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Thousands of lakes on the Tibetan Plateau (TP) play a critical role in the regional water cycle, weather, and climate. In recent years, the areas of TP lakes underwent drastic changes and have become a research hotspot. However, the characteristics of the lake-atmosphere interaction over the high-altitude lakes are still unclear, which inhibits model development and the accurate simulation of lake climate effects. The source region of the Yellow River (SRYR) has the largest outflow lake and freshwater lake on the TP and is one of the most densely distributed lakes on the TP. Since 2011, three observation sites have been set up in the Ngoring Lake basin in the SRYR to monitor the lake-atmosphere interaction and the differences among water-heat exchanges over the land and lake surfaces. This study presents an eight-year (2012–19), half-hourly, observation-based dataset related to lake–atmosphere interactions composed of three sites. The three sites represent the lake surface, the lakeside, and the land. The observations contain the basic meteorological elements, surface radiation, eddy covariance system, soil temperature, and moisture (for land). Information related to the sites and instruments, the continuity and completeness of data, and the differences among the observational results at different sites are described in this study. These data have been used in the previous study to reveal a few energy and water exchange characteristics of TP lakes and to validate and improve the lake and land surface model. The dataset is available at National Cryosphere Desert Data Center and Science Data Bank.

The seasonal ice cover in lakes of the Qinghai–Tibet Plateau is a transient and vulnerable part of the cryosphere, whose characteristics depend on the regional climate: strong solar radiation in the context of the dry and cold environment because of the high altitude and relatively low latitude. We use the first under-ice temperature observations from the largest Tibetan freshwater lake, Ngoring Lake, and a one-dimensional lake model to quantify the mechanism of solar thermal accumulation under ice, which relies on the ice optical properties and weather conditions, as well as the effect of the accumulated heat on the land–atmosphere heat exchange after the ice breakup. The model was able to realistically simulate the feature of the Ngoring Lake thermal regime: the “summer-like” temperature stratification with temperatures exceeding the maximum density point of 3.98 ∘C across the bulk of the freshwater column. A series of sensitivity experiments revealed solar radiation was the major source of under-ice warming and demonstrated that the warming phenomenon was highly sensitive to the optical properties of ice. The heat accumulated under ice contributed to the heat release from the lake to the atmosphere for 1–2 months after ice-off, increasing the upward sensible and latent surface heat fluxes on average by ∼ 50 and ∼ 80 W m−2, respectively. Therefore, the delayed effect of heat release on the land–atmosphere interaction requires an adequate representation in regional climate modeling of the Qinghai–Tibet Plateau and other lake-rich alpine areas.

Background Standardized patient (SP) simulations are well-recognized patterns for practicing clinical skills and interactions. Our previous study showed that a simulation program using occupational SP for Traditional Chinese Medicine (OSP-TCMs) was efficient, however, a high cost and time-intensive nature have limited its use. TCM postgraduates trained as student SPs (SSP-TCMs) present a potentially cost-effective alternative. The purpose of this study was to examine and determine whether SSP simulation offered more benefits over didactic training alone for improving clinical competency among TCM medical students, and conduct a multifaceted analysis comparing SSP-TCMs and OSP-TCMs. Methods This was a prospective, single-blinded, randomized controlled trial. Fourth-year TCM undergraduates were recruited as trainees from the Clinical Medical School, Chengdu University of TCM. Data were collected from September 2018 to December 2020. Trainees were randomly divided into the three following groups: traditional method training group, OSP-TCM training group, and SSP-TCM training group (1:1:1). At the end of a 10-week curriculum, trainees received a two-station examination comprising a systematic online knowledge test and an offline clinical performance examination. Post-training and post-exam questionnaires were administered to collect feedback from these trainees. Results Students assigned to the SSP-TCM training and OSP-TCM training groups received favorable marks for the “systematic knowledge test” and “TCM clinical skills” (2018, Pa=0.018, Pb=0.042; 2019, Pa=0.01, Pb=0.033; 2020, Pa=0.035, Pb=0.039) compared to the TM trainees. Additionally, trainees in the intervention groups demonstrated a positive post-training edge in scores of “medical records” (2018, Pa=0.042, Pb=0.034; 2019, Pa=0.032, Pb=0.042; 2020, Pa=0.026, Pb=0.03) and “TCM syndrome differentiation and therapeutic regimen” (2018, Pb=0.032; 2019, Pa=0.037, Pb=0.024; 2020, Pa=0.036, Pb=0.043). For the simulation encounter assessment given by SP-TCMs, OSP-TCM trainees and SSP-TCM trainees scored higher than TM trainees (2018, Pa=0.038, Pb=0.037; 2019, Pa=0.024, Pb=0.022; 2020, Pa=0.019, Pb=0.021). For the feedback questionnaires, the students in TM group provided less positive feedback for training efficacy and test performance compared to those in the SSP-TCM and OSP-TCM groups. The trainees responded that the training effect of clinical simulations was similar between the SSP-TCM and OSP-TCM groups. SSP-TCMs were more responsive to unexpected emergencies (Pa=0.022, Pb>0.05) and more likely to encourage questioning (Pa=0.029, Pb>0.05) but tended to provide implied hints (Pc=0.015) and utilize medical jargon (Pc=0.007) as compared to OSP-TCMs. Conclusion Simulation training for SSP-TCMs and OSP-TCMs showed great benefits for enhancing clinical competency. SSP-TCM simulation was feasible, practical, and cost-effective, and may serve as an alternative method to OSP-TCM simulation.

The objective of this research is to analyze the quantitative evaluation of human small intestinal bleeding by observing and analyzing animal experiments of small intestinal hemorrhage in rabbit models for the convenience of understanding the role of energy spectrum CT iodine-water diagram in animal experimental research of quantitative evaluation of small intestinal bleeding in rabbit models. Compared with the energy spectrum of iodine-water graph of a rabbit CT model, the present study studied the quantitative evaluation of small intestinal bleeding by using a rabbit model instead of human. According to the method mentioned above and the analysis of experimental data, the role of energy spectrum CT iodine-water map and the quantitative evaluation of human small intestinal bleeding have been understood. It was found that the energy spectrum CT iodine-water map replaces humans in the rabbit model for quantitative evaluation of small intestinal bleeding in animal experiments, which is important in the present study. Besides, based upon the combination of theoretical and experimental data, the ten flow rates set on the base material iodine (water) maps of the arterial phase and the portal phase can be analyzed to detect the leakage of contrast agent. The yield was 100%. The research results showed that the animal experiment of quantitative assessment of small intestinal bleeding by replacing the human body with the rabbit model in the energy spectrum CT iodine-water diagram is critical to humans in the study of small intestinal hemorrhagic diseases. In addition, it can be used to adjust the treatment plan timely according to the amount of bleeding to prevent shock or heavy bleeding that threatens patients’ lives.

IntroductionIt has been reported that GRB7 is closely related to a variety of human solid tumors, but its role in gastric cancer has not been reported yet. The purpose of this study was to investigate the expression level and intracellular effects of GRB7 in human gastric cancer.MethodsReal-time fluorescent quantitative PCR and Western blot were used to detect the expression of GRB7 in gastric cancer cell lines. The immunohistochemical staining and SPSS analysis verified the GRB7 protein expression. Stable gastric cancer cell lines, MTT experiments, clone formation experiments, cell cycle flow cytometry experiments, sphere formation experiments and lateral subpopulation cell sorting experiments were conducted to investigate the role of GRB7 in gastric cancer cells.ResultsWe found that the expression of GRB7 in gastric cancer cell lines was higher than that of the corresponding normal gastric epithelial cells, and correspondingly higher in gastric cancer tissues than its paired adjacent tissues. GRB7 protein was expressed more highly in cancer tissues than in adjacent tissues. GRB7 protein expression levels were positively correlated with the clinical stage of gastric cancer patients, and negatively correlated with the survival prognosis of patients. GSEA analysis of GRB7 mRNA levels in gastric cancer tissues and normal gastric epithelial tissues from public databases showed that GRB7 may affect cell proliferation and related processes of intracellular stem cells. GRB7 can promote the proliferation of gastric cancer cells and is positively related to the self-renewal ability of gastric cancer stem cells.DiscussionThis study shows that GRB7 molecules highly expressed in gastric cancer tissues can promote the proliferation of gastric cancer cells and increase the proportion of gastric cancer stem cells, so it is expected to become a diagnostic molecule or potential therapeutic target for gastric cancer.

Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease. The lack of targeted therapies and poor patient outcome have fostered efforts to discover new molecular targets to treat patients with TNBC. Here, we showed that baculoviral IAP repeat containing 6 (BIRC6) is overexpressed and positively correlated with epidermal growth factor (EGF) receptor (EGFR) in TNBC cells and tissues and that BIRC6 overexpression is associated with poor patient survival. Mechanistic studies revealed that BIRC6 stability is increased by EGF-JNK signaling, which prevents ubiquitination and degradation of BIRC6 mediated by the E3 ubiquitin ligase HECTD1. BIRC6 in turn decreases SMAC expression by inducing the ubiquitin-proteasome pathway, thereby antagonizing apoptosis and promoting the proliferation, colony formation, tumorsphere formation, and tumor growth capacity of TNBC cells. Therapeutically, the PEGylated cationic lipid nanoparticle (pCLN)-assisted delivery of BIRC6 small interfering RNA (siRNA) efficiently silences BIRC6 expression in TNBC cells, thus suppressing TNBC cell growth in vitro and in vivo, and its antitumor activity is significantly superior to that of the EGFR inhibitor gefitinib. Our findings identify an important regulatory mechanism of BIRC6 overexpression and provide a potential therapeutic option for treating TNBC., Graphical abstract, TNBC is the most aggressive subtype of breast cancer, and discovery of new targeted therapies is required. Our findings show that EGF-JNK-HECTD1 signaling can drive the overexpression of BIRC6 in TNBC. Targeting BIRC6 with lipid nanoparticle-coated siRNA represents a very promising approach for treating TNBC.

There are thousands of lakes in the Tibetan Plateau (TP), and most are saline. However, little is known about the responses of TP lakes to climate change, especially saline ones. We investigated the thermal responses of the largest freshwater lake (Ngoring Lake) in the TP and its nearby small saline lake (Hajiang Salt Pond) to climate change using the improved lake scheme in the Community Land model (CLM4-LISSS), in which we primarily developed the salinity parameterizations previously evaluated in the Great Salt Lake in USA and further considered the effect of salinity on the temperature of the maximum density of saline water in the present study. The improved lake model with salinity parameterizations was first applied to a saline lake in the TP, where saline lakes make up the majority of water bodies. The CLM4-LISSS model could effectively simulate lake surface water temperature (LSWT), lake water temperature (LT) and ice thickness in Ngoring Lake. Additionally, the model including our salinity parameterizations significantly improved simulations of LSWT and LT in Hajiang Salt Pond, especially in winter. The LSWT of the two completely opposite lakes were warming in the simulations at a rate above 0.6 °C/decade. Meteorological forces were the main driving factor, with increasing downward longwave radiation, air temperature and air humidity, as well as weakening winds contributing to LSWT increase. Compared to a hypothetical shallow freshwater lake, the greater depth of Ngoring Lake made its surface warm faster, and salinity slightly accelerated the warming of Hajiang Salt Pond. Monthly mean LSWT differences between the two lakes were induced by salinity effects in cold periods and lake depth in the unfrozen period. In response to a warming climate, the LSWT in the ice-free Hajiang Salt Pond rapidly increased from January to April due to the warming climate, whereas the LSWT of Ngoring Lake increased faster in the first and last month of the ice-cover period due to later ice-on and earlier ice-off. This study will provide a useful tool for saline lakes in the TP and help deepen our knowledge about the responses of TP lakes, especially the saline lakes, to climate change, as well as response differences between freshwater and saline lakes and the reasons for these differences.

Introduction Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of adverse pregnancy outcomes in mothers and infants. The aim was to evaluate the sensitivity and specificity of biochemical detection of ICP by ROC curve and to determine the threshold of more reliable experimental indicators. Materials and Methods 305 patients and 305 healthy pregnant women were enrolled in the study. Results The average levels of TBA, ALT, and AST in the ICP group were much higher than those in the control group (P Conclusions This study did not find any single specificity and sensitivity markers that could be used to reliably diagnose ICP. In the future, we will pay more attention to the correlation between sensitive biochemical indicators and adverse pregnancy outcomes.

The Tibetan Plateau (TP) lakes are sensitive to climate change due to its seasonal ice cover, but few studies have paid attention to the freeze-thaw process of TP lakes and its key control parameters. By combining 216 simulation experiments using the LAKE2.0 model with the observations, we evaluated the effects of ice and snow albedo, ice (Kdi) and water (Kdw) extinction coefficients on the lake ice phenology, water temperature, sensible and latent heat fluxes. The reference experiment performs well in simulating the lake temperature, with a small positive bias increasing with depth, but it underestimates the ice thickness. The increase of ice albedo, snow albedo andKdiinduce a significant decrease in water temperature. Compared with the latent heat, the sensible heat flux is more sensitive to these three parameters. The ice thickness increases almost linearly with the increase of ice albedo but decreases with the increase ofKdi. The ice thickness and frozen days vary little withKdw, but increasingKdwcan decrease the water temperature. Compared with the ice albedo, theKdiand snow albedo have a large effect on the number of frozen days. This study brings to light the necessity to improve the parameterizations of the TP lakes freeze-thaw process.

A series of model sensitivity simulations are carried out to calibrate and improve the Weather Research and Forecasting Model coupled with a one-dimensional lake model (WRF-Lake) based on observations over Lake Nam Co. Using the default lake model parameters, the solution of WRF-Lake exhibits significant biases in both the lake thermodynamics and regional climatology, i.e., higher lake surface temperature (LST), earlier onset of summer thermal stratification, and overestimated near-surface air temperature and precipitation induced by the lake’s excessive warming and moistening impacts. The performance of WRF-Lake is improved through adjusting the initial lake temperature profile, the temperature of maximum water density (Tdmax), the surface roughness length, and the light extinction coefficient. Results show that initializing the water temperature with spring observation mitigates the LST overestimation and reduces the timing error of the onset of thermal stratification. By further adjusting Tdmax from 4 °C to the observed value of 3.5 °C, the LST increase from June to mid-July is enhanced and the buildup of thermal stratification is more accurately predicted. Through incorporating the parameterized surface roughness length and decreasing the light extinction coefficient, the model better reproduces the observed daily evolution of LST and vertical lake temperature profile. The calibrated WRF-Lake effectively mitigates the overestimation of over-lake air temperature at 2 m height and precipitation over regions downwind the lake. This suggests that an improved lake scheme within the coupled WRF-Lake is essential for realistically simulating the lake–air interactions and the regional climate over the lake-rich Tibetan Plateau.

Yupeng Liu,1 Suhuan Dai,1 Lijuan Wen,1,2 Yun Zhu,3 Yanan Tan,3 Guoxi Qiu,1 Tingting Meng,1 Fangying Yu,1 Hong Yuan,1 Fuqiang Hu1 1College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, People’s Republic of China; 2National Engineering Research Center for Modernization of Traditional Chinese Medicine - Hakka Medical Resources Branch, School of Pharmacy, Gannan Medical University, Ganzhou 342700, People’s Republic of China; 3Ocean College, Zhejiang University, Zhoushan 316021, Republic of ChinaCorrespondence: Fuqiang HuCollege of Pharmaceutical Science, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, People’s Republic of ChinaTel/Fax +86-571-88208439Email hufq@zju.edu.cnBackground: Phototherapy is a potential new candidate for glioblastoma (GBM) treatment. However inadequate phototherapy due to stability of the photosensitizer and low target specificity induces the proliferation of neovascular endothelial cells for angiogenesis and causes poor prognosis.Methods: In this study, we constructed c(RGDfk)-modified glycolipid-like micelles (cRGD-CSOSA) encapsulating indocyanine green (ICG) for dual-targeting neovascular endothelial cells and tumor cells, and cRGD-CSOSA/ICG mediated dualeffect of PDT/PTT with NIR irradiation.Results: In vitro, cRGD-CSOSA/ICG inhibited cell proliferation and blocked angiogenesis with NIR irradiation. In vivo, cRGD-CSOSA/ICG exhibited increased accumulation in neovascular endothelial cells and tumor cells. Compared with that of CSOSA, the accumulation of cRGD-CSOSA in tumor tissue was further improved after dual-targeted phototherapy pretreatment. With NIR irradiation, the tumor-inhibition rate of cRGD-CSOSA/ICG was 80.00%, significantly higher than that of ICG (9.08%) and CSOSA/ICG (42.42%). Histological evaluation showed that the tumor vessels were reduced and that the apoptosis of tumor cells increased in the cRGD-CSOSA/ICG group with NIR irradiation.Conclusion: The cRGD-CSOSA/ICG nanoparticle-mediated dual-targeting phototherapy could enhance drug delivery to neovascular endothelial cells and tumor cells for anti-angiogenesis and improve the phototherapy effect of glioblastoma, providing a new strategy for glioblastoma treatment.Keywords: angiogenesis, dual-targeting, glycolipid-like micelles, phototherapy, glioblastoma

Since December 2019, there has been an outbreak of a novel coronavirus (COVID-19) infection in Wuhan, China. Meanwhile, the outbreak also drew attention and concern from the World Health Organization (WHO). COVID-19 is another human infectious disease caused by coronavirus. The transmission of COVID-19 is potent and the infection rate is fast. Since there is no specific drug for COVID-19, the treatment is mainly symptomatic supportive therapy. In addition, it should be pointed out that patients with severe illness need more aggressive treatment and meticulous care. Recently, accurate RNA detection has been decisive for the diagnosis of COVID-19. The development of highly sensitive RT-PCR has facilitated epidemiological studies that provide insight into the prevalence, seasonality, clinical manifestations and course of COVID-19 infection. In this review, we summarize the epidemiology and characteristics of COVID-19.

Background CYB5D2 is a member of the membrane-associated progesterone receptors (MAPRs) family and plays essential roles in regulating nerve development. CYB5D2 is associated with tumor suppression in breast cancer. Despite the potential implication of CYB5D2 in cancer progression, its level and clinical significance in cervical cancer tissues has not been investigated yet. Via this study, we aimed to investigate the possible role played by CYB5D2 in epithelial–mesenchymal transition (EMT) in cervical cancer and correlate its level with clinical outcomes. Methods The expressions of CYB5D2 and the EMT marker E-cadherin in different groups of cervical samples were compared using immunofluorescence. Furthermore, co-localization of CYB5D2 and E-cadherin was analyzed in different cervical tissue samples via confocal laser scanning microscopy. The relationship between CYB5D2/E-cadherin and the progression and clinicopathological features of cervical cancer were analyzed, and the prognostic value of CYB5D2 mRNA expression was evaluated in various tumors using the Kaplan-Meier plotter database. Results CYB5D2 and E-cadherin were downregulated in cervical cancer (P0.05). Higher expression levels of CYB5D2 mRNA were predicted to be associated with a better relapse-free survival (RFS) in patients with cervical cancer. E-cadherin expression was associated with invasive tumors, tumor grade, and FIGO stage (P0.05). There was a positive correlation between CYB5D2 and E-cadherin expression in cervical cancer (P

Ngoring Lake is the largest freshwater lake in the Qinghai-Tibet Plateau (TP). The lake water temperature was observed to be generally rising during the ice-covered period from November 2015 to April 2016. This phenomenon appeared in the whole water column, with slowing in deep water and accelerating in shallow water before ice melting. The process is different from low-altitude boreal lakes. There are few studies on its mechanism and effects on lake-atmosphere interaction. Based on the observation data of Ngoring Lake Station, ERA5-Land data, MODIS surface temperature data, and precipitation data of Maduo Station of China Meteorological Administration, the characteristics of water temperature rise in the ice-covered Ngoring Lake are analyzed. LAKE2.3 model, which is currently little used for TP lakes, is applied to explore the influence of local climate characteristics and the main physical parameters on the radiation transfer in water body. The study questions are the continuous rise of water temperature in the ice-covered period, and the effects of different water temperature profiles prior to ice breakup on the lake heat storage per unit area and sensible and latent heat release. The results show that LAKE2.3 represents well the temperature evolution and thermal stratification in Ngoring Lake, especially in the ice-covered period. The strong downward short-wave radiation plays a dominant role, low precipitation gives positive feedback, and smaller downward long-wave radiation, lower temperature and larger wind speed give negative feedback. Increase of ice albedo and ice extinction coefficient reduces the heating rate of water temperature before reaching the maximum density temperature, and increases the maximum temperature that can be reached during ice-covered period, while increasing the water extinction coefficient has little influence on water temperature. The lake temperature in Ngoring Lake rising during the ice-covered period, and the temperature at the upper layer of lake body was higher than that at the maximum density temperature before ice breaking. Compared with the characteristics of three typical ice-covered periods which the lake temperature remained fixed in each layer, and the lake temperature was less than or equal to the maximum density temperature, the difference of heat release after ice breaking lasted for 59–97 days. The higher the lake temperature before breakup, the more heat is stored in the lake, and the more sensible heat and latent heat is released when the ice melts completely and the faster is the heat release.

Paclitaxel (PTX) is a broad-spectrum chemotherapy drug employed in the treatment of a variety of tumors. However, the clinical applications of PTX are limited by its poor water solubility. Adjuvants are widely used to overcome this issue. However, these adjuvants often have side effects and poor biodistribution. The smart drug delivery system is a promising strategy for the improvement of solubility, permeability, and stability of drugs, and can promote sustained controlled release, increasing therapeutic efficacy and reducing side effects. Polymeric prodrugs show great advantages for drug delivery due to their high drug loading and stability. There has been some groundbreaking work in the development of PTX-based stimulus-sensitive polymeric prodrug micelles, which is summarized in this study. We consider these in terms of the four main types of stimulus (pH, reduction, enzyme, and reactive oxygen species (ROS)). The design, synthesis, and biomedical applications of stimulus-responsive polymeric prodrugs of PTX are reviewed, and the current research results and future directions of the field are summarized.

Paeoniflorin (PF) is a monoterpene glucoside with various biological properties, and it suppresses allergic and inflammatory responses in a rat model of urticaria-like lesions (UL). In the present study, we treated OVA-induced mice presenting UL with PF at four circadian time points (ZT22, ZT04, ZT10, and ZT16) to determine the optimal administration time of PF. The pharmacological effects of PF were assessed by analyzing the scratching behavior; histopathological features; allergic responses such as immunoglobulin E (IgE), leukotriene B4 (LTB4), and histamine (HIS) release; inflammatory cell infiltration [mast cell tryptase (MCT) and eosinophil protein X (EPX)]; and mRNA levels of inflammatory cytokines such as interleukin (IL)-12, IL-6, interferon-γ (IFN-γ), and IL-4. It was demonstrated that PF significantly alleviated scratching behavior and histopathological features, and ZT10 dosing was the most effective time point in remission of the condition among the four circadian time points. Moreover, PF decreased the serum levels of IgE, LTB4, and HIS, and PF administration at ZT10 produced relatively superior effectiveness. PF treatment, especially dosing at ZT10, significantly reduced the number of mast cells and granules and diminished the infiltration of MCT and EPX in the skin tissues of mice with UL. Furthermore, the oral administration of PF effectively decreased the inflammatory cytokine levels of IL-12 mRNA. In conclusion, different administration times of PF affected its efficacy in mice with UL. ZT10 administration demonstrated relatively superior effectiveness, and it might be the optimal administration time for the treatment of urticaria.

Dysfunction of the blood-brain barrier (BBB) is a prominent pathological feature of glioblastoma (GBM). Vascular endothelial growth factor (VEGF) is confirmed to be abnormally elevated in the pathogenesis of GBM, causing BBB pathological disruption, which further allows the leakage of neurotoxic blood-derived molecules into the central nervous system (CNS), interfering brain homeostasis and leading to poor patient outcome. Since BBB is an integral and pivotal part of the brain microenvironment, which strongly supports the occurrence and the pathological progression of GBM, here we have selected the VEGFR antagonist axitinib as a BBB functional regulator and hypothesized to regulate pathological BBB restoration for GBM effective treatment.The pathological BBB cell model was constructed to investigate the timeliness and dose effect of axitinib regulating pathological BBB restoration. In order to investigate the efficacy and safety of axitinib regulating pathological BBB restoration for anti-GBM treatment, the orthotropic GBM-bearing mice model was established for in vivo study, and bioluminescent imaging was used to real-time and noninvasively monitor tumor growth response in vivo, and survival time was also recorded.Axitinib under non-cytotoxic dosage regulated pathological BBB restoration in a time-dependent mode, and multiple intervention of axitinib could realize a visible restoration of pathological BBB in vitro. Moreover, axitinib treatment restored pathological BBB in orthotropic GBM-bearing mice. We further confirmed that functional restoration of pathological BBB with axitinib had certain curative effect in prolonging median survival of orthotropic GBM-bearing mice at non-cytotoxic dosages in vivo.The mechanism of axitinib involved in BBB functional regulation in the treatment of GBM is first illuminated in this report; moreover, this is the first report first referring to regulating pathological BBB functional recovery for GBM effective therapeutics. Overall, the view of regulating pathological BBB functional recovery may offer a novel sight for other CNS diseases relating to BBB permeability effective therapeutics.

Objective: To investigate factors associated with fetal fraction and to develop a new predictive method for low fetal fraction before noninvasive prenatal testing. Methods: The study was a retrospective cohort analysis based on the results of noninvasive prenatal testing, complete blood count, thyroxin test, and Down's syndrome screening during the first or second trimester in 14,043 pregnant women. Random forests algorithm was applied to predict the low fetal fraction status (fetal fraction < 4%) through individual information and laboratory records. The performance of the model was evaluated and compared to predictions using maternal weight. Results: Of 14,043 cases, maternal weight, red blood cell, hemoglobin, and free T3 were significantly negatively correlated with fetal fraction while gestation age, free T4, pregnancy-associated plasma protein-A, alpha-fetoprotein, unconjugated estriol, and β-human chorionic gonadotropin were significantly positively correlated with fetal fraction. Compared to predictions using maternal weight as an isolated parameter, the model had a higher area under the curve of receiver operating characteristic and overall accuracy. Conclusions: The comprehensive predictive method based on combined multiple factors was more effective than a single-factor model in low fetal fraction status prediction. This method can provide more pretest quality control for noninvasive prenatal testing.

Stemness and metastasis are the two main challenges in cancer therapy and are related to disease relapse post-treatment. They both have a strong correlation with chemoresistance and poor prognosis, ultimately leading to treatment failure. It has been reported that chemotherapy can induce stemness and metastasis in many cancer types, especially treatment with the chemotherapeutic agent doxorubicin (DOX) in breast cancer. A combination treatment is an efficient and elegant approach in cancer therapy through simultaneous delivery of two or more drugs with a delivery system for its synergistic effect, which is not an additive of two individual drugs. Herein, we report a combinatorial system with DOX and all-trans retinoic acid (ATRA) to address both of the above issues. As a common critical regulatory factor for oncogenic signal transduction pathways, Pin1 is a specific isomerase highly expressed within various tumor cells. ATRA, a newly identified Pin1 inhibitor, can abolish several oncogenic pathways by effectively inhibiting and degrading overexpressed Pin1. We successfully developed a folic acid (FA)-modified chitosan (CSO)-derived polymer (FA-CSOSA) and obtained FA-CSOSA/DOX and FA-CSOSA/ATRA drug-loaded micelles. FA modification can improve the uptake of the nanoparticles in tumor cells and tumor sites via folate receptor-mediated cell internalization. Compared to treatment with DOX alone, the combined treatment induced 4T1 cell apoptosis in a synergistic manner. Reduced stemness-related protein expression and inhibited metastasis were observed during treatment with FA-CSOSA/DOX and FA-CSOSA/ATRA and were found to be associated with Pin1. Further in vivo experiments showed that treatment with FA-CSOSA/DOX and FA-CSOSA/ATRA resulted in 85.5% tumor inhibition, which was 2.5-fold greater than that of cells treated with DOX·HCl alone. This work presents a new paradigm for addressing chemotherapy-induced side effects via degradation of Pin1 induced by tumor-targeted delivery of DOX and ATRA.

Background This study aimed to investigate the correlation between miRNA-216b expression in patients with non-small cell lung cancer (NSCLC) and 18F-fluorodeoxyglucose (FDG) uptake by PET/CT and to explore the clinical application value of 18F-FDG PET/CT in miRNA-216b based on therapy for NSCLC. Methods Eighty patients with NSCLC and 40 healthy subjects were enrolled in our study. The SUVmax of the lesion area by PET/CT imaging was calculated. SUVmax represented the highest concentration of 18F-FDG in the lesion. The expression of miRNA-216b in the plasma and fiber bronchoscopic puncture of NSCLC patients was detected by RT qPCR. Then Pearson correlation analysis was used to analyze the correlation between miRNA-216b expression and 18F-FDG uptake in patients with different types of NSCLC. Results Compared with healthy subjects, SUVmax of early adenocarcinoma and advanced adenocarcinoma were increased. Compared with healthy subjects, SUVmax of early squamous and advanced squamous were increased. And the SUVmax content of advanced adenocarcinoma and squamous cell carcinoma was higher than that of early adenocarcinoma and squamous cell carcinoma. Compared with healthy subjects, the expression of miRNA-216b in the plasma of patients with early and advanced adenocarcinoma was reduced, and the expression of miRNA-216b in the plasma of patients with early and advanced squamous cell carcinoma was reduced. Compared with adjacent tissues, the expression of miRNA-216b in early adenocarcinoma tissues and advanced adenocarcinoma tissues was reduced, and the expression in early squamous cell carcinoma and advanced squamous cell carcinoma was reduced. Pearson correlation analysis showed a negative correlation between SUVmax and miRNA-216b (plasma and tissue) in patients with four types of NSCLC. Conclusion miRNA-216b expression was negatively correlated with 18F-FDG uptake in NSCLC. miRNA-216b could be used for the classification and staging of non-small cell lung cancer. 18F-FDG PET/CT may be used to evaluate the therapeutic response in application of miRNA-216b-based cancer treatment.

The Qinghai-Tibet Plateau possesses the largest alpine lake system, which plays a crucial role in the land-atmosphere interaction. We report first observations on the thermal and radiation regime u...

Background Ovarian cancer is a common malignancy in the female reproductive system with a high mortality rate. The most important reason is multidrug resistance (MDR) of cancer chemotherapy. To reduce side effects, reverse resistance and improve efficacy for the treatment of ovarian cancer, a "core-shell" polymeric nanoparticle-mediated curcumin and paclitaxel co-delivery platform was designed. Methods Nuclear magnetic resonance confirmed the successful grafting of polyethylenimine (PEI) and stearic acid (SA) (PEI-SA), which is designed as a mother core for transport carrier. Then, PEI-SA was modified with hyaluronic acid (HA) and physicochemical properties were examined. To understand the regulatory mechanism of resistance and measure the anti-tumor efficacy of the treatments, cytotoxicity assay, cellular uptake, P-glycoprotein (P-gp) expression and migration experiment of ovarian cancer cells were performed. In addition, adverse reactions of nanoformulation to the reproductive system were examined. Results HA-modified drug-loaded PEI-SA had a narrow size of about 189 nm in diameters, and the particle size was suitable for endocytosis. The nanocarrier could target specifically to CD44 receptor on the ovarian cancer cell membrane. Co-delivery of curcumin and paclitaxel by the nanocarriers exerts synergistic anti-ovarian cancer effects on chemosensitive human ovarian cancer cells (SKOV3) and multi-drug resistant variant (SKOV3-TR30) in vitro, and it also shows a good anti-tumor effect in ovarian tumor-bearing nude mice. The mechanism of reversing drug resistance may be that the nanoparticles inhibit the efflux of P-gp, inhibit the migration of tumor cells, and curcumin synergistically reverses the resistance of PTX to increase antitumor activity. It is worth noting that the treatment did not cause significant toxicity to the uterus and ovaries with the observation of macroscopic and microscopic. Conclusion This special structure of targeting nanoparticles co-delivery with the curcumin and paclitaxel can increase the anti-tumor efficacy without increasing the adverse reactions as a promising strategy for therapy ovarian cancer.

Previous studies have implicated the attractive and promising role of miR‐590‐3p to restore the cardiac function following myocardial infarction (MI). However, the molecular mechanisms for how miR‐590‐3p involves in cardiac fibrosis remain largely unexplored. Using human cardiac fibroblasts (HCFs) as the cellular model, luciferase report assay, mutation, EdU assay and transwell migration assay were applied to investigate the biological effects of miR‐590‐3p on the proliferation, differentiation, migration and collagen synthesis of cardiac fibroblasts. We found that miR‐590‐3p significantly suppressed cell proliferation and migration of HCFs. The mRNA and protein expression levels of α‐SMA, Col1A1 and Col3A were significantly decreased by miR‐590‐3p. Moreover, miR‐590‐3p directly targeted at the 3’UTR of ZEB1 to repress the translation of ZEB1. Interfering with the expression of ZEB1 significantly decreased the cell proliferation, migration activity, mRNA and protein expressions of α‐SMA, Col1A1 and Col3A. Furthermore, the expressions of miR‐590‐3p and ZEB1 were identified in infarct area of MI model in pigs. Collectively, miR‐590‐3p suppresses the cell proliferation, differentiation, migration and collagen synthesis of cardiac fibroblasts by targeting ZEB1. These works will provide useful biological information for future studies on potential roles of miR‐590‐3p as the therapeutic target to recover cardiac function following MI.

The ability of FLake, WRF‐Lake, and CoLM‐Lake models in simulating the thermal features of Lake Nam Co in Central Tibetan Plateau has been evaluated in this study. All the three models with default settings exhibited distinct errors in the simulated vertical temperature profile. Then model calibration was conducted by adjusting three (four) key parameters within FLake and CoLM‐Lake (WRF‐Lake) in a series of sensitive experiments. Results showed that each model's performance is sensitive to the key parameters and becomes much better when adjusting all the key parameters relative to tuning single parameter. Overall, setting the temperature of maximum water density to 1.1 °C instead of 4 °C in the three models consistently leads to improved vertical thermal structure simulation during cold seasons; reducing the light extinction coefficient in FLake results in much deeper mixed layer and warmer thermocline during warm seasons in better agreement with the observation. The vertical thermal structure can be clearly improved by decreasing the light extinction coefficient and increasing the turbulent mixing in WRF‐Lake and CoLM‐Lake during warm seasons. Meanwhile, the modeled water temperature profile in warm seasons can be significantly improved by further replacing the constant surface roughness lengths by a parameterized scheme in WRF‐Lake. Further intercomparison indicates that among the three calibrated models, FLake (WRF‐Lake) performs the best to simulate the temporal evolution and intensity of temperature in the layers shallower (deeper) than 10 m, while WRF‐Lake is the best at simulating the amplitude and pattern of the temperature variability at all depths., Key Points The performance of three one‐dimensional lake models in simulating the thermal structure of Nam Co Lake is evaluated and improvedKey processes related to the simulated thermal regime of alpine lakes on the Tibetan Plateau are indicated and revealed

The selective delivery of DOX into tumor mitochondria in vitro and in vivo, which can be achieved with the aid of a skeletal polymer with positively charged and lipophilic character, may significantly promote its antitumor efficiency as well as eliminate its severe cardiotoxicity. In this study, we developed a polycationic glycolipid polymer (CSOSA) as a skeletal nanomaterial, which was further modified with lipophilic (4-carboxybutyl) triphenylphosphonium bromide (CTPP) cations to form the mitochondria-targeted polymer C-P-CSOSA. In vitro, C-P-CSOSA polymer micelles were internalized more by tumor cells than normal cells and exhibited rapid lysosomal escape capability due to their strong proton buffering ability. When loaded with DOX, the C-P-CSOSA/DOX micelles could selectively target mitochondria in tumor cells and remarkably activate the mitochondrial apoptosis signaling pathway. Importantly, the C-P-CSOSA polymer exhibited significant mitochondrial co-localization in vivo. Moreover, C-P-CSOSA/DOX demonstrated the highest tumor-inhibition rate (75.0%), when compared with CSOSA/DOX (44.8%) and DOX·HCl (55.0%). Meaningfully, C-P-CSOSA/DOX did not cause obvious organ damage and exhibited the longest survival time, indicating the low toxicity of this polymer. This study opens up new avenues for the future clinical translation of mitochondrial-targeted drug delivery systems.

Introduction: Cattail Pollen is a commonly used Chinese medicine for promoting blood circulation and removing blood stasis in infertility patients with endometriosis, but its ingredients and mechanism of action are still unclear. The aims of this study were to explore the potential active ingredients, targets and mechanisms of Cattail Pollen in treating infertility patients with endometriosis based on bioinformatics and molecular docking. Methods: The GSE120103 dataset was downloaded from the Gene Expression Omnibus (GEO) database to screen out differentially expressed genes. Cytoscape software was constructed to construct the protein–protein interaction network and screen for hub proteins, and molecular docking was performed to identify the binding activity of Cattail Pollen active ingredients and infertility genes. Then, DAVID software was used to perform gene ontology (GO) functional analysis and KEGG pathway enrichment analysis on differentially expressed genes. Results: There were 1320 differentially expressed genes in patients with endometriosis. ADCY5, RLN3, and ADCY6 proteins encoded by genes that were upregulated in infertile patients with endometriosis. Eight active ingredients of Cattail Pollen were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform: naringenin ((2R)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one), arachidonic acid, isorhamnetin, β-sitosterol, kaempferol, Testosterone palmitate, kaempferol-3-O-α-L-rhamnosyl(1→2)-β-D-glucoside and quercetin. Molecular docking identified that the binding activity of arachidonic acid with ADCY5, RLN3, and ADCY6; and testosterone palmitate with ADCY5 and ADCY6 was strong. GO analysis suggested that differentially expressed genes were involved in multiple biological processes, cellular components, and molecular functions. KEGG enrichment analysis found that differentially expressed genes were enriched in neuroactive ligand–receptor interaction, cytokine–cytokine receptor interaction, chemokine signaling pathway, and Jak-STAT signaling pathway. Conclusions: This study discovered the differentially expressed genes of naturally conceived and infertile patients with endometriosis, and clarified the effective ingredients, targets, and potential signaling pathways of Cattail Pollen in the treatment of infertility patients with endometriosis.

Background Some Western medicine schools in China established standardized patient (SP) programs for medical education. However, SP programs are rarely applied to the education of traditional Chinese medicine (TCM). In this study, we evaluated the effectiveness of using standardized patient traditional Chinese medicine (SP-TCM) to improve clinical competency among TCM medical students. Methods This study was a prospective, 2-group, parallel-training randomized trial over the course of 5 years. Data were collected from September 2016 to December 2020. Participants in each year were randomly allocated into the traditional-method training group or the SP-TCM training group (1:1) for a 3-month curriculum. Measurement of clinical competency among all trainees was based on a standardized examination composed of scores of medical record documentation, scores of TCM syndrome differentiation and therapeutic regimen, and checklist assessment from both SP-TCMs and TCM professionals. Feedback was collected using semi-constructive questionnaires from both groups. Results Compared with those assigned to traditional-method training, those assigned to SP-TCM training demonstrated significantly greater post-training improvement in medical record documentation and TCM syndrome differentiation and therapeutic regimen. Moreover, SP-TCM trainees outscored those assigned to traditional training in the assessment for encounter performance given by independent SP-TCMs and TCM professionals. The SP-TCM method gained higher satisfaction of training efficacy and test performance than the traditional method. Conclusion This SP-TCM program demonstrated great benefits for improving clinical competency among TCM medical students.

The emergence of energy spectrum CT provides greater diagnostic value for clinical practice. Its advantage is that it can provide more functional imaging parameters and accurate image information for clinical practice, which represents a mainstream direction of CT technology development at present. This paper mainly studies the clinical trial of CAMPO Precision128 Max ENERGY spectrum CT combined with multiple parameters to evaluate the benign and malignant pleural effusion. This paper analyzes the principle and key performance parameters of energy spectrum CT imaging, the etiology of pleural effusion, and its conventional diagnostic methods and uses energy spectrum CT to detect the benign and malignant pleural effusion. In this paper, two groups of patients with different types of pleural effusions were scanned by line spectrum chest CT scans, and energy spectrum analysis software was used to measure and calculate the CT values of conventional mixed energy values of ROI of patients with pleural effusions. For the CT value and energy curve slope measurement value of different single energy keV, independent sample t-test was used to analyze and compare the two sets of data, and finally it has been found out that the two sets of data were similar. According to the experimental results, the curves of energy spectrum of the two groups of data are similar in the descending curve of bow-back. The slope of energy spectrum curve in the leakage group was lower than that in the exudate group, showing statistical significance ( P < 0.05 ). The slope of energy spectrum curve K in the malignant pleural effusion group was significantly higher than that in the benign pleural effusion group, and the difference was statistically significant ( P < 0.05 ). The trend of energy spectrum curves of the two is roughly the same, while at the high energy level, part of the energy spectrum curves of the two are overlapped. The above conclusion indicates that energy spectrum CT plays a certain role in the differential diagnosis of pleural effusion. At the same time, energy spectrum CT also provides a noninvasive and rapid examination method for clinical differentiation of pleural effusion, which has certain clinical application value and prospect.

Qinghai Lake is the largest lake in China. However, its influence on the local climate remains poorly understood. By using an atmosphere-lake coupled model, we investigated the impact of the lake on the local climate. After the adjustment of four key parameters, the model reasonably reproduced the lake-air interaction. Superimposed by the orographic effects on lake-land breeze circulation, the presence of the lake enhanced precipitation over the southern part of the lake and its adjacent land, while slightly reduced precipitation along the northern shore of the lake. The lake effect on local precipitation revealed a distinct seasonal and diurnal variability, reducing precipitation in May (-6.6%) and June (-4.5%) and increasing it from July (5.7%) to November (125.6%). During the open water season, the lake's daytime cooling effect weakened and the nighttime warming effect strengthened, affecting spatial distribution and intensity of lake-induced precipitation. In early summer, precipitation slightly decreased over the north part of the lake due to the lake's daytime cooling. In turn, lake-induced nighttime warming increased precipitation over the southern section of the lake and its adjacent land. With the start of the autumn cooling in September, heat and moisture fluxes from the lake resulted in precipitation increase in both daytime and nighttime over the entire lake. In October, the background atmospheric circulation coupled with the strong lake effects lead to a small amount but high proportion of lake-induced precipitation spreading evenly over the lake.

The traditional material procurement model adopts the principle of obtaining local optimal for pricing. The model results differ greatly from the realistic factors, which weakens the willingness of suppliers to cooperate. Aiming at the above problems, a multi-index pricing model of emergency material procurement based on constraint theory was constructed. According to the constraint theory, this paper analyzes the procurement process of emergency supplies and determines the bottleneck factors of procurement pricing. On the basis of the coordination of the material purchasing strategy mechanism, the framework of the pricing model is completed from the perspective of maximizing the benefits of both the supplier and the purchaser. Through the simulation experiment, it is verified that the model can maximize the interests of both parties and effectively ensure the procurement efficiency of emergency supplies.

Background The study was a retrospective cohort analysis based on the results of noninvasive prenatal screening (NIPS), complete blood count, thyroxin test and Down’s syndrome screening in first or second trimester from 14043 pregnant women. Random forests algorithm was applied to predict the low fetal fraction of cell free DNA (with FF lower than 10th percentile) through individual and laboratory information. Performance of the model was evaluated and compared to prediction using maternal weight.To investigate factors associated with lower FF in the NIPS and to develop a new predictive method for low FF before NIPS. Results Of 14043 cases, maternal weight, RBC, HGB and free T3 were significantly negative correlated with FF while gestation age, free T4, PAPP-A, AFP, uE3 and β-hCG were significantly positive correlated with FF. Compared to prediction using maternal weight as isolated parameter, the model has a higher area under curve(AUC) of Receiver Operating Characteristic (ROC) and overall accuracy. Conclusions The comprehensive predictive method based on combined multiple factors was more effective than single-factor model in low FF status prediction. This method can provide more information for clinical choice and pre-test quality control of NIPS.

Background Noninvasive prenatal testing (NIPT) is commonly used to screen for fetal genetic abnormalities. However, the ability of NIPT to detect copy number variations (CNVs) has not been reported. Accordingly, in this study, we analyzed the efficiency of NIPT for the detection of fetal autosomal CNVs. Methods Patients who were positive for autosomal CNVs by NIPT and underwent diagnostic studies by karyotype analysis and chromosomal microarray (CMA) were evaluated. Samples were divided into groups according to age, in vitro fertilization, fetal‐free DNA concentration, uniquely mapped reads number, CNV size, and CNV type. Results Chromosomal microarray showed that the positive predictive value (PPV) of autosomal CNVs detected by NIPT was 14.89%. Increasing fetal DNA concentrations and uniquely mapped read numbers did not affect the PPV of CNVs detected by NIPT. There were no differences between microduplication and microdeletion PPVs detected by NIPT. The PPV of CNVs less than 10 Mb was significantly higher than that of CNVs greater than 10 Mb detected by NIPT. Conclusion The accuracy of NIPT for autosomal CNVs needs to be improved., The positive predictive value of copy number variations (CNVs) less than 10 Mb was significantly higher than that of CNVs greater than 10 Mb detected by Noninvasive prenatal testing (NIPT). NIPT was effective for detecting CNVs less than 10 Mb.

Objective To estimate the positive predictive value (PPV) of fetal sex chromosome aneuploidy (SCA) screened in non-selective population and explore the rate of pregnancy termination and ultrasound findings for fetal SCA and the factors influencing parents’ decisions in South China. Methods This is a large-scale retrospective cohort of positive SCA screened from unselected singleton pregnancies by non-invasive prenatal testing (NIPT) from a single prenatal center of a tertiary hospital, from January 2016 to November 2019. Clinical information, indications, diagnostic results, ultrasound findings, pregnancy determinations, and follow-up were reviewed and analyzed. Results 248 cases of SCA positive were screened out of 52453, giving a positive detection rate of 0.47%. The majority of indications (42.7%) were low-risk pregnancies. After genetic counseling, 43 pregnancies (17.3%) declined to prenatal diagnosis, the rest of 205 cases (82.7%) conducted with amniocentesis to detect fetal chromosome, of which 95 were confirmed as true positive of SCA with PPV of 46.3% (95/205). The SCA consisted of 68 sex chromosomal trisomies (26 cases of 47,XXY, 20 cases of 47,XXX and 22 cases of 47,XYY), 17 cases of monosomy X (45,X), three cases of 48,XXYY, three cases of mosaicisms (45,X/46,XX), four cases with sex chromosomal deletions, included two cases of 46,X,del(Y)(q11.21), one case of 46,X,del(X)(p11) and one case of 46,X,i(X)(q10). Of the 95 cases confirmed as true positive SCA, 50 cases (52.6%)chose to terminate the pregnancy (82.6%, 64.3%, 17.6% and 33.3% for 45,X, 47,XXY, 47,XXX and 47,XYY, respectively), 45 cases (47.4%) elected to continue the pregnancy. Ninety-three pregnant were also continued pregnancy after the exclusion of SCA. Conclusions NIPT, as a first-tier routine method for screening autosomal aneuploidies, also could play an important role in screening SCA. Low-risk pregnant women are the main indication for the detection of SCA as NIPT test provides to non-selective population. The trend of overall termination rates of SCA-affected pregnancies is decreased. For 47,XXX and 47,XYY with mild phenotype, couples would like to continue the pregnancy. But for 45,X and 47,XXY, parents apt to terminate pregnancy no matter ultrasound abnormalities were found or not. pregnancy determinations are affected by types of SCA, sonographic findings, maternal age, and presence of infertility.

The characteristics of intense diurnal precipitation occurring beneath the South Asian High (SAH) are diagnosed in the summer monsoon season from 2010 to 2015 using observational data. The diagnostics indicate that summer nighttime rainfall events in the northeastern Tibetan Plateau can intensify towards the end of the monsoon period. By defining a transition index to identify the transition day during which the episodes of diurnal convection start to decline, daily thermodynamic properties and precipitation from each year were composited before and after the transition date. The analysis reveals that warmer air, increased moisture, and stronger upward velocity are present in the atmosphere before the transition day, potentially elevating nighttime convective precipitation. Enhanced upward velocity that is present through the two months prior to transition date coincides with the timing of the peak SAH, while weakened upward velocity afterwards coincides with its subsequent retreat. The large-scale lift due to terrain-ambient air interaction underneath the SAH and the increased moisture content can enhance the potential for diurnal convection, which lends support to the nighttime peak of rainfall. This feature persists until the transition date, after which the SAH starts to retreat.

Vascular endothelial growth factor (VEGF) has been implicated as the key regulator of tumor neovascularization. RNAi interference plays a critical role on down-regulation of VEGF, while single VEGF inhibition could not completely suppress angiogenesis and tumor growth; the effect of siRNA is temporary. To improve glioma therapy efficacy, an angiopep-2 (Ap) modified redox-responsive glycolipid-like copolymer co-delivering siVEGF and paclitaxel (PTX), termed as Ap-CSssSA/P/R complexes, was developed in this study. Ap modification significantly enhanced the distribution of Ap-CSssSA in glioma cells both in vitro and in vivo. Ap-CSssSA/P/R complexes could simultaneously deliver siVEGF and PTX into tumor cells, exhibiting great superiority in glioma growth suppression via receptor-mediated targeting delivery and cell apoptosis, accompanied with an obvious inhibition of neovascularization induced by VEGF gene silencing. The present study indicated that the combination delivery of siVEGF and PTX via Ap-modified copolymeric micelles presented a promising and safe platform for glioma targeted therapeutics.

Eurasian freezing lakes cover an almost 180° wide longitude sector between the latitudes 30° and 75° N, and their altitudes range from below the sea surface level up to 5 km elevation. Ice phenology varies widely in this region. However, these variations and their influence factors have been little studied. Analytic models are applied here to examine these variations supported by historical ice and weather data. These models are forced by a linear air–lake heat exchange formula based on local empirical fits. The weather brings latitude–longitude–altitude patterns to the large-scale lake ice phenology. Freezing and breakup dates are forced by the local air temperature and solar radiation, and their rates of change are also important. In addition, freezing depends on lake depth and breakup depends on accumulated ice thickness. Lake depth provides a lag and radiation balance provides a shift with respect to the air temperature in cooling of the lake, and breakup is dictated by spring warming conditions and ice thickness. Due to solar radiation forcing, the common degree-day approach is biased for modelling ice phenology, especially in low latitudes. Analytic models provide a first-order tool for climate sensitivity of ice seasons. The freezing date and breakup date both change by around five days per one-degree shift in air temperature away from the climatological ice margin; however, at this margin, the sensitivity is higher.

The critical process and step in achieving effective antitumor therapies is facilitating endosomal escape, which can enhance the intracellular target delivery of therapeutics. However, the normally adopted approaches tend to result in colloidal instability as a result of the inevitable interactions between the resulting positively charged surfaces of micelles and proteins in vivo. Herein, negatively charged surface shielded polymeric micelles, consisting of polymethylacrylamide derivatives and hydrophilic chitosan ( Mw = 18.8 kDa) linked by 3,3'-dithiodipropionic, are constructed. Until the pH decreases to less than 4.5, the DOX-loaded polymeric micelles (CSO-SS-PDPA/DOX) retain a negative surface charge as a result of the abundant amide groups, which could resist formation of the protein "corona" as visualized by transmission electron microscopy. Robust endosomal escape within tens of minutes due to protonated amine groups and specific redox-responsive drug release is visualized by confocal microscopy. The superior therapeutic efficacy in both 3D tumor spheroids and MCF-7 bearing mice further suggested that the prepared CSO-SS-PDPA/DOX is a promising approach for maintaining colloidal stability while achieving intracellular endosomal/lysosomal escape, which opens new opportunities for drug delivery.

Recent studies have revealed that artesunate (ART) has clear anti-tumor activity, suggesting that it could be a good candidate chemotherapeutic agent. In this study, we researched the inhibitory effect of ART on MCF7 cells and explored the possible mechanisms. MTT assay was used to detect the effect of ART on the proliferation of MCF7 cells. Crystal violet staining was used to observe morphological and quantitative changes. Flow cytometry was used to detect the cell cycle of the drug-acting MCF7 cells. In addition, western blotting was used to detect the drug influence on expression of the ATM, phospho-ATM(S1981), H2AX, γH2AX(S139), CHK2 and phospho-CHK2(T68), cdc25C, and phospho-cdc25C(S216). In the experimental groups, the proliferation of MCF7 cells was inhibited in a dose-dependent manner and the original cell morphology was lost. The number of G2/M phase cells in the experimental groups increased significantly, and the expression of DNA damage response-associated proteins was significantly increased, such as phospho-ATM(S1981), γH2AX(S139), phospho-CHK2(T68), and phospho-cdc25C(S216). ART can inhibit cell proliferation and promote G2/M arrest in MCF7 cells through ATM activation and the ensuing “ATM-Chk2-Cdc25C” pathway, thus implicating ART as a novel candidate for breast cancer chemotherapy.

The Tibetan Plateau (TP) lakes are sensitive to climate change due to ice-albedo feedback, but almost no study has paid attention to the ice albedo of TP lakes and its potential impacts. Here we present a recent field experiment for observing the lake ice albedo in the TP, and evaluate the applicability of the Moderate Resolution Imaging Spectroradiometer (MODIS) products as well as ice-albedo parameterizations. Most of the observed lake ice albedos on TP are

Cancer associated fibroblasts (CAFs) are the most abundant, genetically stable stroma cells and localize near blood vessels within "finger-like" collagen-rich stroma, which lead to restrained drug transport in dense stroma instead of tumor cells inside tumor mass, especially for targeting micelles. Meanwhile, the bioactive cytokines secreted by stroma cells result in microenvironment mediated drug resistance (TMDR). Hence, a biologically inspired Telmisartan (Tel) grafting glycolipid micelles (Tel-CSOSA) are constructed, which can sequentially target angiotensin II type I receptor (AT1R) overexpressed on both CAFs and tumor cells. More Tel-CSOSA are demonstrated to specifically accumulate in tumor site compared to CSOSA. In addition, the retention of Tel-CSOSA is primarily prolonged around tumor vessel in virtue of CAFs targeting and the stroma barrier. In contrast, the elimination of "finger-like" ECM resulting from CAFs apoptosis by Tel-CSOSA/DOX contributes to a more uniform and deeper penetration post-administration, which can enforce subsequently tumor cells targeting. Meanwhile, cytokines are decreased along with CAFs apoptosis so that tumor cells are more vulnerable to chemotherapeutics. Collectively, this strategy of sequentially targeting CAFs and tumor cells could synergistically increase antitumor therapy with reversed TMDR.

Induction melting was used as a routine method to synthesize Mg23Ni10, Mg22LaNi10 and Mg21La2Ni10 alloys, and followed by a detailed microstructural characterization which included X-ray diffraction (XRD), scanning electron microscopy (SEM) with energy dispersive spectrometer (EDS), high resolution transmission electron microscope (HRTEM) and hydrogen absorption/desorption measurements. XRD analysis results showed that Mg2Ni and Mg phases were detected in the XRD pattern of the Mg23Ni10 alloy, however, the La addition results in conversion from Mg to LaMg3 and La2Mg17 phases and appearance of crystal defects included dislocations, twin grain boundary and vacancy in the Mg22LaNi10 and Mg21La2Ni10 alloy textures. The total maximum hydrogen absorption capacity was 4.45wt% for the Mg23Ni10 alloy, however, the Mg22LaNi10 and Mg21La2Ni10 alloys with vacancy, dislocations and twin grain boundary, absorbed 3.66wt% and 3.60wt%, respectively, indicating that the La addition led to decreasing of the maximum hydrogen absorption capacity. Besides, hydrogen absorption/desorption of 90% of saturated state expended for about 456 and 990 s for pristine Mg23Ni10 alloy, by contrast, the time decreased owing to improvement of hydrogen absorption and desorption kinetics in the alloy with La element, with which the uptake time for hydrogen content to 90% of saturated state was 150 and 78 s, and 90% hydrogen can be released in 930 and 804 s for Mg22LaNi10 and Mg21La2Ni10 alloys in the experimental condition.

Mitochondria, crucial regulators of inducing tumor cells apoptosis, can be treated as the prime target for tumor therapy. The selective and responsive release of proapoptotic therapeutics into mitochondria may notably improve antitumor efficiency. Herein, (4-Carboxybutyl) triphenylphosphonium bromide (CTPP), a lipophilic cation, was conjugated with glucolipid-like conjugates (CSOSA) to produce mitochondria-targeted conjugates (CTPP-CSOSA). Loading with weakly acidic drug Celastrol (Cela), CTPP-CSOSA/Cela micelles could selectively respond to mitochondrial alkaline pH (pH 8.0), controlled by the weaker interaction between hydrophobic core of micelles and Cela with higher solubility at pH 8.0. However, there was a slow drug release behavior at pH 7.4 and pH 5.0. It illustrated that CTPP-CSOSA/Cela could realize mitochondrial fast drug release, and decrease drug leakage in the cytoplasm and lysosome. CTPP-CSOSA/Cela highly enhanced ROS levels, which further induced mitochondria membrane potential decreasing and more Cytochrome C releasing into cytoplasm, then promoted tumor cells apoptosis notably. In vivo, CTPP-CSOSA had an enhanced accumulation in tumor tissue, compared with CSOSA. Moreover, the tumor-inhibition rate of CTPP-CSOSA/Cela was 80.17%, which was significantly higher than CSOSA/Cela (58.35%) and Cela (54.89%). Thus, CTPP-CSOSA/Cela micelles with mitochondrial targeting and alkaline pH-responsive release capability could provide a new strategy for tumor therapy.