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To reduce energy consumption and improve service stability and security, various design methods of cutterhead based on lightweight, modal optimization and life prediction were adopted. In the present work, a multi-disciplinary design optimization (MDO) methodology is presented and subsequently applied to the development of cutterhead. According to the requirements of the cutterhead process and the results of sensitivity analysis, the design parameters of each discipline were determined. To alleviate the computational cost caused by calling the results of finite element method (FEM) in design optimization, the Kriging model was employed to approximate the highly nonlinear implicit relationship between the mode frequency, fatigue life and the design parameters. Then, the system-level optimization model and the subsystem-level optimization model of mass, mode frequency and fatigue life were established based on collaborative optimization (CO). Finally, genetic algorithm (GA) was used for iterative optimization between the system-level and subsystem-level model to obtain the overall optimization results. The results showed that the mass of the cutterhead was finally reduced from 90.4 t to 88.5 t, the first-order modal frequency raised from 32 HZ to 37 HZ, and the fatigue life raised from 3.0E5 cycles to 5.5E5 cycles. [ABSTRACT FROM AUTHOR]

To balance the cost and accuracy in the optimization of EDM process parameters, the variable-fidelity surrogate model (VFM) was introduced in this paper to replace the implicit relationship between the EDM process parameters (peak current, duty cycle, pulse period) and performance functions (material remove rate, MRR, and surface roughness, Ra). Low-fidelity (LF) samples were obtained by using the low-cost EDM heat flow simulation, and high-fidelity (HF) samples were obtained by using the EDM machining experiments. By fusing the LF and HF samples, it is possible to establish an accurate expression of the implicit relationship between the EDM process parameters and performance functions in the variable-fidelity framework. Finally, the EDM process parameter model was established, and sequential quadratic programming (SQP) was used to obtain the optimal solution by calling the VFM. Through the verification experiments, the results showed that the parameter combination obtained by VFM is 15.1% higher than the MRR of the low-fidelity model (LFM) and 13.0% higher than the high-fidelity model (HFM), which reaches 88.285 mg/min, while the Ra has slightly decreased and is within the constraint range. From the above research, it can be concluded that the proposed technology has significant advantages and application potential in the field of EDM machining optimization. [ABSTRACT FROM AUTHOR]

Since most cancer nanomedicine relies on the enhanced permeability and retention (EPR) effect to eradicate tumors, strategies that are able to promote nanoparticle (NP) delivery and extravasation are presupposed to elevate the EPR effect for more effective cancer therapeutics. However, nanothermotherapeutics still suffers from limited drug delivery into tumor sites, for even though numerous efforts have been made to enhance the selective tumor targeting of NPs. In this study, we uncovered that radial extracorporeal shock wave therapy (rESWT), an important approach in physical therapy that has been overlooked in cancer treatment in the past, can largely improve the EPR-dependent tumor uptake of NPs. We here defined the optimal low dosage and desirable combinatory manner for rESWT in driving NP accumulation towards tumors. Two underlying biophysical mechanisms responsible for the rESWT-enhanced EPR effect were proposed. On one hand, rESWT-conducted compressive and tensile forces could relieve high intra-tumoral pressure; on the other hand, rESWT-induced cavitation bubbles could directly distend and disrupt tumor blood vessels. All these together synergistically promoted vessel vasodilation, tumor perfusion and NP extravasation. Further experiments revealed that the combinatory therapeutics between rESWT and nanothermotherapeutics greatly improved the tumor-killing efficacy. Thus, our findings open a new path to improve EPR-mediated drug delivery with the assistance of rESWT. [ABSTRACT FROM AUTHOR]

The sustainable development of nanotechnology requires a thorough understanding of the life cycle of synthesized nanomaterials, including environmental release, deposition, exposure, and potential health risks. Titanium dioxide (TiO 2 ) materials containing nanosized TiO 2 (nTiO 2 ) are commonly used as food additives. Thus, dietary intake through foods is the most important route for the exposure of TiO 2 materials. Given the toxic effects of nTiO 2 on the gastrointestinal tract and other tissues, it is imperative to investigate their sources and concentrations in popular foods. Therefore, we conducted a survey on TiO 2 particles in white-colored seafood and surimi products in Beijing. Our data indicated that the total Ti levels reached 6–12 μg/g (dry weight) in some white-colored seafood products, such as squid and cuttlefish, whereas relatively low concentrations were observed in jellyfish at approximately 1–3 μg/g (dry weight). For the locally favorite surimi-based food products in the market, the Ti concentrations ranged from 2 to 81 μg/g (dry weight). The exposure assessment showed that the average daily intake of TiO 2 particles through foods varied from 0.02 to 3.09 μg TiO 2 /kg bw /day, reflected by the Ti concentrations in this study, and that young people of age 20–30 showed the highest exposure level. Together, these results show relatively high concentrations of TiO 2 particles in some seafood and surimi products available in the market, and our findings therefore call for attention on TiO 2 particle exposure and uptake through daily foods. [ABSTRACT FROM AUTHOR]

Ferroportin (FPN) is the only known iron exporter in mammalian cells, and is universally expressed in most types of cells. FPN signaling plays a crucial role in maintaining iron homeostasis through governing the level of intracellular iron. Serum iron storage is conversely related with the estrogen level in the female bodies, and women in post-menopause are possibly subjected to iron retention. However, the potential effects of estrogen on iron metabolism are not clearly understood. Here, FPN mRNA transcription in all selected estrogen receptor positive (ER +) cells was significantly reduced upon 17β-estradiol (E2) treatment; and this inhibitory effect could be attenuated by ER antagonist tamoxifen. Likewise, in murine bone marrow-derived macrophages (BMDMs), FPN reduction with elevated intracellular iron (reflected by increased ferritin) was observed in response to E2; however, ferritin level barely responded to E2 in FPN-null BMDMs. The observation of inhibition of FPN mRNA expression was not replicated in ER − cells upon E2. A functional estrogen response element (ERE) was identified within the promoter of FPN, and this ERE was responsible for the suppressive effect of E2 on FPN expression. Moreover, ovariectomized (OVX) and sham-operated (SHAM) mice were used to further confirm the in vitro finding. The expression of hepatic FPN was induced in OVX mice, compared to that in the SHAM mice. Taken together, our results demonstrated that estrogen is involved in regulating FPN expression through a functional ERE on its promoter, providing additional insights into a vital role of estrogen in iron metabolism. [ABSTRACT FROM AUTHOR]

The malignancy of lung cancer (LC) is serious in the world. Exosomes are well-known natural nanovesicles, which are reported to have the potential to carry functional miRNAs as natural carriers and deliver chemotherapeutic drugs. However, the safety and functions of the engineered exosomes for delivering miRNA for the treatment of LC remain to be evaluated. In this study, we found that miR-563 is related to lung cancer from GeneCard database. RT-qPCR and in situ hybridization (ISH) were used to assess miR-563 expression in clinical samples. We prepared and verified the engineered exosomes loaded with miR-563 both in vitro and in vivo. In vitro, flow cytometry, Western blot, and other experimental methods were performed to evaluate the antitumor effect of miR-563 loaded exosomes. In in vivo, the LC mouse model was used to observe the effect of the prepared exosomes. The safety of using this exosomes was accessed by liver function test, hematological analysis, and H&E staining in major organs of the mice. Our findings indicated that the miR-563 loaded engineered exosomes inhibit the A549 cells growth in vitro, by inhibiting the tumor cell proliferation, migration, and invasion and promoting apoptosis. In in vivo, these engineered exosomes were enriched in tumor tissue after injecting to LC model mice and impacted tumor tissue by inhibiting the tumor volume and tumor weight. Importantly, our study indicated that miR-563 loaded engineered exosomes have the potential for clinical application for LC treatment with acceptable safety profiles. Our findings indicate a novel potential therapeutic target for lung cancer patients by miR-563 loaded engineered exosomes. [ABSTRACT FROM AUTHOR]

The malignancy of lung cancer (LC) is serious in the world. Exosomes are well-known natural nanovesicles, which are reported to have the potential to carry functional miRNAs as natural carriers and deliver chemotherapeutic drugs. However, the safety and functions of the engineered exosomes for delivering miRNA for the treatment of LC remain to be evaluated. In this study, we found that miR-563 is related to lung cancer from GeneCard database. RT-qPCR and in situ hybridization (ISH) were used to assess miR-563 expression in clinical samples. We prepared and verified the engineered exosomes loaded with miR-563 both in vitro and in vivo. In vitro, flow cytometry, Western blot, and other experimental methods were performed to evaluate the antitumor effect of miR-563 loaded exosomes. In in vivo, the LC mouse model was used to observe the effect of the prepared exosomes. The safety of using this exosomes was accessed by liver function test, hematological analysis, and H&E staining in major organs of the mice. Our findings indicated that the miR-563 loaded engineered exosomes inhibit the A549 cells growth in vitro, by inhibiting the tumor cell proliferation, migration, and invasion and promoting apoptosis. In in vivo, these engineered exosomes were enriched in tumor tissue after injecting to LC model mice and impacted tumor tissue by inhibiting the tumor volume and tumor weight. Importantly, our study indicated that miR-563 loaded engineered exosomes have the potential for clinical application for LC treatment with acceptable safety profiles. Our findings indicate a novel potential therapeutic target for lung cancer patients by miR-563 loaded engineered exosomes. [ABSTRACT FROM AUTHOR]

Arsenic (As) is an omnipresent metalloid toxicant, which has elicited serious environmental pollution and health risky problems. Previous studies have uncovered that the As exposure could also cause markedly reduction of serum triglycerides in mice. However, the regulation mechanisms are still largely unknown. The present study is aimed to elucidate the molecular mechanisms of lncRNAs in As-induced lipid metabolic disequilibrium. We demonstrated that lncRNA PU.1 AS was significantly induced in the liver of As-feed mice companied with lower serum triglycerides contents; further in vitro experiment confirmed that PU.1 AS regulated liver cells lipid accumulation by nile red fluorescence staining. Intensive mechanistic investigations illustrated that PU.1 AS could interact with EZH2 protein to regulate its downstream target gene expression, and As-induced PU.1 AS attenuated EZH2-supppressed Sirt6 expression, thereafter leading to a decreased SREBP-1c protein expression, as well as the diminished synthesis of triglycerides in hepatocytes. In conclusion, this study provided a new lncRNA-related regulatory signaling pathway participating in As-induced abnormal lipid metabolism. Unlabelled Image [ABSTRACT FROM AUTHOR]

Radial extracorporeal shock wave therapy (rESWT) has been proven to be effective for nonunion fractures. It was, thus, hypothesized that it may be used as a supplement therapy to promote osteochondral regeneration when combined with a scaffold previously prepared by our research group. In the present study, to verify this hypothesis, New Zealand white adult rabbits were anaesthetized and divided into three groups, as follows: Untreated control group, in which full-thickness cylindrical osteochondral defects were created without repairing; scaffold group, in which rabbits were implanted with the scaffolds; scaffold plus rESWT group, in which rabbits were implanted with scaffolds and then treated with rESWT at 2 weeks post-surgery. At 6 and 12 weeks after surgery, the animals were sacrificed. Nitric oxide (NO) levels in the synovial cavity of the knee joints were measured by the Griess method. In addition, macroscopic observation and the gross score according to the International Cartilage Repair Society (ICRS) histological scoring system were determined. Histological evaluation was also performed by hematoxylin-eosin and Safranin O/fast green staining. The results demonstrated that both the scaffold and scaffold plus rESWT treatments significantly reduced NO levels in the synovial cavity at 6 weeks after surgery (P<0.05), whereas no significant difference was observed at 12 weeks after surgery. The ICRS scores of the scaffold and scaffold plus rESWT groups were significantly higher in comparison with those in the control group (P<0.05), and rESWT further increased these scores at 12 weeks after surgery (P<0.05). Histological results revealed that osteochondral regeneration was improved after treatment with scaffold or scaffold plus rESWT, with the latter displaying better results. These data suggested that rESWT improved the osteochondral regeneration when applied in combination with the scaffold, and that one of the underlying mechanisms may involve the reduction of NO in the synovial fluid. Therefore, rESWT may be a useful treatment for knee osteochondral regeneration. [ABSTRACT FROM AUTHOR]

• Carbon aerogels of few-layer graphene skeletons by pyrolysis of hydrogel precursors. • Low mass density and high electrical conductivity due to NaCl crystal templates. • ORR activity from the resulting N -doped carbon aerogels. • OER activity from Ni3+ species by Fe(OH) 3 oxidation in adsorbed NiFe-LDH colloids. • High-performance bifunctional oxygen catalysts for water splitting and zinc-air batteries. Low-cost, high-performance oxygen catalysts are critical for electrochemical water splitting and metal-air batteries. Herein, carbon aerogels with skeletons consisting of few-layer graphene are derived pyrolytically from a hydrogel precursor using an array of NaCl crystals as the template, exhibiting a high electrical conductivity (869 S m−1) and an ultralow mass density (11.1 mg cm−3). The deposition of NiFe layered double hydroxide (NiFe-LDH) nanocolloids renders the aerogels active towards both the oxygen reduction/evolution reactions (ORR/OER), with the performances highly comparable to those of commercial benchmarks in both alkaline and neutral media. Results from operando Raman spectroscopy measurements and first principles caculations suggest that Fe(OH) 3 colloids facilitate the oxidation of Ni2+, which lowers the energy barrier to 0.42 eV for OER, whereas the nitrogen-doped carbon aerogels are responsible for the ORR activity. With the composites used as bifunctional oxygen catalysts for electrochemical water splitting and rechargeable zinc-air batteries, the performances in both alkaline and neutral media are markedly better than those based on the mixture of commercial Pt/C and RuO 2. Results from this study highlight the unique advantages of ultrathin graphene aerogels in the development of effective catalysts for electrochemical energy devices. [ABSTRACT FROM AUTHOR]

Advanced drug delivery systems are of vital importance to enhance therapeutic efficacy. Among various recently developed formulations, self-assembling hydrogels composed of therapeutic agents have shown promising potential for local drug delivery owing to their excellent biocompatibility, high drug-loading efficiency, low systemic toxicity, and sustained drug release behavior. In particular, therapeutic agents self-assembling hydrogels with well-defined nanostructures are beneficial for direct delivery to the target site via injection, not only improving drug availability, but also extending their retention time and promoting cellular uptake. In brief, the self-assembly approach offers better opportunities to improve the precision of pharmaceutical treatment and achieve superior treatment efficacies. In this review, we intend to cover the recent developments in therapeutic agent self-assembling hydrogels. First, the molecular structures, self-assembly mechanisms, and application of self-assembling hydrogels are systematically outlined. Then, we summarize the various self-assembly strategies, including the single therapeutic agent, metal-coordination, enzyme-instruction, and co-assembly of multiple therapeutic agents. Finally, the potential challenges and future perspectives are discussed. We hope that this review will provide useful insights into the design and preparation of therapeutic agent self-assembling hydrogels. [Display omitted] • The review introduces the therapeutic agents self-assembling hydrogels, highlightingassembly mechanisms and application. • Therapeutic agents include amino acid derivatives, peptides, nucleobases, steroids, triterpenoids, polyphenols and others. • Various self-assembly strategies are summarized. • Current challenges and future perspectives of therapeutic agent self-assembling hydrogels are discussed. [ABSTRACT FROM AUTHOR]

Abstract: Osteoporosis is one of the leading disorders among aged people. Bone loss results from a number of physiological alterations, such as estrogen decline and aging. Meanwhile, iron overload has been recognized as a risk factor for bone loss. Systemic iron homeostasis is fundamentally governed by the hepcidin–ferroportin regulatory axis, where hepcidin is the key regulator. Hepcidin deficiency could induce a few disorders, of which iron overload is the most representative phenotype. However, there was little investigation of the effects of hepcidin deficiency on bone metabolism. To this end, hepcidin-deficient (Hamp1 −/−) mice were employed to address this issue. Our results revealed that significant iron overload was induced in Hamp1 −/− mice. Importantly, significant decreases of maximal loading and maximal bending stress were found in Hamp1 −/− mice relative to wildtype (WT) mice. Moreover, the levels of the C-telopeptide of type I collagen (CTX-1) increased in Hamp1 −/− mice. Therefore, hepcidin deficiency resulted in a marked reduction of bone load-bearing capacity likely through enhancing bone resorption, suggesting a direct correlation between hepcidin deficiency and bone loss. Targeting hepcidin or the pathway it modulates may thus represent a therapeutic for osteopenia or osteoporosis. [Copyright &y& Elsevier]

Lead‐free halide double perovskites (A2BIBIIIX6) with attractive optical and electronic features are considered to be a promising candidate to overcome the toxicity and stability issues of lead halide perovskites (APbX3). However, their poor absorption profiles limit device performance. Here the absorption band edge of Cs2AgBiBr6 double perovskite to the near‐infrared range is significantly broadened by developing doped double perovskites, Cs2(Ag:Cu)BiBr6. The partial replacement of Ag ions by Cu ions in the crystal lattice is confirmed by the X‐ray photoelectron spectroscopy (XPS) and solid‐state nuclear magnetic resonance (ssNMR) measurements. Cu doping barely affects the bandgap of Cs2AgBiBr6; instead it introduces subbandgap states with strong absorption to the near‐infrared range. More interestingly, the near‐infrared absorption can generate band carriers upon excitation, as indicated by the photoconductivity measurement. This work sheds new light on the absorption modulation of halide double perovskites for future efficient optoelectronic devices. [ABSTRACT FROM AUTHOR]

Environmentally friendly halide double perovskites with improved stability are regarded as a promising alternative to lead halide perovskites. The benchmark double perovskite, Cs2AgBiBr6, shows attractive optical and electronic features, making it promising for high‐efficiency optoelectronic devices. However, the large band gap limits its further applications, especially for photovoltaics. Herein, we develop a novel crystal‐engineering strategy to significantly decrease the band gap by approximately 0.26 eV, reaching the smallest reported band gap of 1.72 eV for Cs2AgBiBr6 under ambient conditions. The band‐gap narrowing is confirmed by both absorption and photoluminescence measurements. Our first‐principles calculations indicate that enhanced Ag–Bi disorder has a large impact on the band structure and decreases the band gap, providing a possible explanation of the observed band‐gap narrowing effect. This work provides new insights for achieving lead‐free double perovskites with suitable band gaps for optoelectronic applications. [ABSTRACT FROM AUTHOR]

Environmentally friendly halide double perovskites with improved stability are regarded as a promising alternative to lead halide perovskites. The benchmark double perovskite, Cs2AgBiBr6, shows attractive optical and electronic features, making it promising for high‐efficiency optoelectronic devices. However, the large band gap limits its further applications, especially for photovoltaics. Herein, we develop a novel crystal‐engineering strategy to significantly decrease the band gap by approximately 0.26 eV, reaching the smallest reported band gap of 1.72 eV for Cs2AgBiBr6 under ambient conditions. The band‐gap narrowing is confirmed by both absorption and photoluminescence measurements. Our first‐principles calculations indicate that enhanced Ag–Bi disorder has a large impact on the band structure and decreases the band gap, providing a possible explanation of the observed band‐gap narrowing effect. This work provides new insights for achieving lead‐free double perovskites with suitable band gaps for optoelectronic applications. [ABSTRACT FROM AUTHOR]

To elucidate the role of Hox genes in limb cartilage development, we identified the target genes of HOXA11 and HOXA13 by ChIP‐Seq. The ChIP DNA fragment contained evolutionarily conserved sequences and multiple highly conserved HOX binding sites. A substantial portion of the HOXA11 ChIP fragment overlapped with the HOXA13 ChIP fragment indicating that both factors share common targets. Deletion of the target regions neighboring Bmp2 or Tshz2 reduced their expression in the autopod suggesting that they function as the limb bud‐specific enhancers. We identified the Hox downstream genes as exhibiting expression changes in the Hoxa13 knock out (KO) and Hoxd11‐13 deletion double mutant (Hox13 dKO) autopod by Genechip analysis. The Hox downstream genes neighboring the ChIP fragment were defined as the direct targets of Hox. We analyzed the spatial expression pattern of the Hox target genes that encode two different categories of transcription factors during autopod development and Hox13dKO limb bud. (a) Bcl11a, encoding a repressor of cartilage differentiation, was expressed in the E11.5 autopod and was substantially reduced in the Hox13dKO. (b) The transcription factors Aff3, Bnc2, Nfib and Runx1t1 were expressed in the zeugopodal cartilage but not in the autopod due to the repressive or relatively weak transcriptional activity of Hox13 at E11.5. Interestingly, the expression of these genes was later observed in the autopodal cartilage at E12.5. These results indicate that Hox13 transiently suspends the cartilage differentiation in the autopodal anlage via multiple pathways until establishing the paddle‐shaped structure required to generate five digits. [ABSTRACT FROM AUTHOR]

Nuclear factor (erythroid-derived 2) like 2 (Nrf2) is a key regulator in protecting cells against stress by targeting many anti-stress response genes. Recent evidence also reveals that Nrf2 functions partially by targeting mircroRNAs (miRNAs). However, the understanding of Nrf2-mediated cytoprotection through miRNA-dependent mechanisms is largely unknown. In the current study, we identified a direct Nrf2 targeting miRNA, miR-214, and demonstrated a protective role of miR-214 in erythroid cells against oxidative stresses generated by radiation, excess iron and arsenic (As) exposure. miR-214 expression was transcriptionally repressed by Nrf2 through a canonical antioxidant response element (ARE) within its promoter region, and this repression is ROS-dependence. The suppression of miR-214 by Nrf2 could antagonize oxidative stress-induced cell death in erythroid cells by two ways. First, miR-214 directly targeted ATF4, a crucial transcriptional factor involved in anti-stress responses, down regulation of miR-214 releases the repression of ATF4 translation and leads to increased ATF4 protein content. Second, miR-214 was able to prevent cell death by targeting EZH2, the catalytic core component of PRC2 complex that is responsible for tri-methylation reaction at lysine 27 (K27) of histone 3 (H3) (H3K27me3), by which As-induced miR-214 reduction resulted in an increased global H3K27me3 level and a compromised overexpression of a pro-apoptotic gene Bim. These two pathways downstream of miR-214 synergistically cooperated to antagonize erythroid cell death upon oxidative stress. Our combined data revealed a protective role of miR-214 signaling in erythroid cells against oxidative stress, and also shed new light on Nrf2-mediated cytoprotective machinery. [ABSTRACT FROM AUTHOR]

[Display omitted] • Carbon aerogels with atomically dispersed cobalt by pyrolysis of hydrogel precursor. • CoN x moieties at nanopore edges show preferred adsorption of glucose. • Electrocatalytic activity of CoN x towards glucose oxidation. • Excellent detection of glucose in artificial saliva and human serum samples. Enzyme-free electrochemical glucose sensors have been attracting extensive attention, due to high sensitivity, excellent stability, and low cost, as compared to the conventional counterparts based on biological enzymes such as glucose oxidase. Within this context, development of low-cost, high-performance electrode catalysts represents a critical first step, and nanocomposites with atomically dispersed metal sites have emerged as viable candidates. In this study, nitrogen-doped carbon aerogel (NCA) embedded with CoN x sites is derived pyrolytically from biomass hydrogels and serves as an electrode catalyst for the detection of glucose. The three-dimensional porous skeletons of NCA help disperse the Co single atom sites and facilitate the mass transfer during electrochemical reaction. Theoretical calculations reveal that the single metal sites (CoN 3 and CoN 4) at the edge of nanopores show optimal adsorption towards glucose, and likely make a dominant contribution to the high activity in glucose detection. In electrochemical measurements, the NCA-Co based, enzyme-free glucose sensor shows a detection limit of 0.1 μM, with a wide linear range from 0.5 μM to 6 mM, good stability, high selectivity and excellent reproducibility. Notably, this sensing platform also exhibits an excellent performance in determining the glucose contents in artificial saliva and human serum samples, indicating great potential for practical applications. [ABSTRACT FROM AUTHOR]