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Aim: To evaluate the association between SLCO1B1 polymorphisms and elimination/toxicities of high-dose methotrexate (MTX). Methods: SLCO1B1 rs11045879 and rs4149056 polymorphisms were retrospectively genotyped in 301 children with newly diagnosed acute lymphoblastic leukemia. MTX concentration, doses of leucovorin rescue and toxicities were recorded. Results: SLCO1B1 rs11045879C carriers (CC + CT) had higher plasma MTX levels at 96 hr, and longer MTX elimination time. The number of leucovorin rescue doses in rs4149056C carriers (CC + CT) was more than those in TT ones. Moreover, SLCO1B1 polymorphisms were associated with HDMTX toxicities including thrombocytopenia, renal toxicity and anal mucositis, but not associated with MTX level at other time points or delayed elimination. Conclusions: Our data demonstrate that genotyping of SLCO1B1 might be useful to optimize MTX therapy.

Background: Compounds that target tumor epigenetic events are likely to constitute a prominent strategy for anticancer treatment. Histone deacetylase inhibitors (HDACis) have been developed as prospective candidates in anticancer drug development, and currently, many of them are under clinical investigation. We assessed the anticancer efficacy of a now hydroxamate-based HDACi, YF-343, in triple-negative breast cancer development and studied its potential mechanisms. Methods: YF-343 was estimated as a novel HDACi by the HDACi drug screening kit. The biological effects of YF-343 in a panel of breast cancer cell lines were analyzed by Western blot and flow cytometry. YF-343 exhibited notable cytotoxicity, promoted apoptosis, and induced cell cycle arrest. Furthermore, it also induced autophagy, which plays a pro-survival role in breast cancer cells. Results: The combination of YF-343 with an autophagy inhibitor chloroquine (CQ) significantly suppressed breast tumor progression as compared to the YF-343 treatment alone both in vitro and in vivo. Mechanistically, the molecular mechanism of YF-343 on autophagy was elucidated by gene chip expression profiles, qPCR analysis, luciferase reporter gene assay, chromatin immunoprecipitation assays, immunohistochemical analysis, and other methods. E2F7, a transcription factor, promoted the expression of ATG2A via binding to the ATG2A promoter region and then induced autophagy in triple-negative breast cancer cells treated with YF-343. Conclusion: Our studies have illustrated the mechanisms for potential action of YF-343 on tumor growth in breast cancer models with pro-survival autophagy. The combination therapy of YF-343 and CQ maybe a promising strategy for breast cancer therapy.

Fractional vegetation cover (FVC) is an important parameter to measure crop growth. In studies of crop growth monitoring, it is very important to extract FVC quickly and accurately. As the most widely used FVC extraction method, the photographic method has the advantages of simple operation and high extraction accuracy. However, when soil moisture and acquisition times vary, the extraction results are less accurate. To accommodate various conditions of FVC extraction, this study proposes a new FVC extraction method that extracts FVC from a normalized difference vegetation index (NDVI) greyscale image of wheat by using a density peak k-means (DPK-means) algorithm. In this study, Yangfumai 4 (YF4) planted in pots and Yangmai 16 (Y16) planted in the field were used as the research materials. With a hyperspectral imaging camera mounted on a tripod, ground hyperspectral images of winter wheat under different soil conditions (dry and wet) were collected at 1 m above the potted wheat canopy. Unmanned aerial vehicle (UAV) hyperspectral images of winter wheat at various stages were collected at 50 m above the field wheat canopy by a UAV equipped with a hyperspectral camera. The pixel dichotomy method and DPK-means algorithm were used to classify vegetation pixels and non-vegetation pixels in NDVI greyscale images of wheat, and the extraction effects of the two methods were compared and analysed. The results showed that extraction by pixel dichotomy was influenced by the acquisition conditions and its error distribution was relatively scattered, while the extraction effect of the DPK-means algorithm was less affected by the acquisition conditions and its error distribution was concentrated. The absolute values of error were 0.042 and 0.044, the root mean square errors (RMSE) were 0.028 and 0.030, and the fitting accuracy R2 of the FVC was 0.87 and 0.93, under dry and wet soil conditions and under various time conditions, respectively. This study found that the DPK-means algorithm was capable of achieving more accurate results than the pixel dichotomy method in various soil and time conditions and was an accurate and robust method for FVC extraction.

Waterlogging is becoming an obvious constraint on food production due to the frequent occurrence of extremely high-level rainfall events. Leaf water content (LWC) is an important waterlogging indicator, and hyperspectral remote sensing provides a non-destructive, real-time and reliable method to determine LWC. Thus, based on a pot experiment, winter wheat was subjected to different gradients of waterlogging stress at the jointing stage. Leaf hyperspectral data and LWC were collected every 7 days after waterlogging treatment until the winter wheat was mature. Combined with methods such as vegetation index construction, correlation analysis, regression analysis, BP neural network (BPNN), etc., we found that the effect of waterlogging stress on LWC had the characteristics of hysteresis and all waterlogging stress led to the decrease of LWC. LWC decreased faster under severe stress than under slight stress, but the effect of long-term slight stress was greater than that of short-term severe stress. The sensitive spectral bands of LWC were located in the visible (VIS, 400–780 nm) and short-wave infrared (SWIR, 1 400–2 500 nm) regions. The BPNN Model with the original spectrum at 648 nm, the first derivative spectrum at 500 nm, the red edge position (λr), the new vegetation index RVI (437, 466), NDVI (437, 466) and NDVI’ (747, 1 956) as independent variables was the best model for inverting the LWC of waterlogging in winter wheat (modeling set: R2=0.889, RMSE=0.138; validation set: R2=0.891, RMSE=0.518). These results have important theoretical significance and practical application value for the precise control of waterlogging stress.

N6-methyladenosine (m6A) is one of the most common epigenetic modifications of eukaryotic mRNAs, which is involved in the regulation of gene expressions and biological processes in a variety of cells with dynamic and reversible methylation processes. In recent years, many studies have shown that m6A methylation modification not only acts on the growth, proliferation, and medullary differentiation of acute myeloid leukemia cells, but also participates in the regulation of the proliferation and apoptosis of other hematological tumor cells such as chronic myeloid leukemia and diffuse large B-cell lymphoma, and it can even weaken the efficacy of anti-hematological tumor immunotherapy and induce immune escape leading to tumor resistance. With the successive development of a variety of m6A methylation-related enzyme inhibitors, it will provide new therapeutic ideas for patients with relapsed and refractory hematological tumors. In this paper, we review the research progress on the mechanism of m6A methylation on the occurrence, development, and tumor immunity of various hematological tumors.m6A甲基化修饰在血液肿瘤中的研究进展.N6-甲基腺嘌呤（m6A）甲基化修饰是真核生物mRNA最常见的一种表观遗传修饰方式，以动态、可逆的甲基化过程，参与多种细胞基因表达调控与生物学过程。近年来，诸多研究表明m6A甲基化修饰不仅作用于急性髓系白血病细胞的生长、增殖及髓样分化，还参与调控慢性髓系白血病、弥漫大B细胞淋巴瘤等其他血液肿瘤细胞的增殖与凋亡，甚至可以削弱抗血液肿瘤免疫疗效和诱导免疫逃逸导致肿瘤耐药。多种m6A甲基化相关酶抑制剂的相继研发，将为复发难治血液肿瘤患者提供新的治疗思路。本文就m6A甲基化对各血液肿瘤发生发展和肿瘤免疫的作用机制的研究进展作一综述。.

A specific functional electric component is connected to any branch of the neural circuit, which can enhance the corresponding biological function as a smart sensor, whereas the temperature has a significant effect on the firing rhythm of neurons by regulating channel conductance and excitability. So for this paper, a controllable thermosensitive neuron model is established by paralleling two thermistors in the FitzHugh–Nagumo neural circuit. Especially, the thermistors are controlled by two switches, where three working modes can be selected, for which bifurcation diagrams, time response diagrams and spectral entropy (SE) complexity are used to analyze the dynamic behaviors in different operating modes. It is found that any modulation of thermistor can regulate the branch current and output voltage completely under the three working modes. More importantly, the neuronal activities show different mode transitions from periodic to bursts or chaos. The superior dynamic characteristics and rich firing behavior make the new model more suitable for images encryption. For this purpose, we consider switching the three thermosensitive neuron models continuously to obtain more complex chaotic sequences. Next, based on the feature of high pixel correlation among color image components, a 3D projection scrambling algorithm is designed, and then employed in combination with the universal gravitational diffusion method to propose a color image encryption scheme. In addition, the designed algorithm is executed by encrypting and decrypting some color images. The experimental results show that the algorithm cannot only encrypt the color image effectively, but also has no limitation on the size of the test image. It is worth mentioning that the designed encrypted algorithm has satisfactory security performance and considerable robustness against noise attacks and shearing attacks. The exploration of this paper about the thermosensitive neuron model and its application may provide some theoretical guidance and experimental basis in the field of secure communication.

This study provides a comprehensive, comparative and updated estimates of temporal patterns of lower respiratory infections (LRIs) globally over the past three decades.The data on morbidity and mortality of patients with LRIs at the global, regional and national levels were retrieved from the Global Burden of Disease (GBD) 2019 study.Globally, the incident cases of LRIs increased from 414,342,866 [95% uncertainty interval (UI):383,529,625 to 449, 086,938]in 1990 to 488,902,504(95% UI: 457,572,987 to 522,635,542)in 2019 with the age standardized incidence rate (ASIR) decreased from 8,276/100,000 persons (95% UI: 7,727 to 8,892) to 6,295/100,000 persons (95% UI: 5,887 to 6,737) between 1990 and 2019. Number of LRIs deaths were 2,493,200 (95% UI: 2,268,184 to 2,736,184) in 2019, a decrease of 24.9% (95% UI: -34.4 to -15.4) in the past 30 years. Meanwhile, the age-standardized death rate (ASDR) declined also from 67/100,000 persons (95% UI: 61 to 73) in 1990 to 34/100,000 persons (95% UI: 31 to 38) in 2019. Moreover, the numbers and age-standardized rates per 100,000 persons of morbidity and mortality varied widely by age, sex, Socio-Demographic Index (SDI) quintiles, and geographical locations in 2019.LRIs remain a major public health concern . Some differences in age, sex, SDI quintiles, and geographical locations contribute to LRIs-related global health policy development and health system resource optimization.

Bone marrow transplantation is regarded as the most effective immunotherapy for hematologic cancer, but it generally faces difficulties in matching. Aberrant expression of histone deacetylases (HDACs) is closely related to the occurrence and development of hematological cancer. Recent studies suggested that HDACs might play a critical role in initiating anti-cancer immune response or enhancing anti-cancer immunotherapy. Besides, combining HDAC inhibition and immunotherapy could prevent immunotherapy resistance in some degree and reach an extended treatment window. This review summarized the relationship between HDACs and immune and described the current understanding of HDACs in immunotherapy for hematologic cancer.

Multi-source information fusion (MSIF) is a sophisticated estimating technique that enables users to more precisely analyze complex situations by successfully merging key evidence in the vast, varied, and occasionally contradictory data obtained from various sources. Restricted by the data collection technology and incomplete data of information sources, it may lead to large uncertainty in the fusion process and affect the quality of fusion. Reducing uncertainty in the fusion process is one of the most important challenges for MSIF. In view of this, a multi-source information fusion method based on information sets (MsIFS) is proposed in this paper. First, constructing different agents according to four membership degree functions with the help of the concept of information sets. Then, Shannon agent entropy and Shannon inverse agent entropy are defined, and their summation is used to evaluate the total uncertainty of the attribute values and agents. Finally, a MSIF algorithm is designed by infimum-measure approach. The experimental results show the rationality and effectiveness of our proposed algorithm.

Xiao Hu,1 Feifei Yang,2 Yonghong Liao,2 Lin Li,1 Guoguang Zhao,3 Lan Zhang1 1Department of Pharmacy, Xuanwu Hospital of Capital Medical University, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, People’s Republic of China; 2Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, People’s Republic of China; 3Department of Neurosurgery, Xuanwu Hospital of Capital Medical University, Beijing 100053, People’s Republic of ChinaCorrespondence: Guoguang Zhao; Lan Zhang Email ggzhao@vip.sina.com; lanizhg@126.comBackground and Aim: Polymeric nanoparticles (NPs) have received much attention as promising carrier systems in lung cancer and brain metastases.Methods: Here, for the first time, we investigated the feasibility of using inhaled cholesterol-PEG co-modified poly (n-butyl) cyanoacrylate NPs (CLS-PEG NPs) of docetaxel (DTX) for sustained pulmonary drug delivery in cancer metastasis.Results: Spray-dried or freeze-dried NPs yielded sustained drug release in vitro. In vitro inhalation evaluation data indicated that the inhalation formulation had better inhalability. Compared with intravenous (IV) administration, pharmacokinetic data suggested that the inhalation formulation prolonged plasma concentration of DTX for greater than 24 h and is more quickly and completely absorbed into the rat lung after intratracheal (IT) administration. Furthermore, freeze-dried powders were found to increase the t1/2 and area under curve (AUC) by 2.3 and 6.5 fold compared to the free drug after IT administration, and spray-dried powders were found to increase the t1/2 and AUC by 3.4 and 8.8 fold, respectively. After pulmonary administration of the inhalation formulation, DTX appeared to prolong the pulmonary absorption time. In addition, the inhalation formulation was distributed to the brain in a sustained release manner.Conclusion: These experimental results demonstrated that freeze- and spray-dried powders have the potential for pulmonary sustained release, and they also have the potential to be used as a novel treatment for the delivery of drugs that pass through the air–blood barrier and enter the brain and are efficient carriers for the treatment of brain metastasis.Keywords: pulmonary delivery, docetaxel, lung cancer, spray-drying, dry powder

DCN1, a co-E3 ligase, interacts with UBC12 and activates cullin-RING ligases (CRLs) by catalyzing cullin neddylation. Although DCN1 has been recognized as an important therapeutic target for human diseases, its role in the cardiovascular area remains unknown. Here, we first found that DCN1 was upregulated in isolated cardiac fibroblasts (CFs) treated by angiotensin (Ang) II and in mouse hearts after pressure overload. Then, structure-based optimizations for DCN1-UBC12 inhibitors were performed based on our previous work, yielding compound

Background: Vegetation heat-stress assessment in the reclamation areas of coal gangue dumps is of great significance in controlling spontaneous combustion. Methods: The study simulated the heat-stress environment of a coal gangue dump reclamation area through a temperature gradient experiment. We collected leaf spectrum and water content data on alfalfa plants commonly planted in such areas. We then obtained the optimal spectral features of appropriate leaf water content indicators through time series analysis, correlation analysis, and least absolute shrinkage operator (lasso) regression analysis. A spectral feature-based long short-term memory (SF-LSTM) model is proposed to estimate alfalfa's heat stress level. Results: Comparing three leaf water content indicators, we found that the live fuel moisture content (LFMC) varies significantly with time and has high regularity. Correlation analysis of the raw spectrum, first-derivative spectrum, vegetation indexes and leaf water content data shows that LFMC and spectral data were the most strongly correlated. Combined with lasso regression analysis, the optimal spectral features were the first-derivative spectral value at 1661 nm (abbreviated as FDS (1661)), RVI (1525, 1771), DVI (1412, 740) and NDVI (1447,1803). When the classification strategies were divided into three categories and the time sequence length of the spectral features was set to five consecutive monitoring dates, the SF-LSTM model had the highest accuracy in estimating the heat stress level in alfalfa. The accuracy of the training set was > 95% and the accuracy of the verification set was about 90%. Conclusion: The results provide an important theoretical basis and technical support for vegetation heat-stress assessment in coal gangue dump reclamation areas.

Myocardial injury is a nonnegligible problem in cardiovascular diseases and cancer therapy. The functional feature of N-containing heterocycles in the cardiovascular field has attracted much attention in recent years. Herein, we discovered a lead compound 12a containing 1,3,4-oxadiazole by extensive screening of anticancer derivatives containing nitrogen-heterocycle, which exhibited potential protective activity against oxidative stress in cardiomyocytes. Follow-up structure-activity relationship (SAR) studies also highlighted the role of substitution sites and bisamide moiety in enhancing the protective activity against oxidative stress. Specifically, compound 12d exhibited low cytotoxicity under high concentration and potent myocardial protection against oxidative stress in H9c2 cells. Preliminary mechanistic studies showed compound 12d could decrease the expression of cardiac hypertrophy and oxidative stress-related proteins/genes and reduce mitochondria-mediated cell apoptosis, thereby enhancing the cell vitality of injured cardiomyocytes. In this study, 1,3,4-oxadiazole may represent a novel pharmacophore that possesses potential myocardial protection and provides more choices for future optimization of cardiovascular drugs, especially for the treatment of onco-cardiology.

Three-dimensional (3D) culture of neural progenitor cells (NPCs) in hydrogels represents a powerful means for recapitulating neurodevelopment, disease modelling and drug discovery. However, the differentiation of NPCs to oligodendrocytes in 3D scaffolds remains a great challenge. In this study, polyvinyl alcohol (PVA) − sodium alginate (SA) composite hydrogels intended for NPC culture in 3D were fabricated by ionic crosslinking between SA and calcium ions. It was demonstrated that adding PVA to the composite hydrogels resulted in increases in pore size and swelling rate and decreases in elastic moduli as the PVA proportion was enhanced. In addition, the composite hydrogels were biocompatible with mouse NPCs and improved the proliferation of the encapsulated NPCs compared with SA hydrogels. Moreover, when velvet antler polypeptides (VAPs), which were capable of facilitating the differentiation of NPCs to oligodendrocyte fate in 2D, were loaded into PVA-SA hydrogels, NPCs differentiated into neurons, astrocytes and oligodendrocytes, with the presence of VAPs promoting oligodendrogenesis in a dose-dependant manner. The present composite hydrogels provide a suitable scaffold for the construction of neural tissue engineering and neurological disease modelling.

The role of polysaccharides in quality control of ginseng is underestimated. Large-scale comparison on the polysaccharides of Panax ginseng (PG), P. quinquefolius (PQ), P. notoginseng (PN), Red ginseng (RG), P. japonicus (ZJS), and P. japonicus var. major (ZZS), was performed by both chemical and biological approaches. Holistic fingerprinting at polysaccharide and the hydrolyzed oligosaccharide and monosaccharide levels utilized various chromatography methods, while OGD and OGD/R models on H9c2 cells were introduced to evaluate the protective effects on cell viability and mitochondrial function. Polysaccharides from six ginseng species exhibited remarkable content difference (RG > PG/ZZS/ZJS/PQ > PN), but weak differentiations in molecular weight distribution and oligosaccharide profiles, while Glc and GalA were richer for monosaccharide compositions of PG and RG polysaccharides, respectively. RG polysaccharides (25/50/100 μg/mL) showed significant cardiomyocyte protection by regulating mitochondrial functions. These new evidences may provide support for the supplementary role of polysaccharides in quality control of ginseng.

Purpose. This study is aimed at investigating brain structural changes and structural network properties in complete spinal cord injury (SCI) patients, as well as their relationship with clinical variables. Materials and Methods. Structural MRI of brain was acquired in 24 complete thoracic SCI patients ( 38.50 ± 11.19 years, 22 males) within the first postinjury year, while 26 age- and gender-matched healthy participants ( 38.38 ± 10.63 years, 24 males) were enrolled as control. The voxel-based morphometry (VBM) approach and graph theoretical network analysis based on cross-subject grey matter volume- (GMV-) based structural covariance networks (SCNs) were conducted to investigate the impact of SCI on brain structure. Partial correlation analysis was performed to explore the relationship between the GMV of structurally changed brain regions and SCI patients’ clinical variables, including injury duration, injury level, Visual Analog Scale (VAS), American Spinal Injury Association Impairment Scale (AIS), International Classification of Functioning, Disability and Health (ICF) scale, Self-rating Depression Scale (SDS), and Self-rating Anxiety Scale (SAS), after removing the effects of age and gender. Results. Compared with healthy controls, SCI patients showed higher SDS score ( t = 4.392 and p < 0.001 ). In the VBM analysis, significant GMV reduction was found in the left middle frontal cortex, right superior orbital frontal cortex (OFC), and left inferior OFC. No significant difference was found in global network properties between SCI patients and healthy controls. In the regional network properties, significantly higher betweenness centrality (BC) was noted in the right anterior cingulum cortex (ACC) and left inferior OFC and higher nodal degree and efficiency in bilateral middle OFCs, while decreased BC was noted in the right putamen in SCI patients. Only negative correlation was found between GMV of right middle OFC and SDS score in SCI patients ( r = − 0.503 and p = 0.017 ), while no significant correlation between other abnormal brain regions and any of the clinical variables (all p > 0.05 ). Conclusions. SCI patients would experience depressive and/or anxious feelings at the early stage. Their GMV reduction mainly involved psychology-cognition related rather than sensorimotor brain regions. The efficiency of regional information transmission in psychology-cognition regions increased. Greater GMV reduction in psychology region was related with more severe depressive feelings. Therefore, early neuropsychological intervention is suggested to prevent psychological and cognitive dysfunction as well as irreversible brain structure damage.

Size-transformable nanomedicine has the potential to overcome systemic and local barriers, leading to efficient accumulation and penetration throughout the tumor tissue. However, the design of this type of nanomedicine was seldom based on active targeting and intracellular size transformation. Here, we report an intracellular size-transformable nanosystem, in which small and positively charged nanoparticles (

Storage energy is an effective means and key technology for overcoming the intermittency and instability of photovoltaic (PV) power. In the early stages of the PV and energy storage (ES) industries, economic efficiency is highly dependent on industrial policies. This study analyzes the key points of policies on technical support, management drive, and financial support. Focusing on the efficiency of PV power and the power load of users, including households and enterprises, in Shanghai City over 24 h in 2016, this study analyzes the costs, benefits, internal rates of return, and investment recovery periods of distributed PV (DPV) and ES systems in the current policy context. This study also discusses the influences of various policy variables, including the ES battery capacity, the peak-valley price ratio, feed-in tariffs for DPV, and the ratio of grid-connected surplus PV power, on economic efficiency. The results show that in China's current policy context, both household and enterprise users of PV power would gain some economic benefits if PV systems were fitted with aqueous sodium-ion batteries of an appropriate capacity. Finally, this study offers some additional government policy suggestions.

This study was to analyze the pyrrolizidine alkaloids (PAs) in Eupatorium fortunei herbs and its derived finished products with a view to evaluating their effects on the proliferation and oligodendrogenesis of neural progenitor cells (NPCs). Using a LC-MS/MS method with 32 PAs reference standards, 8 PAs including intermedine, intermedine N-oxide, lycopsamine, lycopsamine N-oxide, retronecine, seneciphylline and senkirkine and 7-acetylintermedine N-oxide were identified with intermedine N-oxide and lycopsamine N-oxide being most abundant. The total PA amounts were found to vary from 0.18 to 61.81 μg/g in 30 batches of herbs and from 0.86 to 36.96 μg/g in 4 commercial finished products, respectively. Risk assessments indicated that the short-term intake seemed unlikely lead to acute toxic effects but the chronic use warranted cautions. Using NPCs derived from mouse induced pluripotent stem cells as an in vitro testing model, intermedine, intermedine N-oxide and lycopsamine N-oxide appeared to decrease cell viability at 30 μM whereas intermedine N-oxide inhibited oligodendrogenesis of NPCs at 10 μM. The present results suggested that the PAs in the majority of E. fortunei herbs and the derived products not only resulted in their exposure far exceeding the acceptable intake limit (i. e. 1.0 μg PA per day for adults) in herbal medicinal products recommended by the European Medicines Agency but also induced neurotoxicity to NPCs in vitro.

Due to intestinal cytochrome P450 (CYP450)-mediated metabolism and P-glycoprotein (P-gp) efflux, poor oral bioavailability hinders ginsenoside-Rh1 (Rh1) and ginsenoside-Rh2 (Rh2) from clinical application. In this study, Rh1 and Rh2 were incorporated into two self-microemulsions (SME-1 and SME-2) to improve oral bioavailability. SME-1 contained both CYP450 and P-gp inhibitory excipients while SME-2 only consisted of P-gp inhibitory excipients. Results for release, cellular uptake, transport, and lymph node distribution demonstrated no significant difference between either self-microemulsions in vivo, but were elevated significantly in comparison to the free drug. The pharmaceutical profiles in vivo showed that the bioavailability of Rh1 in SME-1 (33.25%) was significantly higher than that in either SME-2 (21.28%) or free drug (12.92%). There was no significant difference in bioavailability for Rh2 between SME-1 (48.69%) or SME-2 (41.73%), although they both had remarkable increase in comparison to free drug (15.02%). We confirmed that SME containing CYP450 and P-gp inhibitory excipient could distinctively improve the oral availabilities of Rh1 compared to free drug or SME containing P-gp inhibitory excipient. No notable increase was observed between either SME for Rh2, suggesting that Rh2 undergoes P-gp-mediated efflux, but may not undergo distinct CYP450-mediated metabolism.

Polymeric micelles are considered promising carriers for pulmonary drug delivery. Their interaction with the respiratory epithelium, however, is mostly unknown. In the present study, methoxypoly (ethylene glycol) (mPEG)-poly (lactic-co-glycolic acid) (PLGA) micelles containing curcumin acetate (CA) or a mixture of CA and Nile Red (NR) were prepared using the solvent evaporation method. Calu-3 and NCI-H441 human respiratory epithelial cell monolayers were used as in vitro models of upper and lower respiratory tract epithelium barrier, respectively, to study the cellular uptake and transport of the vesicles. The results show that Calu-3 and NCI-H441 cells internalized micellar particles and that micelles were able to translocate across the cell monolayers. Micelles were more readily internalized into and permeated across Calu-3 cell monolayers when compared to NCI-H441 cells. Furthermore, the presence of inhibitors of endocytic processes, such as methyl-β-cyclodextrin, NaN3 and hypertonic sucrose attenuated the cellular uptake and trafficking of micelles. In conclusion, this study demonstrated that mPEG-PLGA micelles translocate human respiratory epithelium in vitro through clathrin-, energy- and cholesterol-mediated endocytosis.

The main objective of this study was to test the hypothesis that inhaled nanocrystals of a highly lipophilic drug could be used as a novel approach for producing sustained pulmonary delivery. Curcumin acetate, an ester prodrug of curcumin, was utilized as a highly lipophilic model drug. Curcumin acetate was subjected to wet ball milling to produce different particle sizes of nanocrystals and microparticles, and the milled curcumin acetate was spray-dried to yield similar inhalable microparticles. Following intrapulmonary administration in rats, pharmacokinetic experiments indicated that curcumin acetate significantly extended the pulmonary absorption time by 7.2-fold compared to curcumin, possibly due to the high lipophilicity of the former. The biodistribution data showed that aerosolized curcumin acetate nanocrystals 123.7 nm in size not only prolonged pulmonary retention, with the AUC value of curcumin acetate being 7.62-fold higher than that of the microparticles 1120 nm in size, but also increased the local in vivo release rate by 3.3-fold and the local availability of converted curcumin by 25.1-fold. In addition, the improved local availability resulted in better pharmacological efficacy in a monocrotaline-induced rat model of pulmonary arterial hypertension. This study was the first to demonstrate that inhalable nanocrystals are a feasible means for the sustained pulmonary delivery of highly lipophilic drugs.

The aim of this study was to investigate hemodynamic differences in different brain regions of normal macaque brains using dynamic susceptibility contrast (DSC) perfusion magnetic resonance (MR) imaging. Twelve male subjects were selected for DSC perfusion MR imaging (age 4–8 years). The relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) images were obtained by post-processing software. The values of rCBV and rCBF were recorded from the frontal cortex, parietal cortex, occipital cortex, head of caudate nucleus, posterior limb of internal capsule, thalamus, midbrain, pons, cerebellar, semioval area and splenium of the corpus callosum. The figures of rCBV and rCBF can clearly demonstrate the hemodynamic differences in various cerebral parts. It has been noted that rCBV and rCBF values have no significant difference between the right and left hemisphere (P > 0.05). The values of rCBF from cerebral cortex were significantly higher than that of white matter (P

The aim of this study was to produce fine particles with different corrugated degree of surface by spray-drying and to investigate the effect of surface morphology on in vitro aerosol performance of the particles within HFA 134a based metered dose formulations. Compositions of rizatriptan and scutellarin were spray-dried using different spray-drying parameters, and particles were suspended within HFA 134a. The surface morphology were determined using scanning electron microscopy (SEM), while the aerodynamic performance of MDIs was evaluated using a next generation pharmaceutical impactor. The surface morphology of spray-dried particles could vary from smooth to moderately corrugated, and to raisin-like depending upon spray-drying parameters and preparation compositions. In general, increasing inlet temperature, decreasing feed concentration and/or adding leucine to the feed solution tended to increase the corrugated degree of particle surface. Deposition results indicated that raisin-like particle based MDIs for all compositions of the two drugs produced significantly better aerodynamic performance in terms of fine particle fractions and mass median aerodynamic diameters relative to the formulations of the corresponding smooth or slightly corrugated particles when the particle compositions were the same. The present results demonstrated that wrinkled particles increased fine particle fractions within surfactant-free MDI formulations.

Cajaninstilbene acid (CSA) exerts wide pharmacological activities, such as anti-inflammation, hypoglycaemic activity, analgesic effect and cognition improvement. However, it underwent severe phase II metabolism mediated by UDP-glucuronosyltransferase (UGT) in the gastrointestinal (GI) tract after oral administration, affecting its oral bioavailability. In the present study, we utilize UGT inhibitory excipient containing self-microemulsion (SME) delivery system to reduce the production of glucuronide metabolites and increase its oral bioavailability. The present results showed that although similar properties in physiochemical, cytotoxicity, cellular uptake, absorption and transport across rat everted gut sacs between SME-1 (inhibitory excipient containing SME) and SME-2 (control SME, without inhibitory excipient), an improved absolute bioavailability of 57.3 % was conferred by SME-1, significantly higher than the value of 35.4 % by SME-2 and 34.0 % by free CSA. Noticeably, the significantly lower AUC value of CSA glucuronide was determined in rats treated with SME-1 than those either treated with SME-2 or free CSA. Thus, the ability of SME-1 to enhance oral bioavailability of CSA is mainly attributed to the inhibition of phase II metabolism in the GI tract.

This study intended to investigate the in vivo pulmonary fate of intratracheally dosed nanosuspensions of fluticasone propionate (FP). Three FP suspensions, including a microsuspension and two nanosuspensions with different dissolution profiles, were prepared and they exhibited comparable aerodynamic performances after nebulization via a jet nebulizer. Following intratracheal administration to rats, the microsuspension underwent extensive mucociliary clearance, leading to a limited absorption time whereas the nanosuspensions decreased the mucociliary clearance and allowed dissolution rate-limiting and extended pulmonary absorption, resulting in prolonged pulmonary retention and long-acting anti-inflammatory efficacy in a lipopolysaccharide induced lung injury model. Delaying the FP dissolution of a nanosuspension by phospholipid coating increased AUC value in lung tissues to 1.72-fold of a conventional nanosuspension, but led to a decreased pharmacological efficacy. This study demonstrated that inhalable nanosuspensions were a feasible means for the sustained pulmonary delivery of FP and the local anti-inflammatory efficacy was highly dependent on the dissolution profiles.

SnS2/few layer boron nitride nanosheets composites were synthesized via a one-step hydrothermal method. The as-prepared samples were characterized by X-ray diffraction, transmission electrical microscopy, UV–vis diffuse reflectance spectroscopy, Fourier transform infrared spectroscopy, photoluminescence emission spectra and electrochemical impedance spectroscopy, respectively. Rhodamine B was adopted to evaluate the degradation efficiency of the as-prepared samples under visible light irradiation. Experimental results showed that, compared to pure SnS2, the few layer boron nitride nanosheets could improve photocatalytic activities of the samples for the degradation of Rhodamine B. With increasing the usage amount of the few layer boron nitride nanosheets, the degradation efficiency was first increased and then decreased. When the usage amount of the few layer boron nitride nanosheets was 10 wt%, it exhibited the highest degradation efficiency of 93.7% in 210 min, which was higher than 50% of pure SnS2. After it was recycled for four times, it still possessed 88.7% of degradation efficiency. This was increased by 1008.7% than pure SnS2. Moreover, it had band gap energy of 1.78 eV, obviously smaller than 2.06 eV of pure SnS2. In addition, a possible photocatalytic mechanism was also presented.

Three new coordination polymers, [Zn(H2biim)(pzdc)]n (1), [Cd(H2biim)(pzdc)]n (2) and [Cd(H2biim)0.5(ip-OH)]n (3) (H2biim = 2,2′-biimidazolate, H2pzdc = 2,3-pyrazinedicarboxylic acid, H2ip-OH = 5-hydroxylisophthalic acid), have been hydrothermally synthesized and characterized by elemental analysis, infrared spectra and X-ray single-crystal diffraction. Complexes 1 and 2 are isostructural and display two-dimensional (2D) undulated layers with 3-connected (4.82) topologies, which are further extended into three-dimensional (3D) supramolecular structures through hydrogen-bonding and C–H⋯π interactions. Complex 3 is a relatively rare 3D compound, featuring a binodal (4,5)-connected (44.62)(44.66) topology. A comparison of all the complexes demonstrates that the structural characteristics of the dicarboxylate ligands play a great role in the modulation of the coordination structures. Moreover, their luminescent properties and thermal stabilities were also investigated.

Six new coordination polymers, [CdCl 2 (bbim)] n ( 1 ), [ZnCl 2 (bbbm)] n ( 2 ), [ZnCl(HCOO)(bbbm)] n ( 3 ), [Cd(PhCOO) 2 (bbim)] n ( 4 ), [Cd(PhCOO) 2 (bbbm)] n ( 5 ), and {[Zn(ip-OH)(bbim)]·DMF} n ( 6 ) [bbim = 1,1′-(1,4-butanediyl)bis(2-methylbenzimidazole), bbbm = 1,1′-(1,4-butanediyl)bis(benzimidazole), H 2 ip-OH = 5-hydroxylisophthalic acid], have been prepared and characterized by elemental analysis, infrared spectra and X-ray single-crystal diffraction. Complexes 1 – 5 have one-dimensional (1D) chain structures. Complexes 1 , 3 and 4 possess similar 1D meso-helical chain structures, which are extended into 2D or 3D supramolecular network through intermolecular hydrogen-bonding, C–H⋯ π and π ⋯ π interactions. Complexes 2 and 5 exhibit similar 1D infinite helical chains. The 1D chains further form a three-dimensional (3D) supramolecular structure through intermolecular hydrogen-bonding and π ⋯ π interactions in 2 , but form a 2D supramolecular layer via C–H⋯ π interactions in 5 . Complex 6 possesses a 2D 4 4 -sql network. Furthermore, luminescent properties and thermal stabilities of 1 – 6 were also investigated.

In this paper, we propose a real time method to detect vehicles on road by using a vehicle mounted monocular camera. Based on lane detection design, low time cost and high accuracy vehicle detecting and tracking algorithm is achieved. Robust and fast lane detection has been achieved using Hough transform in combination with a line merging method. The lane data are used for effective vehicle hypothesis generation. A subsequent validation, based on the area ratio of hypothesis vehicle, is used to eliminate false positives. Further, a data fusion mechanism is proposed to incorporate temporal information for stably updating vehicle detection results over time. Experimental results show that, without specific hardware and software optimizations, our method is able to detect vehicles on road with low false alarm rate at real time speeds of 30 frames per second.

Polymeric micelles represent interesting delivery systems for pulmonary sustained release. However, little is known about their in vivo release and translocation profile after delivery to the lungs. In the present study, curcumin acetate (CA), which is an ester prodrug of curcumin, or the mixture of CA and Nile red was encapsulated into PEG–PLGA micelles by a solvent evaporation method. The micellar formulation increased the stability of CA in water and physiologically relevant fluids and led to a sustained drug release in vitro. Following intratracheal (IT) administration to rats, CA loaded micelles achieved not only prolonged pulmonary retention with AUC values almost 400-fold higher than by IV route, but also local sustained release up to 24 h. In addition, IT delivery of micelles appeared to facilitate the uptake into the pulmonary vascular endothelium and efficiently translocate across the air–blood barrier and penetrate into the brain. Co-localization of CA and Nile red confirmed that micelles in lung and brain tissue were still intact. This study is the first to demonstrate that aerosolized PEG–PLGA micelles are a promising carrier for both pulmonary and non-invasive systemic sustained release of labile drugs.

Self-microemulsifying (SME) drug delivery system has been developed to increase oral bioavailabilities, and inhibitory excipients are capable of improving oral bioavailability by inhibiting enzyme mediated intestinal metabolism. However, the potential of enzyme inhibitory excipients containing SME in boosting resveratrol bioavailability remains largely uninvestigated. In this study, we set out to prepare SME-1 with UGT inhibitory excipients (excipients without inhibitory activities named SME-2 as control) to increase the bioavailability of RES by inhibiting intestinal metabolism. Results demonstrated that similar physicochemical properties such as size, polydistribution index and in vitro release, cellular uptake and permeability in Caco-2 cells as well as in vivo lymphatic distribution between inhibitory SME-1 and non-inhibitory SME-2 were observed. In vivo study demonstrated that the molar ratios of RES-G/RES were 7.25±0.48 and 5.06±2.42 for free drug and SME-2, respectively, and the molar ratio decreased to 0.36±0.10 in SME-1 group. Pharmacokinetic study confirmed that the inhibitory excipients containing SME demonstrated potential in increasing bioavailability of RES from 6.5% for the free RES and 12.9% for SME-2 to 76.1% in SME-1 through modulating the glucuronidation by UGT inhibitory excipients.

Herb extracts were shown to inhibit the activity of UDP-glucuronosyltransferases (UGTs) in vitro. However, the actual in vivo effect of the inhibitory ability on oral bioavailability is yet verified. In this study, resveratrol (RES) was used as a model drug to study the effect of three Chinese herb extracts, Ganoderma, Rhodiola and grape seed, on the in vitro and in vivo inhibition of glucuronidation and the in vivo bioavailability of RES. Overall, although herb extracts might show inhibition on glucuronidation of RES in vitro and in vivo, the inhibition of glucuronidation did not necessarily mean to improve the in vivo bioavailability of RES.