted reproductive toxicity induced by HFD in Wistar rats, which provides novel experimental evidence and an explanation for magnified reproductive toxicity triggered by SiNPs in HFD rats.

Summary Background Repair of DNA double-strand breaks (DSBs) by homologous recombination requires 5′-3′ resection of the DSB ends. In vertebrates, DSB resection is initiated by the collaborative action of CtIP and the MRE11-RAD50-NBS1 (MRN) complex. However, how this process occurs within the context of chromatin is still not well understood. Results Here we identify the human SRCAP chromatin remodeling complex as a factor that promotes CtIP-dependent DNA-end resection. We show that SRCAP, which is mutated in Floating-Harbor syndrome, confers resistance to DNA damage-inducing agents and is recruited to DSBs. Moreover, we demonstrate that SRCAP is required for DNA-end resection, and thereby for recruitment of RPA and RAD51 to DSBs, and for the ensuing homologous recombination. Finally, we reveal that SRCAP forms a complex with CtIP and promotes accumulation of CtIP at DSBs through a mechanism involving its ATPase activity. Conclusions Our study implicates the human SRCAP chromatin remodeling complex as a novel regulator of DNA damage responses that orchestrates proper signaling and repair of DSBs in the context of chromatin.

Researches had shown that silica nanoparticles (SiNPs) could reduce the quantity and quality of sperms. However, chronic effects of SiNPs have not been well addressed. In this study, mice spermatocyte cells (GC-2spd cells) were continuously exposed to SiNPs (5 μg/mL) for 30 passages and then the changes of microRNA (miRNA) profile and mRNA profile were detected. The function of miRNAs was verified by inhibitors to explore the regulation role of miRNAs in reproductive toxicity induced by SiNPs. The results showed that SiNPs induced cytotoxicity, and activated autophagy in GC-2spd cells. SiNPs led to a total of 1604 mRNAs (697 up-regulated and 907 down-regulated) and 15 miRNAs (6 up-regulated such as miRNA-138 and miRNA-494 and 9 down-regulated) with different expression in GC-2spd cells. The combined miRNA profile and mRNA profile showed that 415 mRNAs with different expression in 5 μg/mL SiNPs group were regulated by miRNA. Furthermore, our study demonstrated that SiNPs decreased the expressions of AKT mRNAs. Moreover, SiNPs had an activation effect on the AMPK/TSC/mTOR pathway. However, inhibitor of miRNA-494 could attenuate the expression levels of AMPK, TSC, LC3Ⅱ and alleviate the decreased of AKT, mTOR, p-mTOR induced by SiNPs. The above results suggested that the low-dose SiNPs exposure could promote autophagy by miRNA-494 targeting AKT, thereby activating AMPK/TSC/mTOR pathway in GC-2spd cells. MiRNA-494 is an important regulator of autophagy by targeting AKT, which provides new evidence for the male reproductive toxicity mechanism of SiNPs.

The safety concern on silica nanoparticles (SiNPs) is rapidly expanding with its increased production for industrial, environmental, and pharmaceutical applications. We have reported SiNPs induced endothelial dysfunction, which potentially precedes atherosclerosis and ultimately contributes to cardiovascular disease. However, its molecular mechanisms haven't been clearly determined. Here, we observed the subchronic exposure of SiNPs induced vascular injury, accompanied by oxidative stress, ER stress and apoptosis in the artery. Further, their detailed interactions in SiNPs-induced vascular injury were investigated in vitro. SiNPs were internalized and deposited the intracellular ER region of human umbilical vein endothelial cells (HUVECs), and triggered the activation of ER stress as validated by the up-regulated PERK/eIF2α/ATF4, IRE1/XBP1 and ATF6 pathways. Mechanistic analyses by using ER stress inhibitor (4-PBA or Salubrinal) and antioxidant agent N-acetylcysteine (NAC) confirmed an ER stress-dependent oxidative stress and apoptosis induced by SiNPs, which mediated the consequent vascular endothelial injury, ultimately contributing to vascular disease.

Specific anti-Alicyclobacillus IgG antibody was immobilized on the surface of magnetic nanoparticles for the development of immunomagnetic nanoparticles (IMPs), which will be used for the immunocapture of Alicyclobacillus spp. The immunobinding efficacy of oxidized antibody using oriented immobilization was evaluated by comparing its Alicyclobacillus acidoterrestris (A. acidoterrestris) capturing capacity with that of a randomly immobilized system and physical adsorption. The results indicated that oriented immobilization of oxidized antibody onto the (3-aminopropyl) triethoxysilane coated magnetic nanoparticles exhibited better recognition capacity than others. In the process, the sugar moiety in the CH2 domain of the antibody's fragment crystallizable region (Fc region) was oxidized and translated into aldehyde group. The reactions between the aldehyde groups of antibody and amine groups of magnetic nanoparticles could prompt the accurate orientation of antibody binding at the Fc region. At optimum condition, the maximum antibody adsorption capacity of magnetic nanoparticles could arrive to 75.6 μg/mg and the separation efficiency for A. acidoterrestris could be up to 80% or more. The results showed that the obtained IMPs and optimized protocol exhibited a higher recognition ability for Alicyclobacillus spp. and a lower nonspecific adsorption of others. Based on the specific binding affinity of the oriented immobilization process, the immobilization approach proposed here may be an attractive strategy for the preparation of IMPs for immunocapture and rapid detection of Alicyclobacillus spp. in apple juice.

The immunomagnetic separation (IMS) technique was used in combination with an enzyme-linked immunosorbent assay (ELISA) procedure to shorten the total analysis time and improve the sensitivity for the detection of Alicyclobacillus spp. in apple juice samples. The specificity of IMS-ELISA for twenty strains of Alicyclobacillus spp. and eighteen strains of non-Alicyclobacillus spp. was determined and there was little cross-reaction with non-Alicyclobacillus strains. Artificially contaminated apple juice with different concentrations of Alicyclobacillus acidoterrestris was detected by IMS-ELISA, and the detection limit of the assay in apple juice was 10(3)CFU/mL. Furthermore, the sample inoculated with 1CFU/mL of A. acidoterrestris could be detected as positive after incubation for 24h. The IMS-ELISA described, allows for the identification of suspect positive samples within 3h of testing versus 3-5days required by standard culture methods while significantly reducing the materials and labor required for the detection of Alicyclobacillus spp. in apple juice samples. As compared with the standard culture method performed concurrently on the same set of samples, the sensitivity, specificity and accuracy of IMS-ELISA for 102 naturally contaminated apple juice samples were 91.3%, 96.02% and 95.09%, respectively. These results demonstrated that the newly proposed IMS-ELISA procedure can be a potentially useful analytical method for the detection of Alicyclobacillus spp. in apple juice.

Waste cider yeast is a natural by-product generated through the production of fermentable beverages. In this work, the biosorption of patulin (PAT) from apple juice using waste cider yeast was investigated. The yeast cells were treated with caustic, ethanol and heats. Among the treatments, the highest PAT uptake (58.29%) was obtained with the caustic treated waste yeast. The effects of pH and initial concentration of PAT were assessed. The results showed that the adsorption percentage of PAT increased simultaneously with the increase of pH and approached equilibrium at pH 4.5. The removal of PAT increased with decreasing of toxin levels. The experimental data were analyzed using the Langmuir and Freundlich equations. It has been observed that the adsorption equilibrium was best described by the Langmuir model. The Langmuir constants were q max (μg/g) = 8.1766 and b (L/mg) = 0.0640. In packed bed column studies, it was found that Ca-alginate gel was a good biosorbent for PAT removal and immobilized caustic treated yeast particles in the gel increased the biosorption capacity of the gel.

The Y-family of DNA polymerases support of translesion DNA synthesis (TLS) associated with stalled DNA replication by DNA damage. Recently, a number of studies suggest that some specialized TLS polymerases also support other aspects of DNA metabolism beyond TLS in vivo. Here we show that mouse polymerase kappa (Polκ) could accumulate at laser-induced sites of damage in vivo resembling polymerases eta and iota. The recruitment was mediated through Polκ C-terminus which contains the PCNA-interacting peptide, ubiquitin zinc finger motif 2 and nuclear localization signal. Interestingly, this recruitment was significantly reduced in MSH2-deficient LoVo cells and Rad18-depleted cells. We further observed that Polκ-deficient mouse embryo fibroblasts were abnormally sensitive to H2O2 treatment and displayed defects in both single-strand break repair and double-strand break repair. We speculate that Polκ may have an important role in strand break repair following oxidative stress in vivo.

Huntington disease (HD) is an inherited, fatal neurodegenerative disorder characterized by the progressive loss of striatal medium spiny neurons. Indications of oxidative stress are apparent in brain tissues from both HD patients and HD mouse models; however, the origin of this oxidant stress remains a mystery. Here, we used a yeast artificial chromosome transgenic mouse model of HD (YAC128) to investigate the potential connections between dysregulation of cytosolic Ca2+ signaling and mitochondrial oxidative damage in HD cells. We found that YAC128 mouse embryonic fibroblasts exhibit a strikingly higher level of mitochondrial matrix Ca2+ loading and elevated superoxide generation compared with WT cells, indicating that both mitochondrial Ca2+ signaling and superoxide generation are dysregulated in HD cells. The excessive mitochondrial oxidant stress is critically dependent on mitochondrial Ca2+ loading in HD cells, because blocking mitochondrial Ca2+ uptake abolished elevated superoxide generation. Similar results were obtained using neurons from HD model mice and fibroblast cells from HD patients. More importantly, mitochondrial Ca2+ loading in HD cells caused a 2-fold higher level of mitochondrial genomic DNA (mtDNA) damage due to the excessive oxidant generation. This study provides strong evidence to support a new causal link between dysregulated mitochondrial Ca2+ signaling, elevated mitochondrial oxidant stress, and mtDNA damage in HD. Our results also indicate that reducing mitochondrial Ca2+ uptake could be a therapeutic strategy for HD. Background: Oxidative damage has been implicated in the pathology of Huntington disease (HD). Results: Strikingly higher mitochondrial Ca2+ loading and superoxide generation cause significantly higher levels of mitochondrial DNA damage in HD cells. Conclusion: Excessive mitochondrial Ca2+ loading-dependent oxidant generation is a causative factor for HD. Significance: Our data reveal new links between dysregulated mitochondrial Ca2+ signaling and elevated oxidative DNA damage in HD.