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Tumor cells and surrounding immune cells undergo metabolic reprogramming, leading to an acidic tumor microenvironment. However, it is unclear how tumor cells adapt to this acidic stress during tumor progression. Here we show that carnosine, a mobile buffering metabolite that accumulates under hypoxia in tumor cells, regulates intracellular pH homeostasis and drives lysosome-dependent tumor immune evasion. A previously unrecognized isoform of carnosine synthase, CARNS2, promotes carnosine synthesis under hypoxia. Carnosine maintains intracellular pH (pHi) homeostasis by functioning as a mobile proton carrier to accelerate cytosolic H+mobility and release, which in turn controls lysosomal subcellular distribution, acidification and activity. Furthermore, by maintaining lysosomal activity, carnosine facilitates nuclear transcription factor X-box binding 1 (NFX1) degradation, triggering galectin-9 and T-cell-mediated immune escape and tumorigenesis. These findings indicate an unconventional mechanism for pHi regulation in cancer cells and demonstrate how lysosome contributes to immune evasion, thus providing a basis for development of combined therapeutic strategies against hepatocellular carcinoma that exploit disrupted pHi homeostasis with immune checkpoint blockade.

MTBH, a novel hesperetin derivative, possesses in vivo hepatoprotective effects against carbon tetrachloride (CCl4)-induced acute liver injury in Institute of Cancer Research (ICR) mice. This study investigated the pharmacokinetics and tissue distribution of MTBH and its conjugated metabolites in rats after a single dose of MTBH. Male Sprague–Dawley (SD) rats were orally administered (25, 50, 100 mg/kg) or intravenously administered (25 mg/kg) MTBH and blood samples were withdrawn at specific times. Moreover, after a single oral dose of MTBH (200 mg/kg), tissues (heart, liver, spleen, lung, kidney, stomach, intestine, brain and muscle) were collected at scheduled time points. The concentration of MTBH in plasma and tissues was assayed by HPLC before and after hydrolysis with β-glucuronidase or sulfatase. The glucuronides/sulfates were extensively present in the plasma, moreover, the free form was detectable in the plasma, but in a small amount equivalent to nearly 0.85–1.46 % of the amount of glucuronides/sulfates, the absolute bioavailability of MTBH was approximately 31.27 %. In tissues, the free form appeared in all tissues examined, with trace amount in brain and muscle, and considerable concentration in stomach and lung. Glucuronides/sulfates were the major forms in intestine, kidney and liver, whereas not detectable in heart, brain and muscle. The liver and intestine were found likely to accumulate MTBH at a high concentration among all tissues. The free form of MTBH was present in the circulation and all assayed organs, whereas its glucuronides/sulfates were the major forms in plasma and intestine, kidney and liver after a single dose.

A 2-D airfoil shape optimization in transonic low-Reynolds number regime is conducted. A Navier–Stokes flow solver with a transition model (k-ω SST γ-Reθ) is used to evaluate the fitness function. Single-point and multi-point formulations of the optimization results are compared. In addition, the effects of Mach number and angles of attack on aerodynamic characteristics of the optimized airfoils are investigated under low Reynolds number (Re = 17,000) and high-subsonic-flow (Ma,∞=0.6−0.9) conditions. The results show that the corresponding drag divergence Mach number curves of the conventional airfoil present almost a parallel shifting at the entire Mach number range. By contrast, the unconventional airfoil starts showing a significant drag reduction when Mach number is greater than 0.75. Besides, the maximum lift-to-drag ratio is highly influenced by the Mach number because of the formation, movement, type, and strength of a shock wave. In addition, the distinguishing difference in the conclusion between two airfoils is that the lift fluctuation of the conventional airfoil amplifies with the increase of the Mach number. However, the unconventional airfoil shows an opposite trend.

Constrained multi-objective optimization problems (CMOPs) exist widely in the real world, which simultaneously contain multiple constraints to be satisfied and multiple conflicting objectives to be optimized. Therefore, the challage in addressing CMOPs is how to better balance constraints and objectives. To remedy this issue, this paper proposes a novel dual-population based constrained multi-objective evolutionary algorithm to solve CMOPs, in which two populations with different functions are employed. Specifically, the main population considers both objectives and constraints for solving the original CMOPs, while the auxiliary population is used only for optimization of objectives without considering constraints. In addition, a dynamic population size reducing mechanism is proposed, which is used to adjust the size of the auxiliary population, so as to reduce the consumption of computing resoruces in the later stage. Moreover, an independent external archive is set to store feasible solutions found by the auxiliary population, so as to provide high-quality feasible solutions for the main population. The experimental results on 55 benchmark functions show that the proposed algorithm exhibits superior or at least competitive performance compared to other state-of-the-art algorithms.

ABSTRACTIntroductionPhosphodiesterase 4B (PDE4B) is a crucial enzyme in the phosphodiesterases (PDEs), acting as a regulator of cyclic adenosine monophosphate (cAMP). It is involved in cancer process through PDE4B/cAMP signaling pathway. Cancer occurs and develops with the regulation of PDE4B in the body, suggesting that PDE4B is a promising therapeutic target.Areas coveredThis review covereed the function and mechanism of PDE4B in cancer. We summarized the possible clinical applications of PDE4B, and highlighted the possible ways to develop clinical applications of PDE4B inhibitors. We also discussed some common PDEs inhibitors, and expected the development of combined targeting PDE4B and other PDEs drugs in the future.Expert opinionThe existing research and clinical data can strongly prove the role of PDE4B in cancer. PDE4B inhibition can effectively increase cell apoptosis, inhibit cell proliferation, transformation, migration, etc., indicating that PDE4B inhibition can effectively inhibit the development of cancer. Other PDEs may antagonize or coordinate this effect. As for the further study on the relationship between PDE4B and other PDEs in cancer, it is still a challenge to develop multi-targeted PDEs inhibitors.

In the present study, an efficient overset grid method by means of parallel implicit hole-cutting is proposed for the sake of simulating unsteady flows in aerospace engineering involving multiple bodies in relative movement. In view of the degraded computational efficiency and robustness for conventional overset grid assembly, several innovative techniques are developed within the overset grid assembly process, viz., a bookkeeping alternative digital tree method to speed up the donor-cell searching, a fast parallel advancing front algorithm to accelerate the wall-distance calculation and a message-passing strategy with efficient information communication and lower storage expenditure within distributed computational architecture. The contribution of the developed techniques is evidenced by comparison with the existing alternative ways in terms of computing efficiency. Subsequently, the overset grid method is embedded into an in-house programed URANS solver to examine its capability in predicting the flow field of complex applications such as helicopter, store separation and component deploying. Results show that the developed overset grid methodology is, in practice, able to resolve the aerodynamic characteristics of complex aerospace engineering with a high-fidelity flow topology and accuracy.

ABSTRACTBreast carcinoma is one of the common causes of cancer-related mortality in women. Maternally expressed gene 3 (MEG3), a lncRNA located at 14q32, can be involved in carcinogenesis. In this study, we discovered that MEG3 was downregulated by CpG hypermethylation within its gene promoter. Functionally, treatment of breast cancer cells with the DNA methylation inhibitor 5-AzadC as well as silencing of DNA methyltransferase-1 (DNMT1) could decrease the abnormal hypermethylation of the MEG3 promoter, reverse MEG3 expression, inhibit cell proliferation and promote cell apoptosis. In addition, we found that MEG3 expression was negatively correlated with DNMT1. Mechanistically, MEG3 knockdown combined with 5-AzadC or sh-DNMT1 treatment restored the expression of Notch1 receptor, leading to the Notch1 pathway activation, and promoted the progression of epithelial mesenchymal transformation (EMT). Finally, the mice tumor model experiments showed that DNMT1 knockdown can increase MEG3 expression and inhibit tumor growth. Collectively, our findings uncovered that DNMT1-mediated MEG3 demethylation leads to MEG3 upregulation, which in turn inhibits the Notch1 pathway and EMT process in breast cancer.

A wing is an important part of the aircraft to improve aerodynamic performance. The current study is focused on an adaptive surrogate algorithm for airfoil aerodynamic optimization, which is based on a multi-output Gaussian process model. The conventional design method seriously relies on wind tunnel experiments and expensive computational simulations. The metamodels can significantly improve design efficiency and hence reduce the overall design costs. An active learning algorithm is proposed to improve the effectiveness of the multi-output Gaussian process model. The NSGA-II algorithm is adopted to obtain the optimal Pareto set with the optimization objectives of lift and drag coefficients for adaptive airfoil shapes. Besides, the Bezier curve and radial basis function are utilized in this study for airfoil mesh deformation. The results show that the airfoil shape can be obtained effectively by integrating the metamodel, active learning algorithm, and multi-objective optimization algorithm. The optimized results are of great engineering applications.

Background: Xanthatin is a plant-derived bioactive sesquiterpene lactone from the Xanthium strumariumL., and it has been used as a traditional Chinese medicine. Recently, many studies have reported that xanthatin hasanticancer activity. However, a comprehensive understanding of the mechanism underlying the antitumor effects ofxanthatin is still lacking. Objective: To systematically and comprehensively identify the underlying mechanisms of xanthatin on cancer cells,quantitative proteomic techniques were performed. Methods: Xanthatin induced HT-29 colon cancer cells death was detected by lactate dehydrogenase (LDH) release celldeath assay. Differentially abundant proteins in two groups (xanthatin treatment groups and control groups) of humanHT-29 colon cancer cells were identified using tandem mass tag (TMT) quantitative proteomic techniques. All thesignificant differentially abundant proteins were generally characterized by performing hierarchical clustering, GeneOntology (GO) enrichment analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses.We chose Western blot analysis to validate the candidate proteins in the proteomics results. Results: A total of 5637 proteins were identified, of which 397 significantly differentially abundant proteins in thegroups were quantified. Based on the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses,we found that p53-related signaling played an important role in xanthatin-treated HT-29 colon cancer cells. p53-upregulated modulator of apoptosis (Puma), Sestrin-2 and p14ARF, which were selected from among p53-relatedsignaling proteins, were further validated, and the results were consistent with the tandem mass tag quantitative proteomicresults. Conclusion: We first investigated the molecular mechanism underlying the effects of xanthatin treatment on HT-29colon cancer cells using tandem mass tag quantitative proteomic methods and provided a global comprehensive understandingof the antitumor effects of xanthatin. However, it is necessary to further confirm the function of the differentiallyabundant proteins and the potentially associated signaling pathways.

This article reports an investigation into dynamic characteristics of the laminar separation bubbles (LSBs) associated with aerodynamic loads unsteadiness of a cambered thin airfoil in pitching-up motions at low Reynolds number flows. Unsteady Reynolds-averaged Navier–Stokes (URANS) simulations were conducted for a 4%c cambered thin airfoil at Reynolds number of 30,000 and 60,000. The airfoil pitches up from 0° to 25°angles of attack at dimensionless pitch rate α˙of 0.0398 and 0.0199. The k−ωSST γ−R˜eθtturbulence transition model was used to account for the effect of transition on LSBs’ development. The LSBs are shown to evolve in their shape and size during the pitching motion. The influence of the LSBs on the airfoil upper surface during pitching motion continues to a higher incidence in comparison with that under static conditions before developing into a fully detached flow. Vortex merging is observed in the rear part of the LSBs in the turbulent portion for a Reynolds number of 30,000. At Reynolds number 60,000, the changing of the LSB length during pitching-up motion is similar to that of steady cases, except a delayed transition is observed as incidence increases. The results show further insight into the dynamic characteristics of the LSBs and their relation to the aerodynamic performance of the airfoil.

Background: The strong inter-individual pharmacokinetic variability and the narrow therapeutic window of tacrolimus (TAC) have hampered the clinical application. Gene polymorphisms play an important role in TAC pharmacokinetics. Here, we investigate the influence of genotypes of IL-10, CYP3A5, CYP2C8,and ABCB1on dose-adjusted trough blood concentrations (the C0/Dratio) of TAC to reveal unclear genetic factors that may affect TAC dose requirements for renal transplant recipients. Methods: Genetic polymorphisms of IL-10, CYP3A5, CYP2C8,and ABCB1in 188 renal transplant recipients were determined using Kompetitive Allele Specific PCR (KASP). Statistical analysis was applied to examine the effect of genetic variation on the TAC C0/Dat 5, 10, 15, and 30 days after transplantation. Results: Recipients carrying the IL-10 -819C> T TTgenotype showed a significantly higher TAC C0/Dthan those with the TC/CCgenotype (p< 0.05). Additionally, the TAC C0/Dvalues of recipients with the capacity for low IL-10activity (-819 TT)engrafted with CYP3A5non-expressers were higher compared to the intermediate/high activity of IL-10 -819C> T TCor CCcarrying CYP3A5expressers, and the difference was statistically significant at different time points (p< 0.05). Conclusions: Genetic polymorphisms of IL-10 -819C> Tand CYP3A5 6986A> Ginfluence the TAC C0/D, which may contribute to variation in TAC dose requirements during the early post-transplantation period. Detecting IL-10 -819C> Tand CYP3A5 6986A> Gpolymorphisms may allow determination of individualized tacrolimus dosage regimens for renal transplant recipients during the early post-transplantation period.

Mutations of tumor suppressor protein p53 are present in almost about 50% of all cancers. It has been reported that the p53 mutations cause aggregation and subsequent loss of p53 function, leading to cancer progression. Here in this study we focus on the inhibitory effects of cationic osmolyte molecules acetylcholine chloride, and choline on an aggregation prone 10 amino acid p53 mutant peptide WRPILTIITL, and the corresponding wildtype peptide RRPILTIITL in vitro. The characterization tools used for this study include Thioflavin- T (ThT) induced fluorescence, transmission electron microscopy (TEM), congo red binding, turbidity, dynamic light scattering (DLS), and cell viability assays. The results show that acetylcholine chloride in micromolar concentrations significantly inhibit p53 mutant peptide aggregation in vitro, and could be promising candidate for p53 mutant/ misfolded protein aggregation inhibition.

The original version of this article unfortunately contained a mistake in the affiliations.

Aim:To investigate the influence of CYP3A5and IL-10polymorphisms on tarcolimus metabolism and renal function for renal transplantation recipients at a stable period. Methods:CYP3A5and IL-10polymorphisms, together with other clinical factors, were collected for 149 renal transplantation patients at postoperative stable period. Statistics analysis was performed to explore key factors affecting tarcolimus metabolism. Results:CYP3A56986A >Gand IL-10 -819C >Tsignificantly impacted tacrolimus metabolism (p < 0.001). CYP3A5 6986A >G Gallele and IL-10 -819C >T Tallele were associated with poorer tacrolimus metabolic capability. Patients with various tacrolimus metabolism rates presented little difference in renal functions at stable period. Conclusion:Genotyping of CYP3A5and IL-10might benefit the precision dosage of tacrolimus for renal transplantation recipients.

AbstractThe effects of ageing and incorporation of ion-exchange membrane on the electrosorption performance of activated carbon (AC) electrodes-based electrosorption modules were investigated. It was found that the surface area of aged electrode decreased while the average pore size increased. In addition, more surface functional groups, especially –COOH groups were created on the electrode surface due to ageing. All these lead to a decrease in the electrosorption capacity and electrosorption rate. Incorporation of ion-exchange membranes can improve the desalination performance of the electrosorption module, especially for the aged electrode.

Peptide hydrogels are widely used for biomedical applications owing to their good biocompatibility and unique advantages in terms of amino acid-based structures and functions. However, the exploration of the peptide/saccharide composite hydrogels as potential biomaterials for chronic diabetic wound healing is still limited. Herein, hyaluronic acid (HA) was incorporated into diphenylalanine (FF) conjugated with different aromatic moieties by a one-pot reaction. Our results showed that the dipeptide derivatives modified by benzene (B), naphthalene (N), and pyrene (P) self-assembled into composite hydrogels with uniform distribution and good mechanical properties in the presence of HA. The obtained N-FF/HA composite hydrogel exhibited greatly improved self-healing properties viainjection syringe needle operation and good biocompatibility on human skin fibroblast (HSF) cells. Besides, the structure of thinner nanofibers and honeycomb networks inside the composite hydrogel allowed for a longer sustained release of curcumin, a hydrophobic drug for anti-inflammation and wound healing. The curcumin-loaded N-FF/HA composite hydrogels could promote chronic wound healing in the streptozotocin-induced type I diabetic mouse model. The results suggested that our developed saccharide-peptide hydrogels could serve as very promising synthetic biomaterials for applications in both drug delivery and wound healing in the future.

A broadband elastic wave absorption by a sub-wavelength and lightweight structure is of considerable significance in vibration suppression, especially for low frequencies in plate-like structure. However, it has always been a great challenge. In this research, we systematically study the flexural wave diffraction in a thin plate. Based on the diffraction mechanism, we propose the concept of sub-wavelength lossy gradient elastic metasurface for flexural wave absorption. We theoretically reveal high-efficiency and quasi-omnidirectional absorption behavior, which stem from maximum multireflection-enhanced absorption of the 0th order diffraction. We experimentally demonstrate a robust high-efficiency absorption in the frequency range from 343 to 1000 Hz (larger than 1.5 octaves). In addition, we propose a general approach which involves new physics of adjusting an arrangement sequence of subunits to suppress the first-order diffraction mode. This allows to further reduce the sub-wavelength thickness of the metasurface while maintaining its high-efficiency absorption. Our designs could provide new routes to broadband vibration suppression and cancelation in low frequency by lossy elastic metamaterials and metasurfaces. [ABSTRACT FROM AUTHOR]