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Cytochrome P450-modified bacterial terpenoids remain in a vast chemical space to be explored. In the present study, we conducted global genome mining of 223,829 bacterial genomes and identified 2892 bacterial terpenoid biosynthetic gene clusters (BGCs) with cytochrome P450 genes. Among these, we selected 562 with multiple P450 enzymes, which were further clustered as 355 gene cluster families by sequence similarity analysis. We then chose lev, a BGC from Streptomyces levisMCCC1A01616, for heterologous expression and discovered four new a-amorphene-type sesquiterpenoids, levinoids A–D (1–4). The structures and absolute configurations of these four new compounds were determined by employing extensive NMR analysis, NMR chemical shift calculations with DP4+, and ECD calculations. Furthermore, levinoid C (3) exhibited a moderate level of neuroprotective activity (EC50= 21 µM) in the glutamate-induced excitotoxicity cell model. Our findings highlight the untapped chemical diversity of P450-modified bacterial terpenoids, opening new avenues for further exploration and discovery.

Biological voltage-gated ion channels, which behave as life’s transistors, regulate ion transport precisely and selectively through atomic-scale selectivity filters to sustain important life activities. By this inspiration, voltage-adaptable ionic transistors that use ions as signal carriers may provide an alternative information processing unit beyond solid-state electronic devices. This review provides a comprehensive overview of the first generation of biomimetic ionic transistors, including their operating mechanisms, device architecture development, and property characterizations. Despite its infancy, significant progress has been made in the applications of ionic transistors in fields such as DNA detection, drug delivery, and ionic circuits. Challenges and prospects of full exploitation of ionic transistors for a broad spectrum of practical applications are also discussed.

Directly performing remote sensing scene classification (RSSC) on satellites can effectively relieve pressures on data downlinks. However, existing convolutional neural network (CNN)-based methods with dense multiplication operations require a vast resource overhead and can hardly be deployed on resource-limited space platforms. In this article, an all adder neural network ( $\text{A}^{2}$ NN) with a generative-based hybrid knowledge distillation (GHKD) training strategy is proposed to solve this problem. In contrast to traditional CNNs, the $\text{A}^{2}$ NN discards all multiplication operations in the convolutional layers of the network and is instead completely composed of adder kernels; thus, this network has lower resource overheads than existing CNNs in hardware deployment. Compared with CNNs, the $\text{A}^{2}$ NN has a considerably lower RSSC accuracy; fortunately, this can be mitigated with the proposed GHKD training strategy. This strategy combines a hybrid KD method and a knowledge-matching-based generative learning method. The hybrid KD method utilizes the weight distribution knowledge in the adder neural network (ANN) to guide the high-performance classification knowledge in the CNN to be smoothly transferred to the $\text{A}^{2}$ NN, which consists entirely of adder kernels and has a considerably different structure than the CNN. The knowledge-matching-based generative learning method generates effective samples by matching the knowledge of the feature distribution of the real samples in the knowledge sources to augment the training database for hybrid KD. Extensive experiments and analyses on six public RSSC datasets show that the proposed GHKD training strategy significantly improves the RSSC performance of the proposed $\text{A}^{2}$ NN, achieving comparable performance to CNNs on most datasets.

Rapid endothelialization is extremely essential for the success of small-diameter tissue-engineered vascular graft (TEVG) (<6 mm) transplantation. However, severe inflammation in situoften causes cellular energy decline of endothelial cells. The cellular energy supply involved in vascular graft therapy remains unclear, and whether promoting energy supply would be helpful in the regeneration of vascular grafts needs to be established. In our work, we generated an AMPK activator (5-aminoimidazole-4-carboxamide ribonucleotide, AICAR) immobilized vascular graft. AICAR-modified vascular grafts were successfully generated by the co-electrospinning technique. In vitroresults indicated that AICAR could upregulate energy supply in endothelial cells and reprogram macrophages (MΦ) to assume an anti-inflammatory phenotype. Furthermore, endothelial cells (ECs) co-cultured with AICAR achieved higher survival rates, better migration, and angiogenic capacity than the controls. Concurrently, a rabbit carotid artery transplantation model was used to investigate AICAR-modified vascular grafts at different time points. The results showed that AICAR-modified vascular grafts had higher patency rates (92.9% and 85.7% at 6 and 12 weeks, respectively) than those of the untreated group (11.1% and 0%). In conclusion, AICAR strengthened the cellular energy state and attenuated the adverse effects of inflammation. AICAR-modified vascular grafts achieved better vascular remodeling. This study provides a new perspective on promoting the regeneration of small-diameter vascular grafts.

This work develops a model of the temperature and resistance for the RESET of confined phase change memory (PCM). The confined PCM, unlike the mushroom type, has heating inside the cell and higher resistance sensitivity to active region size. The ideal temperature profile is derived from a steady-state heat conduction formulation based on a quasi-3D approach. A thermal subcircuit is then proposed to implement the heating module, considering the thermoelectric effect (TEE) and temperature dependence of phase change materials, to obtain the active region size. The resistance of the irregular active region is then calculated using an integral method. Calibrated TCAD simulations and experimental data are used to verify the model with desired scalability and accuracy.

[Display omitted] • Regime diagrams are built using the capillary number and the droplet length. • Variations of the two critical transitional conditions are discussed. • Evolutions of necking processes under four influencing parameters are explored. • Two collapsing mechanisms are identified relying on the physical properties. • The critical neck width agrees with the theoretical prediction in all cases. Dynamic behaviors of droplets in asymmetric unilateral Y-junctions are experimentally studied. Three breakup regimes are categorized, namely no breakup, breakup with gaps and breakup with obstruction, and regime diagrams are constructed by the capillary number and the normalized droplet length. Influences of the bifurcation angle and the viscosity ratio on the two critical conditions between neighboring regimes are revealed. In particular, necking processes in the obstructed breakup regime are discussed and they are divided into three stages according to the evolution of the thinning rate. At the two previous stages driven by the two-phase flow, the necking processes show distinct characteristics under the influences of four different parameters, including capillary number, droplet length, viscosity ratio, and bifurcation angle, and the corresponding reasons are provided in detail. By contrast, the final pinch-off stage is driven by two different mechanisms depending merely on the physical properties of liquid systems. The neck collapsing of the low-viscosity droplet is driven by the potential flow while that of the high-viscosity droplet is driven by the two-fluid Stokes flow. Quantitative relations between the minimum neck width and the remaining time are built in the two situations and are found to coincide with the theoretical predictions, respectively. [ABSTRACT FROM AUTHOR]

Prenylation can impart pharmacological advantages to bioactive compounds. Global genome mining for prenylated cyclodipeptides identified a gczABCBGC from Streptomyces griseocarneus132 containing a cyclodipeptide synthase and two prenyltransferase genes. Subsequent heterologous expression allowed isolation and characterization of griseocazines, which displayed potent neuroprotective activity. Further biotransformation analyses revealed that prenyltransferases GczB and GczC catalyzed the stereospecific prenylation of cWW and attached geranyl and farnesyl groups to a cyclodipeptide scaffold, respectively.

Delayed ripening in tomato (Solanum lycopersicumL.) increases the supply of fruit during the growing season. Small heat shock proteins (sHSPs) are expressed during specific periods of plant growth and development. SlHSP17.7gene is specifically expressed at different stages of fruit ripening; however, the mechanism by which SlHSP17.7(Solyc06g076540.1.1) regulates tomato fruit ripening remains unclear. SlHSP17.7-RNA interference (RNAi) lines were already generated from Solanum chmielewskiiin previous study. The transverse diameter, vertical diameter, average single fruit weight, and abscisic acid (ABA) levels of all fruit remarkably decreased. The fruit became hard at the mature-green stage, and the hardness gradually decreased as the fruit ripened. The expression of fruit softening-related genes significantly increased from the mature-green to completely mature stages. Silencing SlHSP17.7through RNAi delayed ripening by 10 days. These results suggest that SlHSP17.7may delay fruit ripening by regulating the ABA content. This study provides a new theoretical basis for regulating fruit ripening by sHSPs and broadens the understanding of the regulation pathways of fruit ripening.

We conducted global genome mining of 162,672 bacterial genomes and identified 829 cyclodipeptide (CDP) biosynthesis gene clusters (BGC) containing a cytochrome P450 gene. Heterologous expression of BGC from Saccharopolyspora hirsutaDSM 44795 led to the identification of two novel crownlike CDPs, cyctetryptomycin A (4) and B (5), which possess unprecedented complex macrocycle and show neuroprotective activity. The two cytochrome P450s found in the BGC catalyze sequential reactions leading to the cyclization of diketopiperazine dimers.

The development of stealth devices that are compatible with both infrared (IR) and radar systems remains a significant challenge, as the material properties required for effective IR and radar stealth are often contradictory. In this work, based on an IR electrochromic device (IR-ECD), concepts of metamaterial manipulating electromagnetic waves are applied to develop a multifunctional ultrathin metasurface with a low radar cross section (RCS) and variable infrared emissivity. This paper presents a linear-to-linear polarization conversion metasurface (PCM) designed by hollowing the IR-ECD. In this way, the IR-ECD based on polyaniline (PANI) can also modulate the reflection waves in the microwave band without affecting its features in the infrared region. Thus, the proposed metasurface integrates both microwave stealth and variable infrared emissivity through a single layer. The measured results show that a 10 dB RCS reduction is achieved in the band of 8.46–9.5 GHz, and the infrared emissivity can be adjusted from 0.870 to 0.513 in the infrared stealth band of 8–14 μm. Due to the ultrathin thickness (only 0.081λ0at 9 GHz), low RCS in the X-band, and variable infrared emissivity, the designed multifunctional stealth metasurface has promising applications on military platforms with various surrounding environments.

Silver nanowires (NWs) (AgNWs) have emerged as the most promising conductive materials in flexible optoelectronic devices owing to their excellent photoelectric properties and mechanical flexibility. It is widely acknowledged that the practical application of AgNW networks faces challenges, such as high surface roughness, poor substrate adhesion, and limited stability. Encapsulating AgNW networks with graphene has been recognized as a viable strategy to tackle these issues. However, conventional methods like self-assembly reduction–oxidation or chemical vapor deposition often yield graphene protective layers with inherent defects. Here, we propose a novel one-step hot-pressing method containing ethanol solution that combines the spontaneous transfer and encapsulation process of rGO films onto the surface of the AgNWs network, enabling the preparation of flexible rGO/AgNWs/PET (reduced graphene oxide/silver NWs/polyethylene terephthalate) electrodes. The composite electrode exhibits outstanding photoelectric properties (T≈ 88%, R≈ 6 Ω sq–1) and possesses a smooth surface, primarily attributed to the capillary force generated by ethanol evaporation, ensuring the integrity of the rGO delamination process on the original substrate. The capillary force simultaneously promotes the tight encapsulation of rGO and AgNWs, as well as the welding of the AgNWs junction, thereby enhancing the mechanical stability (20,000 bending cycles and 100 cycles of taping tests), thermal stability (∼30 °C and ∼25% humidity for 150 days), and environmental adaptability (100 days of chemical attack) of the electrode. The electrode’s practical feasibility has been validated by its exceptional flexibility and cycle stability (95 and 98% retention after 5000 bending cycles and 12,000 s long-term cycles) in flexible electrochromic devices.

Living organisms use ions and small molecules as information carriers to communicate with the external environment at ultralow power consumption. Inspired by biological systems, artificial ion-based devices have emerged in recent years to try to realize efficient information-processing paradigms. Nanofluidic ionic memristors, memory resistors based on confined fluidic systems whose internal ionic conductance states depend on the historical voltage, have attracted broad attention and are used as neuromorphic devices for computing. Despite their high exposure, nanofluidic ionic memristors are still in the initial stage. Therefore, systematic guidance for developing and reasonably designing ionic memristors is necessary. This review systematically summarizes the history, mechanisms, and potential applications of nanofluidic ionic memristors. The essential challenges in the field and the outlook for the future potential applications of nanofluidic ionic memristors are also discussed.

To meet people’s pursuit of healthy low-fat cuisine, this study developed low-fat microwaved peanut snacks (LMPS) made from partially defatted peanuts (PDP) with different defatting ratios. The effects of defatting treatment on the structural characteristics, texture, color, and nutrient composition of LMPS were comprehensively explored. The structural characteristics of LMPS were characterized using X-ray micro-computed tomography (Micro-CT) and scanning electron microscope (SEM). The results demonstrated that the porosity, pore number, pore volume, brightness, brittleness, protein content, and total sugar content of LMPS all significantly increased (P< 0.05) with the increase in the defatting ratio. At the micro level, porous structure, cell wall rupture, and loss of intracellular material could be observed in LMPS after defatting treatments. LMPS made from PDP with a defatting ratio of 64.44% had the highest internal pore structural parameters (porosity 59%, pore number 85.3×105, pore volume 68.23 mm3), the brightest color (L* 78.39±0.39), the best brittleness (3.64±0.21 mm-1), and the best nutrition (high protein content, 34.02%±0.38%; high total sugar content, 17.45%±0.59%; low fat content, 27.58%±0.85%). The study provided a theoretical basis for the quality improvement of LMPS.

After long-term water injection development, most of the oilfields in China have entered the stage of high-water cut, which has reached up to 90%. Due to the strong heterogeneity of the reservoir, more than 50% of the oil remains underground in most oilfields. Therefore, how to predict the distribution and content of remaining oil quickly and accurately in heterogeneous reservoir has become the key of EOR. In this paper, a new effective water-flooding unit model is established based on a three-dimensional flow function, which can characterize the influence of vertical heterogeneity on flow and the streamline distribution. In addition, two shape functions are defined in the model to characterize the oil–water two-phase flow characteristics in an injection-production unit. The results show that the streamline in the lower part of the positive rhythm reservoir is denser, which leads to the formation of dominant seepage channel with ease. However, for the reverse rhythm reservoir, dominant seepage channel forms in the upper part of the reservoir. Besides, for the two types of reservoirs, the greater the permeability difference is, the faster the water cut increases. Furthermore, under the same rhythm condition, the positive rhythm reservoir reaches 90% water cut half a year earlier than the anti-rhythm reservoir. This study provides new insight and guidance for the development of remaining oil in rhythmic reservoirs.

Complex experimental design is a common problem in the preparation of theranostic nanoparticles, resulting in poor reaction control, expensive production cost, and low experiment success rate. The present study aims to develop PEGylated bismuth (PEG-Bi) nanoparticles with a precisely controlled one-pot approach, which contains only methoxy[(poly(ethylene glycol)]trimethoxy-silane (PEG-silane) and bismuth oxide (Bi2O3). A targeted pyrolysis of PEG-silane was achieved to realize its roles as both the reduction and PEGylation agents. The unwanted methoxy groups of PEG-silane were selectively pyrolyzed to form reductive agents, while the useful PEG-chain was fully preserved to enhance the biocompatibility of Bi nanoparticles. Moreover, Bi2O3not only acted as the raw material of the Bi source but also presented a self-promotion in the production of Bi nanoparticles via catalyzing the pyrolysis of PEG-silane. The reaction mechanism was systematically validated with different methods such as nuclear magnetic resonance spectroscopy. The PEG-Bi nanoparticles showed better compatibility and photothermal conversion than those prepared by the complex multiple step approaches in literature studies. In addition, the PEG-Bi nanoparticles possessed prominent performance in X-ray computed tomography imaging and photothermal cancer therapy in vivo. The present study highlights the art of precise reaction control in the synthesis of PEGylated nanoparticles for biomedical applications.

This paper looks at the Green for Grain Project in northern Shaanxi Province. Based on remote sensing monitoring data, this study analyzes the locations of arable land in northern Shaanxi in the years 2000, 2010 and 2013 as well as spatio-temporal changes over that period, and then incorporates data on the distribution of terraced fields to improve the input parameters of a RUSLE model and simulate and generate raster data on soil erosion for northern Shaanxi at different stages with a accuracy verification. Finally, combined with the dataset of farmland change, compared and analyzed the characteristics of soil erosion change in the converted farmland to forest (grassland) and the unconverted farmland in northern Shaanxi, so as to determine the project’s impact on soil erosion over time across the region. The results show that between 2000 and 2010, the soil erosion modulus of repur-posed farmland in northern Shaanxi decreased 22.7 t/ha, equivalent to 47.08% of the soil erosion modulus of repurposed farmland in 2000. In the same period, the soil erosion modulus of non-repurposed farmland fell 10.99 t/ha, equivalent to 28.6% of the soil erosion modulus of non-repurposed farmland in 2000. The soil erosion modulus for all types of land in northern Shaanxi decreased by an average of 14.51 t/ha between 2000 and 2010, equivalent to 41.87% of the soil erosion modulus for the entire region in 2000. This suggests that the Green for Grain Project effectively reduced the soil erosion modulus, thus helping to protect the soil. In particular, arable land that was turned into forest and grassland reduced erosion most noticeably and contributed most to soil conservation. Nevertheless, in the period 2010 to 2013, which was a period of consolidation of the Green for Grain Project, the soil erosion modulus and change in volume of soil erosion in northern Shaanxi were significantly lower than in the previous decade.

The Warburg effect, which originally described increased production of lactate in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, polarization of macrophages and activation of T cells. This phenomenon is intimately linked to several diseases including neoplasia, sepsis and autoimmune diseases1,2. Lactate, which is converted from pyruvate in tumour cells, is widely known as an energy source and metabolic by-product. However, its non-metabolic functions in physiology and disease remain unknown. Here we show that lactate-derived lactylation of histone lysine residues serves as an epigenetic modification that directly stimulates gene transcription from chromatin. We identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce the production of lactate by glycolysis, and this acts as a precursor that stimulates histone lactylation. Using M1 macrophages that have been exposed to bacteria as a model system, we show that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, increased histone lactylation induces homeostatic genes that are involved in wound healing, including Arg1. Collectively, our results suggest that an endogenous ‘lactate clock’ in bacterially challenged M1 macrophages turns on gene expression to promote homeostasis. Histone lactylation thus represents an opportunity to improve our understanding of the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer.

Min-entropy is the standard for quantisation of uncertainty of security key source under the worst case. It indicates the upper bound of length of security key that is able to be extracted from its source. The openly published min-entropy estimation methods are all based on experimental data or statistical tests to obtain the underlying probability distribution of the security key source, where huge number of samples are required and therefore are not feasible from engineering perspective. Aimed at computational complexity optimisation, this paper proposes a novel model for SRAM PUF min-entropy estimation based on the generic coupling relationship between entropy and average energy consumption of the SRAM cell. The model mainly investigates the way of min-entropy evaluation derived from the average energy consumption of memory cell during power-up stage via simulation. We apply the model to estimate the min-entropy of IS62WV51216BLL SRAM chip. The experimental results demonstrated that the accuracy of the proposed min-entropy estimation model is in parallel with that of conventional methods while its computational efficiency surpasses them to a large extent.

To investigate whether angiopoietin-1 (Ang-1) could regulate the endothelial progenitor cells (EPCs) survival and the effect of accelerating intra-aneurysmal organization and occlusion of the aneurysm neck.

Supplemental Digital Content is available in the text.Forkhead box protein M1 (FoxM1) has been associated with cancer progression and metastasis. However, the function of FoxM1 in tongue squamous cell carcinoma (TSCC) remains largely unknown. The purpose of this study was to determine the role of FoxM1 in regulation of epithelial–mesenchymal transition (EMT) and migration of TSCC cells. We found that FoxM1 induced EMT and increased invasion/migration capacity in SCC9 and SCC25 cells. FoxM1 stimulation increased c-Met, pAKT, and vimentin levels but decreased E-cadherin level. Chromatin immunoprecipitation assay established that FoxM1 is bound to the promoter of c-Met to activate its transcription. In turn, c-Met promoted the expression of FoxM1 and pAKT. Blocking AKT signaling attenuated the invasion and migration of SCC9 and SCC25 cells stimulated by FoxM1 or c-Met. These results indicate that a positive feedback loop controls the EMT and migration of TSCC cells induced by FoxM1 and c-Met through AKT. Furthermore, the expression levels of FoxM1, pAKT, and c-Met were found to significantly increase in TSCC tissues compared with normal tissues, and these three biomarkers were concomitantly expressed in TSCC tissues. Clinical association analyses indicated that the expression of FoxM1, c-Met, and pAKT was associated with clinicopathological characteristics of patients with TSCC including tumor stage, tumor size, and lymph node metastasis. Taken together, our findings suggest that FoxM1 promotes the EMT, invasion and migration of TSCC cells, and cross-talks with c-Met/AKT signaling to form a positive feedback loop to promote TSCC development.

ABSTRACTNinety-six crossbred [(Landrace × Yorkshire) × Duroc] finishing pigs with an average initial body weight of 67.02 ± 1.46 kg were used in this 10-week feeding trial to evaluate effect of dietary kapok seed meal (KSM) supplementation in finishing pigs. Pigs were randomly allotted into three dietary treatments (eight replicates/treatment and four pigs/pen). The dietary treatments were: (1) Control (CON), basal diet; (2) K1.5, CON + 1.5% KSM; and (3) K3.0, CON + 3.0% KSM. Overall, average daily feed intake linearly decreased (P < .05) with the increase in the level of dietary KSM supplementation. KSM groups elevated concentration of low-density lipoprotein in blood at the 10th week (P < .05). Moreover, meat colour in sensory evaluation linearly increased (P < .05) as dietary KSM concentration increased. Myristic acid, palmitic acid, stearic acid, linolenic aid, saturated fatty acids (SFAs) and SFAs/polyunsaturated fatty acids ratio linearly increased (P < .05) as dietary KSM concentration increased, except for palmitoleic acid and oleic acid where the ratio linearly decreased (P < .05). The present study results indicated that finishing pig supplemented with 3% KSM could improve meat quality and enhance the content of fatty acids of carcass fats and muscle without any adverse effect on growth performance.

China had implemented the national strategies for Major Function-oriented Zones (MFOZs) to realize the goal of national sustainable development since 2010. This study analyzed and compared spatio-temporal characteristics and differences in built-up area for China’s MFOZs using a China’ s Land Use Database (CLUD) derived from high-resolution remotely sensed images in the periods of 2000–2010 and 2010–2013. To sum up: (1) The percentage of built-up area in each of the MFOZs was significantly different, revealing the gradient feature of national land development based on the distribution of the main functions. (2) Annual growth in built-up area in optimal development zones (ODZs) decreased significantly during 2010–2013 compared with the period 2000–2010, while annual growth in built-up area in key development zones (KDZs), agricultural production zones (APZs) and key ecological function zones (KEFZs) increased significantly. (3) In ODZs, the average annual increase in built-up area in the Yangtze River Delta region was significantly higher than in other regions; the average area increase and rate of increase of built-up area in KDZs was faster in the western region than in other regions; average annual area growth of built-up area in APZs in the northeast, central and western regions was twice as high as the previous decade on average; the annual rate of change and increase in the dynamic degree of built-up area were most notable in KEFZs in the central region. (4) The spatial pattern and characteristics of built-up area expansions in the period 2010–2013 reflected the gradient feature of the plan for MFOZs. But the rate of increase locally in built-up area in ODZs, APZs and KEFZs is fast, so the effective measures must be adopted in the implementation of national and regional policies. The conclusions indicated these methods and results were meaningful for future regulation strategies in optimizing national land development in China.

The poor therapeutic efficacy of hydrophobic chemotherapeutic drugs is an intrinsic limitation to successful chemotherapy. In the present study, a multitask delivery system based on arginine-glycine-aspartic acid peptide (RGD) decorated vitamin E succinate (VES)-grafted-chitosan oligosaccharide (CSO)/RGD-conjugated d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS-RGD) mixed micelles (VeC/T-RGD MM) was first prepared for targeted delivery of a hydrophobic anticancer drug, paclitaxel (PTX), to improve the efficacy of U87MG tumor therapy. VES grafted CSO (VES-g-CSO) and TPGS-RGD were synthesized as nanocarriers, and PTX loaded VeC/T-RGD MM (PTX@VeC/T-RGD MM) was prepared via the organic solvent emulsification–evaporation method. The PTX@VeC/T-RGD MM was 150.2 nm in diameter with uniform size distribution, 5.92% drug loading coefficient, and no obvious particle size changes within 7 days. The PTX@VeC/T-RGD MM showed sustained-release properties in vitroand high cytotoxicity, and could be efficiently taken up by human glioma U87MG cells. The tumor inhibitory rate of PTX@VeC/T-RGD MM treatment in U87MG tumor spheroids and U87MG tumor bearing mice was 49.3% and 88.4%, respectively, which indicated a superior therapeutic effect. PTX@VeC/T-RGD MM did not damage normal tissues in safety evaluations. These findings suggested that PTX@VeC/T-RGD MM could be developed for the delivery of hydrophobic drugs to U87MG tumors.

An efficient and stereoretentive copper-catalyzed cross-coupling of glycosyl thiosulfonate and boronic acid for the construction of thioglycosides is described. The good functional group compatibility of this method allows the preparation of many bioactive aryl/alkenyl thioglycosides, including the hSGLT1 inhibitor.

Previous research on tissue-engineered blood vessels (TEBVs) has mainly focused on the intima or adventitia unilaterally, neglecting the equal importance of both layers. Meanwhile, the efficacy of grafts modified with vascular endothelial growth factor (VEGF) merely has been limited. Here, we developed a small-diameter graft that can gradually release VEGF and γ secretase inhibitor IX (DAPT) to enhance tissue regeneration and remodeling in both the intima and adventitia. In vitro, experiments revealed that the combination of VEGF and DAPT had superior pro-proliferation and pro-migration effects on endothelial cells. In vivo, the sustained release of VEGF and DAPT from the grafts resulted in improved regeneration and remodeling. Specifically, in the intima, faster endothelialization and regeneration of smooth muscle cells led to higher patency rates and better remodeling. In the adventitia, a higher density of neovascularization, M2 macrophages and fibroblasts promoted cellular ingrowth and replacement of the implant with autologous neo-tissue. Furthermore, western blot analysis confirmed that the regenerated ECs were functional and the effect of DAPT was associated with increased expression of vascular endothelial growth factor receptor 2. Our study demonstrated that the sustained release of VEGF and DAPT from the graft can effectively promote tissue regeneration and remodeling in both the intima and adventitia. This development has the potential to significantly accelerate the clinical application of small-diameter TEBVs.

We designed a novel series of bifunctional inhibitors of α-glucosidase and aldose reductase (ALR2) based on the structure of hydroxychalcone. The two enzymes relate to blood glucose level and anomalously elevated polyol pathway of glucose metabolism under hyperglycemia, respectively. Most compounds in the series exhibited a potent inhibitory activity for both enzymes, and a significant antioxidant property was shown. Further in vivostudies of 11jand 14dusing streptozotocin (STZ)-induced diabetic rats as a model found that 11jachieved not only good antihyperglycemic and glucose tolerance effect in a dose-dependent manner (p< 0.01) but also showed effective inhibition of polyol pathway. 14dsignificantly suppressed the maltose-induced postprandial glucose elevation. Additionally, they effectively improved lipid metabolisms and restored an antioxidant ability. Therefore, the two compounds may be promising agents for the prevention and treatment of diabetic complications.

Previously we constructed a fusion protein based on GLP-1 and globular adiponectin but unfortunately its yield was low because it was mainly expressed as inclusion bodies. Herein to optimize the soluble expression of this fusion protein we tried several fusion tag systems. Fusion tags, including GST-, Trx- and MBP-tag, greatly improved the soluble expression of the fusion protein. However, these tag-fusion proteins were aggregation-prone as judged by Native PAGE and gel filtration chromatography, and this aggregation reduced the specificity of enterokinase-mediated enzyme cleavage which was essential to remove the fusion tags. To improve the specificity of protein cleavage, we employed on-column cleavage for downstream purification. Finally using optimized expression followed by on-column cleavage, we obtained the product fusion protein with a yield of 1.2 mg per g wet bacterial cells which was 8-fold higher than before. This method improved the yield and simplified the process, and as a convenient method it can also be used for the preparation of other aggregation-prone proteins.

The transport and deposition of particulate materials through fractures is widely involved in environmental engineering and resource development engineering. A 3D Computational Fluid Dynamics-Discrete Element Method (CFD-DEM) coupling method was used to investigate the particle and fluid flow. The Gauss Model was applied to construct the rough surfaces. First, the numerical results were compared with the previous results and reasonable agreements were obtained. Second, the results indicated a novel flow pattern of particles in rough fractures. Then, a comprehensive particle sedimentary analysis indicated that the deposition distance of particles was inversely proportional to the particle size and density ratio. In addition, the particle deposition rates were increased by the mean roughness and there was an uneven sediment distribution impacted by roughness. Reasons for this uneven sediment distribution were analyzed in detail. Moreover, the bridge plugs of particles considering the closure of fractures were simulated as well. A part of particulate materials would be filtered at the inlet due to size effect and the transport distance of entered particles decreased significantly when the particle was large. A critical particle radius (R< 0.27 mm) that can flow through closure fracture in this work was found. This work can provide a clear insight into the migration and deposition characteristics of particles in the rough fractures underground.

It is important to identify epidermal growth factor receptor (EGFR) mutations, which have a good value for the individualized management of patients with non–small-cell lung cancer. A novel method for detecting the mutations on exons 19, 21 of EGFRin primary carcinoma samples by a fluorescence polarization (FP) assay was developed in this research. Firstly, 2 pairs of general primers of exons 19, 21 of EGFRwere, respectively, used to amplify the target regions in each exon in 2 reactions. Then, 2 probes specific for wild or mutation exons 19, 21 of EGFRwere labeled with tetramethyl 6-carboxyrhodamine or 6-carboxyfluorescein hybridized, respectively, with their target amplicons, and the hybridization resulted in an increase in the FP values. Exon 19 deletion and exon 21 missense mutation were determined by the analysis of the FP values. EGFRmutations in 372 non–small-cell lung cancer samples were analyzed in parallel with an FP assay and a sequencing assay. There was no significant difference between the mutation status results obtained with the FP assay and the results obtained with the sequencing assay. The minimum detection level established with this assay was 40 copiesuL. Reliable results could be obtained when more than 30 ng of DNA was tested by a FP assay. An FP assay was able to detect the mutation DNA of EGFReven when its content was as low as 10. An FP assay allowed the semiautomated detection of EGFRmutations in solution, and it was much simpler and cost effective than the traditional methods.

We have developed and standardized a novel technology, mutant-enriched liquidchip (MEL), for clinical detection of EGFR mutations. The MEL integrates a mutant-enriched PCR procedure with liquidchip technology for detections of EGFR exon 19 deletions and L858R mutation on both formalin-fixed and paraffin-embedded (FFPE) slides and plasma samples from patients with non-small cell lung cancer (NSCLC). The detection sensitivity was 0.1 of mutant DNA in the presence of its wild-type DNA. The cross-reaction rate was lower than 5. To evaluate the MEL platform, the EGFR mutation status of 59 patients with advanced NSCLC treated with EGFRTKIs (Tyrosine Kinase Inhibitors) were tested on their FFPE samples. EGFR exon 19 deletions and L858R were detected in 21 patients (21/59) and 76.2 (16/21) of them had partial response to the EGFR-TKIs, while by sequencing method, only 4 (4/59) mutations were detected. Plasma samples from 627 patients with various stages of NSCLC were examined with the MEL and 22 of EGFR exon 19 deletions and L858R were detected. Furthermore, in patients with advanced disease there are more mutations detected in plasma samples than in patients with less advanced disease. In conclusion, the MEL is a sensitive, stable, and robust technology for detecting EGFR DNA mutations from both FFPE and plasma samples from patients with NSCLC and is now routinely used for clinical diagnosis.

The detection of the p16INK4apromoter methylation status has a good value for the prognosis, early detection, and individualized management of patients with non-small cell lung cancer. A novel method detecting the p16INK4apromoter methylation status of primary carcinoma tissue samples by a fluorescence polarization assay was developed in this research. A pair of general primers was used to amplify a 305-basepair fragment in the promoter region of p16INK4a. Two probes specific for either methylated p16INK4aor unmethylated p16INK4aDNA labeled with either tetramethyl 6-carboxyrhodamine or 6-carboxy-fluorescein hybridized, respectively, with their target amplicons, and the hybridization increased the fluorescence polarization values. The p16INK4apromoter methylation status was determined by the analysis of the fluorescence polarization values. One hundred and twenty-nine non-small cell lung cancer samples were analyzed in parallel with a fluorescence polarization assay and a gel-based methylation-specific polymerase chain reaction (PCR) assay. There was no significant difference between the results of the p16INK4apromoter methylation status obtained with the fluorescence polarization assay and the results obtained with the gel-based methylation-specific PCR assay. The minimum detection level of the fluorescence polarization assay was 25 copiesL. The fluorescence polarization assay allowed the semiautomated detection of the methylated p16INK4aand unmethylated p16INK4apromoters directly in the solution with 1 PCR cycle, and it was much simpler than methylation-specific PCR and methylation-specific multiplex ligation-dependent probe amplification assays.

To facilitate expression and purification of an analog of GLP-1 (mGLP-1), an intein system was employed in this study. A recombinant fusion protein, CBD-DnaB-mGLP-1, was constructed and expressed in the form of inclusion body. After refolding, the intein-mediated self-cleavage was triggered by pH and temperature shift. By using chitin beads column followed by single step purification, about 2.58 mg of mGLP-1 with the purity of up to 98 could be obtained from 1 L medium. Tricine-SDS-PAGE, RP-HPLC, and ESI-MS were undertaken to determine the purity and molecular weight of mGLP-1. The glucose-lowering activity of mGLP-1 was also preliminarily determined.