Binding patterns of inhibitors to different pockets of kinesin Eg5.

The kinesin-5 family member, Eg5, plays very important role in the mitosis. As a mitotic protein, Eg5 is the target of various mitotic inhibitors. There are two targeting pockets in the motor domain of Eg5, which locates in the α2/L5/α3 region and the α4/α6 region respectively. We investigated the interactions between the different inhibitors and the two binding pockets of Eg5 by using all-atom molecular dynamics method. Combined the conformational analysis with the free-energy calculation, the binding patterns of inhibitors to the two binding pockets are shown. The α2/L5/α3 pocket can be divided into 4 regions. The structures and binding conformations of inhibitors in region 1 and 2 are highly conserved. The shape of α4/α6 pocket is alterable. The space of this pocket in ADP-binding state of Eg5 is larger than that in ADP·Pi-binding state due to the limitation of a hydrogen bond formed in the ADP·Pi-binding state. The results of this investigation provide the structural basis of the inhibitor-Eg5 interaction and offer a reference for the Eg5-targeted drug design.

Bisphenols can promote antibiotic resistance by inducing metabolic adaptations and natural transformation.

Whether bisphenols, as plasticizers, can influence bacterial uptake of antibiotic resistance genes (ARGs) in natural environment, as well as the underlying mechanism remains largely unknown. Our results showed that four commonly used bisphenols (bisphenol A, S, F, and AF) at their environmental relative concentrations can significantly promote transmission of ARGs by 2.97-3.56 times in Acinetobacter baylyi ADP1. Intriguingly, we observed ADP1 acquired resistance by integrating plasmids uptake and cellular metabolic adaptations other than through reactive oxygen species mediated pathway. Metabolic adaptations including upregulation of capsules polysaccharide biosynthesis and intracellularly metabolic enzymes, which enabled formation of thicker capsules for capturing free plasmids, and degradation of accumulated compounds. Simultaneously, genes encoding DNA uptake and translocation machinery were incorporated to enhance natural transformation of antibiotic resistance carrying plasmids. We further exposed aquatic fish to bisphenols for 120 days to monitor their long-term effects in aquatic environment, which showed that intestinal bacteria communities were dominated by a drug resistant microbiome. Our study provides new insight into the mechanism of enhanced natural transformation of ARGs by bisphenols, and highlights the investigations for unexpectedly-elevated antibiotic-resistant risks by structurally related environmental chemicals.

Bisphenols induce cardiotoxicity in zebrafish embryos: Role of the thyroid hormone receptor pathway.

Bisphenols are frequently found in the environment and have been of emerging concern because of their adverse effects on aquatic animals and humans. In this study, we demonstrated that bisphenol A, S, and F (BPA, BPS, BPF) at environmental concentrations induced cardiotoxicity in zebrafish embryos. BPA decreased heart rate at 96 hpf (hours post fertilization) and increased the distance between the sinus venosus (SV) and bulbus arteriosus (BA), in zebrafish. BPF promoted heart pumping and stroke volume, shortened the SV-BAdistance, and increased body weight. Furthermore, we found that BPA increased the expression of the dio3b, thrß, and myh7 genes but decreased the transcription of dio2. In contrast, BPF downregulated the expression of myh7 but upregulated that of thrß. Molecular docking results showed that both BPA and BPF are predicted to bind tightly to the active pockets of zebrafish THRß with affinities of -4.7 and -4.77 kcal/mol, respectively. However, BPS did not significantly affect dio3b, thrß, and myh7 transcription and had a higher affinity for zebrafish THRß (-2.13 kcal/mol). These findings suggest that although BPA, BPS, and BPF have similar structures, they may induce cardiotoxicity through different molecular mechanisms involving thyroid hormone systems. This investigation provides novel insights into the potential mechanism of cardiotoxicity from the perspective of thyroid disruption and offer a cautionary role for the use of BPA substitution.

Porous gold with three-level structural hierarchy.

Facilitating the mass transfer and enlarging the active surface area are two mutually exclusive demands in porous materials, while structural hierarchy could settle this issue by constructing continuous channels with different length scales. However, it is a great challenge to fabricate porous metallic materials with three or more geometrically similar hierarchy levels. Herein, a novel strategy combining vapor phase dealloying with electrochemical dealloying is proposed to achieve nanoporous gold (NPG) with three-level nested hierarchy (N3PG), in which the length scale covers micron (5866.8 ± 1445.5 nm), submicron (509.9 ± 106.0 nm), and nanometer (20.1 ± 3.0 nm) for each level. Notably, the structural superiority of such material is manifested by its faster charge transfer behaviors, as benchmarked with unimodal and bimodal NPG (N1PG and N2PG). The present strategy is of great potential to fabricate other hierarchically porous metals with enhanced functional and structural properties.

Dealloying-Derived Nanoporous Bismuth for Selective CO2 Electroreduction to Formate.

Electrochemical CO2 reduction (CO2ER) to formate is an attractive approach for CO2 utilization. Here, we report a nanoporous bismuth (np-Bi) catalyst fabricated by chemically dealloying a rapidly solidified Mg92Bi8 alloy for CO2ER. The np-Bi catalyst exhibits a three-dimensional interconnected ligament-channel network structure, which can efficiently convert CO2 to formate with a selectivity of ≤94% and an activity of 62 mA cm-2 in a wide potential range. Remarkably, the np-Bi catalyst delivers an industry-level current density of ∼500 mA cm-2 for formate production at a low overpotential of 420 mV in the flow cell. The outstanding CO2ER performance can be attributed to the enlarged surface area with abundant accessible active sites and highly curved surfaces with enhanced intrinsic activity. This work highlights the structural synergies for enhancing CO2ER.

Atomistic mechanism of phase transformation between topologically close-packed complex intermetallics.

Understanding how topologically close-packed phases (TCPs) transform between one another is one of the challenging puzzles in solid-state transformations. Here we use atomic-resolved tools to dissect the transition among TCPs, specifically the µ and P (or σ) phases in nickel-based superalloys. We discover that the P phase originates from intrinsic (110) faulted twin boundaries (FTB), which according to first-principles calculations is of extraordinarily low energy. The FTB sets up a pathway for the diffusional in-flux of the smaller 3d transition metal species, creating a Frank interstitial dislocation loop. The climb of this dislocation, with an unusual Burgers vector that displaces neighboring atoms into the lattice positions of the product phase, accomplishes the structural transformation. Our findings reveal an intrinsic link among these seemingly unrelated TCP configurations, explain the role of internal lattice defects in facilitating the phase transition, and offer useful insight for alloy design that involves different complex phases.

Transgenerational effects of parental bisphenol S exposure on zebrafish (Danio rerio) reproduction.

Bisphenol S (BPS) is extensively used for production of polycarbonates and other commodities, and is often detected in environment and biota. Parental BPS exposure has been reported to interfere with reproductive development of offspring, but limited information is available on its multigenerational reproductive toxicity. In our present study, zebrafish (Danio rerio) were exposed to BPS (1 and 100 µg/L) from 3 hpf to 120 dpf, and the effects on reproduction, sex steroid hormones, DNA methylation levels and gene transcription involved in steroidogenesis and DNA methylation were investigated in unexposed F1-2 offspring. The results showed that 100 µg/L BPS exposure increased DNA methylation in F1 testes, and 1 µg/L BPS led to DNA methylation in F2 ovaries. The increased DNA methylation levels led to decreased expression of steroidogenic enzymes, including cyp11a, cyp17 and 3ßhsd, which might be a main reason for the elevated plasma 17ß-estradiol and decreased testosterone levels. In addition, sex ratio indicated a female dominance trend, and reproductive capacity of male fish was severely impaired. Overall, these findings suggest that parental BPS exposure impairs reproductive development of unexposed offspring via DNA methylation and BPS-induced epigenetic modification inheritance has a long-term effect on the fitness and sustainability of fish populations.

Transcriptomics unveiled metabolic perturbations in Desmodesmus quadricauda by sulfacetamide: Key functional genes involved in the tolerance and biodegradation process.

Antibiotic contamination in the environment has significant adverse effects on benthic microorganisms, which causes dysfunction of normal ecological processes. However, in-depth molecular mechanisms underlying the potential ecological impacts of these emerging pollutants are poorly understood. In this study, metabolic perturbations in a freshwater microalga, Desmodesmus quadricauda by sulfacetamide (SFM) were investigated using transcriptomics. The results found 28 genes in the tricarboxylic acid cycle and oxidative phosphorolysis pathways were significantly downregulated by 3.97 to 6.07, and 2.47 to 5.99 folds by 0.1 and 1 mg L-1 SFM, respectively. These results indicated that SFM disrupted the microalgal cellular activities through inhibition of energy metabolism. Whilst, the upregulated genes have been most enriched in porphyrin and chlorophyll metabolism (hemE, hemL, hemY, chlD, chlP, PAO, and CAO), and arachidonic acid metabolism (GGT1_5 and gpx). Expression of these genes was significantly upregulated by up to 3.36 times for tolerance against SFM. Moreover, the genes encoding decarboxylase, oxidoreductases, α-amylase, hydrolases, O-acetyltransferase, and lyase were upregulated by >2 folds, which can induce di/hydroxylation, decarboxylation, bond cleavage and deamination. These findings provide insights into the molecular mechanisms of the ecotoxicological effects of antibiotics on microalgae, and supply useful information for their environmental risk assessment and management.

Bisphenol S exposure accelerates the progression of atherosclerosis in zebrafish embryo-larvae.

Bisphenol S (BPS), widely utilized in manufacturing of daily necessities, is a toxicant with potential to induce atherosclerotic cardiovascular disease (ASCVD). However, the mode of action by which BPS exposure induces ASCVD remains unknown. Here, macrophages that were exposed to BPS in combination with oxidized low-density lipoprotein (oxLDL) exhibited enhanced formation of foam cells, a hallmark of ASCVD. Furthermore, zebrafish embryo-larvae were exposed to BPS (0, 1, 10 and 100 µg/L) for 15 days (d) and the characteristic symptoms of ASCVD including an inflammatory response, macrophage recruitment around blood vessels, and accumulation of oxLDL on vascular endothelium, were induced in 15-d larvae. After zebrafish were exposed to BPS for 45 d, BPS mobilized fatty acid metabolism and activated peroxisome proliferator-activated receptor signaling in larval liver, the hub of endogenous lipid metabolism, causing an increase in plasma LDL. Driven by high plasma LDL levels, the caudal artery of zebrafish larvae exhibited lipid accumulation and a thickened area with a large number of collagen fibers, accompanied by characteristic lesions, as well as hyperlipidemia, erythrocyte aggregation, thinner blood vessel walls and increased levels of leukocytes and thromboocytes in plasma. Our data demonstrate that BPS accelerates the progression of ASCVD using zebrafish embryo-larvae as a model.

Metabolic perturbations of Lolium perenne L. by enrofloxacin: Bioaccumulation and multistage defense system.

Plants are readily exposed to the antibiotics residues in reclaimed water indicating an urgent need to comprehensively analyze their ecotoxicological effects and fate of these emerging contaminants. Here, we unraveled the dissemination of enrofloxacin (ENR) in a pasture grass, Lolium perenne L., and identified multistage defense systems as its adaptation mechanism. Uptaken concentrations of ENR ranged from 1.28 to 246.60 µg g-1 with bioconcentration factors (BCF) upto 15.13, and translocation factors (TF) upto 0.332. The antioxidant enzymatic activities such as superoxide dismutase, peroxidase, and catalase were increased by upto 115%. Further transcriptomics demonstrated that differentially expressed genes (DEGs) involved in glycolysis, tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and glutathione metabolism were significantly up-regulated by 1.56-5.93, 3-7 and 1.04-6.42 times, respectively; whilst, the DEGs in nitrogen and sulfur metabolism pathways were significantly up-regulated by 1.06-5.64 and 2.64-3.54 folds. These processes can supply energy, signaling molecules, and antioxidants for detoxification of ENR in ryegrass. Such results provide understanding into fasting grass adaptability to antibiotics by enhancing the key protective pathways under organic pollutant stresses in environments.

Unraveling the mechanism of long-term bisphenol S exposure disrupted ovarian lipids metabolism, oocytes maturation, and offspring development of zebrafish.

Bisphenol S (BPS) acts as a xenoestrogen and disturbs the female reproductive system; however, the underlying mechanism has not been elucidated. In this study, the effect of chronic BPS exposure (1 µg/L and 100 µg/L) on ovarian lipid metabolism in zebrafish was investigated to determine its influence on adult reproductive capacity and offspring development. The results showed that long-term (240 days) exposure to BPS induced lipid accumulation in the ovaries by promoting the transport of more lipids from the circulation to the ovaries and by upregulating triacylglycerol synthesis-related genes. Significantly increased expression of cpt2, acadm, acadl, and pparα, which are involved in ß-oxidation in the ovarian mitochondria, indicated that more energy was provided for oocyte maturation in exposed zebrafish ovaries. Thus, the proportion of full-grown stage oocytes in ovaries and egg reproduction were elevated at an accelerated rate, which earlier than normal reproductive cycle (8-10 days posts pawning). Moreover, the maternally BPS-exposed F1 embryos (2 h post-spawning, hpf) showed higher neutral lipid levels, impaired hatching capacity, and increased occurrence of larval deformities. All these findings demonstrated that stimulated lipid synthesis and ß-oxidation in zebrafish ovaries significantly contribute to BPS-induced oocyte precociousness with subsequent effects on the development of unexposed offspring. This study provides new insight into the impact of xenoestrogens on oviparous reproduction in females and offspring development from the perspective of ovarian lipid metabolism.

Anomalous structure transition in undercooled melt regulates polymorphic selection in barium titanate crystallization.

The crystallization processes of titanates are central to the fabrication of optical and electrical crystals and glasses, but their rich polymorphism is not fully understood. Here, we show when and how polymorphic selection occurs during the crystallization of barium titanate (BaTiO3, BT) using in situ high energy synchrotron X-ray diffraction and ab initio molecular dynamic simulation. An anomalous structure transition is found in molten BT during cooling across the cubic-hexagonal transition temperature, which enables nucleation selection of BT by manipulating the undercooling: a cubic phase is preferred if nucleation is triggered at large undercooling, whereas a hexagonal phase is promoted at small undercooling. We further reveal that the nucleation selection between the cubic and the hexagonal phase is regulated by the intrinsic structure property of the melt, in particular, the degree of polymerization between Ti-O polyhedra. These findings provide an innovative perspective to link the polymorphic crystallization to the non-isomorphic structure transition of the melt beyond the conventional cognition of structural heredity.

How Kinesin-1 Utilize the Energy of Nucleotide: The Conformational Changes and Mechanochemical Coupling in the Unidirectional Motion of Kinesin-1.

Kinesin-1 is a typical motile molecular motor and the founding member of the kinesin family. The most significant feature in the unidirectional motion of kinesin-1 is its processivity. To realize the fast and processive movement on the microtubule lattice, kinesin-1 efficiently transforms the chemical energy of nucleotide binding and hydrolysis to the energy of mechanical movement. The chemical and mechanical cycle of kinesin-1 are coupled to avoid futile nucleotide hydrolysis. In this paper, the research on the mechanical pathway of energy transition and the regulating mechanism of the mechanochemical cycle of kinesin-1 is reviewed.

Probing the Microstructure in Pure Al & Cu Melts: Theory Meets Experiment.

In the present work, a new model of the atomic cluster structure, which is determined by metal Wulff construction with the crystal structure inside, is proposed to describe the structures of metallic melts. The shapes of the structures are determined by surface energies of different crystal plane groups, calculated from density functional theory (DFT), while the size is given by the pair distribution function (PDF) of the experimental high-temperature X-ray diffraction (HTXRD). Taking Aluminum (Al) and Copper (Cu) as the representative examples, we demonstrate that the simulated XRD curves from present models match the experimental results quite well, not only regarding the position and width of the peaks but also the relative intensity of the first and second peaks. These results indicate a successful model to describe the properties of metallic melts. The model also explains a main peak deviation phenomenon between the XRD of metallic melt and the solid ones in pure metal Al. Finally, a physical picture of metallic melt is given, which is mainly composed of atomic cluster structures and free atoms around them.

Bisphenol S exposure alters behavioral parameters in adult zebrafish and offspring.

The environmental emission of bisphenol S (BPS), which is globally utilized in the manufacturing of polycarbonates, epoxy resin and thermal paper, has affected the aquatic ecosystem. Thus, effects of BPS exposure on the fitness of aquatic animals have been noted. Here, adult male and female zebrafish were used as aquatic model organisms and separately exposed to environmentally relevant doses of BPS (0, 1, 10 and 100 µg/L) for 14 days. The results showed that BPS changed the body pigment of zebrafish and slowed the maturation of oocytes in the ovary, resulting in a significant decrease in the shoaling behavior of adult zebrafish and the attraction of BPS-treated females during the mating process. Furthermore, in the subgeneration of adult zebrafish exposed to BPS for 7 days, survival behaviors, such as locomotor, phototaxis and feeding behaviors, deviated from normal behaviors. After exposing the adult zebrafish to BPS for an additional 7 days, the above described survival behaviors and light adaptation were disrupted in offspring. Our data, based on intergenerational behavioral studies, demonstrate that BPS affects the behaviors of aquatic animals and the ability of offspring to feed and avoid predators, possibly jeopardizing the survival of aquatic animals.

Long-term bisphenol S exposure aggravates non-alcoholic fatty liver by regulating lipid metabolism and inducing endoplasmic reticulum stress response with activation of unfolded protein response in male zebrafish.

Environmental chemical exposures have been implicated as risk factors for the development of non-alcoholic fatty liver (NAFLD). Bisphenol S (BPS), widely used in multitudinous consumer products, could disrupt lipid metabolism in the liver. This study aimed at examining the hypothesis that long-term exposure to BPS promotes the development of liver fibrosis and inflammation by means of the application of a semi-static exposure experiment that exposed zebrafish to 1, 10, and 100 µg/L BPS from 3 h post fertilization to 120 day post fertilization. Results showed that the 120-d BPS exposure elevated plasma aspartate aminotransferase and alanine aminotransferase activities, increased triacylglycerol (TAG) and total cholesterol levels in male liver, and even induced hepatic apoptosis and fibrosis. Hepatic lipid accumulation observed in the 30-d BPS-exposed zebrafish was recovered after a 90-d depuration phase, thereby indicating that long-term BPS exposure promotes the progression of simple steatosis to non-alcoholic steatohepatitis. Furthermore, BPS exposure for 120-d promoted the synthesis of TAG and lipotoxic free fatty acids by elevating the transcription of srebp1, acc, fasn, and elovl6, induced endoplasmic reticulum (ER) stress with increasing expression levels of unfolded protein response (UPR) genes (perk, hsp5, atf4a, and ddit3), and then stimulated the expression of two key autophagy genes (atg3 and lc3) and inflammatory genes (il1b and tnfα). It is indicated that BPS can induce the development of steatohepatitis via the activation of the PERK-ATF4a pathway of the UPR. Data gathered suggest that environmental pollutants-induced ER stress with the activation of UPR can potentially trigger the NAFLD development in males. Overall, our study provided new sights into understanding of the adverse health effects of metabolism disrupting chemicals.

Bisphenol S Induces Ectopic Angiogenesis in Embryos via VEGFR2 Signaling, Leading to Lipid Deposition in Blood Vessels of Larval Zebrafish.

Bisphenol S (BPS), used as a bisphenol A substitute, has been detected in various environments. However, the safety of BPS is still unclear. Here, zebrafish embryos were exposed to BPS (0, 1, 10, and 100 µg/L) for 24, 48, 72, 96 h, and 15 days. BPS induced ectopic sprouting of budding blood vessels in embryos, but the blood flow velocity within these lesions was unchanged at 48 h. At 72 h postfertilization (hpf), by observing the subintestinal venous plexus responsible for yolk absorption, we found that VEGFR2 transduced an angiogenic signal and that the subsequent reduction in blood flow velocity inhibited yolk absorption. At 96 hpf, yolk consumption was still delayed because of the disturbed transportation route, resulting in transient extensive lipid retention in the blood vessels. After feeding, obvious atherogenic lipids were discovered in the blood vessels, especially in bends, bifurcations, and stenoses. This dynamic visualization of the pathogenesis demonstrates a plausible mechanistic link between BPS exposure-induced embryonic vessel overgrowth and an increased atherosclerosis risk.

Dealloyed porous gold anchored by in situ generated graphene sheets as high activity catalyst for methanol electro-oxidation reaction.

A novel one-step method to prepare the nanocomposites of reduced graphene oxide (RGO)/nanoporous gold (NPG) is realized by chemically dealloying an Al2Au precursor. The RGO nanosheets anchored on the surface of NPG have a cicada wing like shape and act as both conductive agent and buffer layer to improve the catalytic ability of NPG for methanol electro-oxidation reaction (MOR). This improvement can also be ascribed to the microstructure change of NPG in dealloying with RGO. This work inspires a facile and economic method to prepare the NPG based catalyst for MOR.

Long-term bisphenol S exposure induces fat accumulation in liver of adult male zebrafish (Danio rerio) and slows yolk lipid consumption in F1 offspring.

Bisphenol S (BPS), as a substitute for bisphenol A, was frequently detected in human urine and blood. It has been reported that BPS could disrupt fat metabolism in vivo and vitro although mechanisms remain unclear. Additionally, there is no study that the disruptive effect of BPS on parental fat metabolism indirectly interferes with the lipid metabolism of offspring. Here, after 120-d exposure to 1, 10, 100, and 1000 µg/L BPS, the transcription level of genes involved in lipid metabolism in liver and feeding regulation of brain-gut axis, as well as the hepatic triacylglycerol (TAG) and plasma lipid levels were investigated in both male and female zebrafish. Results showed that in male liver, fatty acid synthesis and degradation were inhibited by reducing transcription levels of srebp1 and pparα, and the synthesis of TAG was significantly increased using fatty acid as a precursor by elevating agpat4 and dgat2 mRNA expression levels. As a consequence, fat accumulation and the increased TAG levels were observed in male liver, and lipid levels were also elevated in male plasma. In female liver, there was no excessive fat accumulation and BPS exposure had a non-monotonic effect on the gene expression of fasn, dagt2, and pparα. Notably, the unexposed offspring showed a large amount of yolk lipid remain at 5 days post fertilization. This study obviously demonstrated that long-term BPS exposure increases the risk of non-alcoholic fatty liver disease in male zebrafish and life-cycle exposure hazard on offspring is noteworthy.

A glassy carbon electrode modified with nitrogen-doped reduced graphene oxide and melamine for ultra-sensitive voltammetric determination of bisphenol A.

A composite was prepared at room temperature from nitrogen-doped reduced graphene oxide (N-rGO) and melamine via π-interaction. An ultra-sensitive electrochemical sensor for the determination of trace levels of bisphenol A (BPA) was obtained by coating a glassy carbon electrode (GCE) with the composite. The structure and morphology of composite were characterized by FTIR, Raman, XRD, XPS, SEM and TEM. Because of the synergetic effects of N-rGO and melamine, the modified GCE displays considerably enhanced sensitivity to BPA. The voltammetric response, typically measured at a peak of 0.48 V (vs. SCE) is linear in the 0.05 to 20 µM BPA concentration range, and the detection limit is 0.8 nM (at S/N = 3). The sensor is reproducible, stable and selective. It was applied to analyze baby bottles, drinking cups, mineral water bottles and shopping receipts that were spiked with BPA, and the recoveries reached 99.1-101.4%. Graphical abstract Illustration of fabricating the electrochemical sensor for detecting BPA. N-G/M: nitrogen-doped reduced graphene oxide and melamine composite; GCE: glassy carbon electrode.