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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.

Based on the hourly gauge-satellite merged precipitation product with the horizontal resolution of 0.1° latitude/longitude during 2008–2014, diurnal variations of the summer precipitation amount (PA), frequency (PF), and intensity (PI) with different duration time over the regions east to Tibetan Plateau have been systematically revealed in this study. Results indicate that the eight typical precipitation diurnal patterns identified by the cluster analysis display pronounced regional features among the plateaus, basins, plains, hilly and coastal areas. The precipitation diurnal cycles are significantly affected by the sub-grid terrain fluctuations. The PA, PF and PI of the total rainfall show much more pronounced double diurnal peaks with the sub-grid topography standard deviation (SD) decreased. Meanwhile, the diurnal peaks of PA and PF (PI) strengthen (weaken) with the sub-grid topography SD enhanced. Over the elevated mountain ranges, southeastern hilly and coastal regions, the PA and PF diurnal patterns of the total rainfall generally show predominant late-afternoon peaks, which are closely associated with the short-duration ( $$\leqslant \,$$ 3 h) rainfall. Along the Tibetan Plateau to its downstream, the diurnal peaks of PA, PF and PI for the total rainfall all exhibit obvious eastward phase time delay mainly due to the diurnal evolutions of long-duration (> 6 h) rainfall. However, the 4–6 h rainfall leads to the eastward phase time delay of the total rainfall along the Taihang Mountains to its downstream. Further mechanism analysis suggests that the midnight to morning diurnal evolution of the long-duration rainfall is closely associated with the diurnal variations of the upward branches of thermally driven mountain-plain solenoids and the water vapor transport associated with the accelerated nocturnal southwesterly winds. The late-afternoon peak of the short-duration PA over the southeastern hilly and coastal regions is ascribed to the strong local thermal convections due to the solar heating in afternoon, while the early-evening peak of the short-duration PA over the elevated mountain ranges is significantly contributed by the upward warm-moist wind from the surrounding low-lying basins or plains.

The special climate environment creates a distinctive air-lake interaction characteristic in the Tibetan Plateau (TP) lakes, where the variations of surface roughness lengths also differ somewhat from those of other regions. However, how different categories of roughness lengths affect the lake surface energy exchange and the planetary boundary layer height (PBLH) remains unclear in the TP lakes. In this study, we used a tuned Weather Research and Forecasting (WRF) model version 3.6.1 to investigate the responses of the freeze-up date, turbulent fluxes, meteorological variables, and PBLH to surface roughness length variations in Ngoring Lake. Of all meteorological variables, the lake surface temperature responded to roughness length variations most sensitively; increasing roughness lengths can put the lake freeze-up date forward. The effect of momentum roughness length on wind speed was significantly affected by the fetch length. The increase in the roughness length for heat can induce the increment of the nightly PBLH in most months, especially for the central lake area in autumn. The primary factors that contribute to sensible heat flux (H) and latent heat flux (LE) were the roughness lengths for heat and momentum during the ice-free period, respectively. Increasing roughness length for heat can increase the nightly PBLH, and decreasing roughness length for moisture can also promote growth of the PBLH, but there was no obvious correlation between the momentum roughness length and the PBLH.

High-altitude lakes are frequently exposed to extreme meteorological conditions, but the surface and atmospheric boundary layer (ABL) processes have received little attention under specific weather conditions. This study used the multi-source field data, re-analysis and remote sensing data to investigate the varying patterns and driving forces of the convective boundary layer (CBL) height over Ngoring Lake in the Tibetan Plateau (TP) before and after the cold air incursion. Daily cumulative surface heat flux and buoyancy flux over the land were markedly larger than those over the lake on a clear summer day, but an opposite pattern was observed accompanied by the cold air incursion. CBLs determined by the potential temperature thinned (depth

The existence of blood–brain barrier (BBB) greatly hindered the penetration and accumulation of chemotherapeutics into glioblastoma (GBM), accompany with poor therapeutic effects. The growth of GBM supervene the impairment of tight junctions (TJs); however, the pathogenesis of BBB breakdown in GBM is essentially poorly understood. This study found that vascular endothelial growth factor (VEGF) secreted by GBM cells plays an important role in increasing the permeability of BBB by disrupting endothelial tight junction proteins claudin-5 and thus gave doxorubicin (DOX)-loaded glycolipid-like nanoparticles (Ap-CSSA/DOX), an effective entrance to brain tumor region for GBM-targeting therapy. In addition, VEGF downregulates the expression of claudin-5 with a dose-dependent mode, and interfering with the VEGF/VEGFR pathway using its inhibitor axitinib could reduce the permeability of BBB and enhance the integrity of the barrier. Ap-CSSA/DOX nanoparticles showed high affinity to expressed low-density lipoprotein receptor-related proteins 1 (LRP1) in both BBB and GBM. And BBB pathological fenestration in GBM further exposed more LRP1 binding sites for Ap-CSSA/DOX nanoparticles targeting to brain tumor, resulting in a higher transmembrane transport ratio in vitro and a stronger brain tumor biodistribution in vivo, and finally realizing a considerable antitumor effect. Overall, taking advantage of BBB pathological features to design an appropriate nanodrug delivery system (NDDS) might provide new insights into other central nervous system (CNS) diseases treatment.

Glioblastoma (GBM) is one of the malignant tumors with high mortality, and the presence of the blood brain barrier (BBB) severely limits the penetration and tissue accumulation of therapeutic agents in the lesion of GBM. Active targeting nanotechnologies can achieve efficient drug delivery in the brain, while still have a very low success rate. Here we revealed a previously unexplored phenomenon that chemotherapy with active targeting nanotechnologies causes pathological BBB functional recovery through VEGF-PI3K-AKT signaling pathway inhibition, accompanied with up-regulated expression of Claudin-5 and Occludin. Seriously, pathological BBB functional recovery induces a significant decrease of intracerebral active targeting nanotechnologies transport during GBM multiple administration, leading to chemotherapy failure in GBM therapeutics. To address this issue, we chose AKT agonist SC79 to transiently re-open functional recovering pathological BBB for continuously intracerebral delivery of brain targeted nanotherapeutics, finally producing an observable anti-GBM effect in vivo, which may offer new sight for other CNS disease treatment.

Lake surface water temperature (LSWT) is of vital importance for hydrological and meteorological studies. The LSWT ground measurements in the Tibetan Plateau (TP) were quite scarce because of its harsh environment. Thermal infrared remote sensing is a reliable way to calculate historical LSWT. In this study, we present the first and longest 35-year (1981–2015) daytime lake-averaged LSWT data of 97 large lakes (>80 km2 each) in the TP using the 4-km Advanced Very High Resolution Radiometer (AVHRR) Global Area Coverage (GAC) data. The LSWT dataset, taking advantage of observations from NOAA’s afternoon satellites, includes three time scales, i.e., daily, 8-day-averaged, and monthly-averaged. The AVHRR-derived LSWT has a similar accuracy (RMSE = 1.7 °C) to that from other data products such as MODIS (RMSE = 1.7 °C) and ARC-Lake (RMSE = 2.0 °C). An inter-comparison of different sensors indicates that for studies such as those considering long-term climate change, the relative bias of different AVHRR sensors cannot be ignored. The proposed dataset should be, to some extent, a valuable asset for better understanding the hydrologic/climatic property and its changes over the TP. Machine-accessible metadata file describing the reported data (ISA-Tab format)

Redox-responsive nanomaterials applied in drug delivery systems (DDS) have attracted an increasing attention in pharmaceutical research as a carrier for antitumor therapy. However, there would be unwanted drug release from a redox-responsive DDS with no selection at nontarget sites, leading to undesirable toxicities in normal tissues and cells. Here, an A54 peptide modified and PEGylated reduction cleavable glucolipid conjugate (A54-PEG-CSO-ss-SA, abbreviated to APCssA) was designed for intracellular delivery of doxorubicin (DOX). The synthesized APCssA could be assembled via micellization self-assembly in aqueous water above the critical micelle concentration (54.9 μg/mL) and exhibited a high drug encapsulation efficiency (77.92%). The APCssA micelles showed an enhanced redox sensitivity in that the disulfide bond could be degraded quickly and the drug would be released from micelles in 10 mM levels of glutathione (GSH). The cellular uptake studies highlighted the affinity of APCssA micelles toward the h...

Usage of combination therapies to deliver multiple therapeutics to increase treatment efficacy has shown promising results in the clinic. In an effort to maximize the synergistic effect of co-delivery of a drug and siRNA, we have developed a time-dependent sequential drug delivery system (DDS) based on a disulfide-linked chitosan-based nanocarrier (CS-ss-SA) for the co-delivery of paclitaxel (PTX) and Bcl-2 specific siRNA (siBcl-2). This CS-ss-SA nanocarrier is able to transport both drug and siRNA by entrapment of PTX and adsorption of siRNA on the shell by electrostatic attraction. We show that this nanocarrier transports siRNA into tumor cells via its glycolipid-like spatial structure and releases a hydrophobic model drug, Nile Red 8-11 h later. Next, when siRNA and the hydrophobic drug PTX were co-delivered to tumor cells, a synergistic effect was observed in both cell cycle arrest and cell viability. Ultimately, the co-delivery of PTX and siBcl-2 by CS-ss-SA may prove to be more efficacious and may even help overcome drug resistance.

// Tingting Meng 1 , Jingwen Liu 1 , Lijuan Wen 1 , Ming Yuan 1 , Bolin Cheng 1 , Yingwen Hu 1 , Yun Zhu 1 , Xuan Liu 1 , Hong Yuan 1 , Fuqiang Hu 1 1 Institute of Pharmaceutics, College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, China Correspondence to: Fuqiang Hu, email: hufq@zju.edu.cn Keywords: multi-cycle chemotherapy, tumor repopulation, drug delivery, cancer stem cell, microenvironment Received: April 05, 2016 Accepted: September 13, 2016 Published: September 21, 2016 ABSTRACT Multi-cycle chemotherapy is commonly used in the clinic, while the phenomena of enrichment of cancer stem cells (CSCs) and enhanced multi-drug resistance (MDR) are commonly involved. This research was designed for evaluating this successive administration. Chitosan oligosaccharide-g-stearic acid (CSOSA) polymer was used as the drug delivery system (DDS) to perform tri-cycle chemotherapy on a new tumor model induced by mammosphere cells. In vitro , on CSCs enriched mammospheres model, the doxorubicin-loaded CSOSA (CSOSA/DOX) displayed an improved growth inhibition effect measured by acid phosphatase assay (APH). While in vivo , the CSOSA/DOX micelles blocked tumor progression and led to a marked decrease of CSCs proportion as well as MDR capacity. What’s more, the CSOSA/DOX helped decay the microenvironment and attenuate systemic side effects. We concluded that the CSOSA polymer could be a potential DDS for long-term multi-cycle chemotherapy in antitumor research.

Rupture of abdominal aortic aneurysm (AAA) is a devastating event that can be prevented by inhibiting the growth of small aneurysms. Therapeutic strategies targeting certain events that promote the development of AAA must be developed, in order to alter the course of AAA. Chronic inflammation of the aortic mural is a major characteristic of AAA and is related to AAA formation, development and rupture. Daphnetin (DAP) is a coumarin derivative with anti-inflammatory properties that is extracted from Daphne odora var. However, the effect of DAP on AAA development remains unclear. The present study investigated the effect of DAP on the formation and development of experimental AAAs and its potential underlying mechanisms. A mice AAA model was established by intra-aortic infusion of porcine pancreatic elastase (PPE), and mice were intraperitoneally injected with DAP immediately after PPE infusion. The maximum diameter of the abdominal aorta was measured by ultrasound system, and aortic mural changes were investigated by Elastica van Gieson (EVG) staining and immunohistochemical staining. The results demonstrated that DAP significantly suppressed PPE-induced AAA formation and attenuated the depletion of aortic medial elastin and smooth muscle cells in the media of the aorta. Furthermore, the density of mural macrophages, T cells and B cells were significantly attenuated in DAP-treated AAA mice. In addition, treatment with DAP resulted in a significant reduction in mural neovessels. These findings indicated that DAP may limit the formation and progression of experimental aneurysms by inhibiting mural inflammation and angiogenesis. These data confirmed the translational potential of DAP inclinical AAA inhibition strategies.

Lakes are sensitive indicators of climate change. There are thousands of lakes on the Tibetan Plateau (TP), more than 1200 of them having an area larger than 1 km2, but few observation data of lakes are available. Therefore, the thermal condition of the plateau lakes under the background of climate warming remain poorly understood. In this study, the China Meteorological Forcing Dataset developed by Institute of Tibetan Plateau Research, Chinese Academy of Sciences (ITPCAS), MODIS Land Surface Temperature (LST) data and buoy observation data were used to reveal the response of thermal conditions of Qinghai Lake to the recent climate change and to analyze the applicability of Freshwater Lake Model (FLake) to Qinghai Lake. Despite some deviations caused by model simplifications and uncertain forcing data, FLake demonstrated a good ability in capturing the seasonal variations of the lake surface temperature and the internal thermal structure of Qinghai Lake. The simulated lake surface temperature demonstrated a positive trend from 1979 to 2012, positively correlated with the air temperature and the downward longwave radiation, while negatively correlated with the wind speed and with the solar radiation but failing to pass the significance test. The simulated internal thermodynamic structure revealed that, if the impact of salinity is not considered, the Qinghai Lake is a dimictic lake with two overturn periods occurring in late spring and late autumn respectively. The surface and mean water temperatures significantly increased from 1979 to 2012, while the bottom temperatures showed no significant trend, even decreasing slightly from 1989 to 2012. The warming was the strongest in winter for both LST and air temperature. With the warming of the climate, the earlier ice break-up and later ice-on were simulated, having a strong effect on lake-air temperature differences in January and May.

Responsive drug release in tumor mitochondria is a pre-requisite for mitochondria-targeted drug delivery systems to improve the efficacy of this promising therapeutic modality. To this end, a photothermal stimulation strategy for mitochondria-responsive drug release along with heat shock is developed to maximize the antitumor effects with minimal side effects. Methods: This strategy relies on mitochondrial-targeted delivery of doxorubicin (DOX) through a photothermal and lipophilic agent IR-780 iodide (IR780)-modified glycolipid conjugates (CSOSA), which can synergistically triggers high-level reactive oxygen species (ROS) to kill tumor cells. Results: Specifically, upon laser irradiation, the photothermal conversion by IR780-CSOSA can not only weaken the hydrophobic interaction between the core of micelles and DOX and trigger unexpected micelle swelling to release DOX in mitochondria for the amplification of ROS, but also induce mitochondria-specific heat shock to promote the fast evolution of ROS at the same locus to eradicate cancer cells in a more effective way. Furthermore, IR780-CSOSA micelles may independently realize the real-time diagnosis and imaging on multiple tumor models. Deep penetration into tumors by IR780-CSOSA/DOX micelles can be manipulated under laser irradiation. Conclusion: Such multifunctional IR780-CSOSA/DOX micelles with integration of mitochondria-responsive drug release and heat shock are demonstrated to be superior to the non-mitochondria-responsive therapy. This study opens up new avenues for the future cancer diagnosis and treatment.

The impacts of inhomogeneity of the oasis interior on the oasis self-maintenance mechanism are investigated by using the mesoscale model MM5 (the fifth-generation Pennsylvania State University National Center for Atmospheric Research (NCAR) mesoscale model) with satellite observations of land use types, vegetation fraction and surface-layer soil moisture from MODIS (Moderate Resolution Imaging Spectroradiometer) data. Four simulations were performed, among which the CTL (control simulation) and MOD (moderated simulation with parameters replaced by MODIS data) were used to validate the model results; EXP1 (experiment 1) and EXP2 (experiment 2) were designed to study the inhomogeneity of oasis interior. Results show that the changes of oasis heterogeneity influence the surface heat-flux partitioning, which leads to a larger "cold-wet" effect over the oasis. Vertical sections of humidity illustrate the existence of a moisture-inversion level, and the deeper moisture inversion of EXP1 and EXP2 further indicates that the relative homogeneity in the oasis interior helps produce stronger humidity inversion over the oasis, thus limiting evaporation. This is further verified by the analysis of the secondary circulation, which shows that the more homogeneous land surface conditions lead to stronger secondary circulation and less turbulent drafts over the oasis interior, playing a positive role in the oasis self-maintenance and development.

The development of advanced gene delivery carriers with stimuli-responsive release manner for tumor therapeutics is desirable, since they can exclusively release the therapeutic gene via their structural changes in response to the specific stimuli of the target site. Moreover, interactions between macrophages and drug delivery systems (DDSs) seriously impair the treatment efficiency of DDSs, thus macrophages uptake inhibition would to some extent improve the intracellular uptake of DDSs in tumor cells. Herein, a PEGylated redox-responsive gene delivery system was developed for effective cancer therapy. PEG modified glycolipid-like polymer (P-CSSO) was electrostatic interacted with p53 to form P-CSSO/p53 complexes, which exhibited an enhanced redox sensitivity in that the disulfide bond was degraded and the rate the plasmid released from P-CSSO was 2.29-fold that of nonresponsive platform (P-CSO-SA) in 10 mM levels of glutathione (GSH). PEGylation could significantly weaken macrophages uptake, while enhance the accumulation of P-CSSO in tumor cells both in vitro and in vivo. Compared with nonresponsive complexes (P-CSO-SA/p53) (59.2%) and Lipofectamine™ 2000/p53 complexes (52.0%), the tumor inhibition rate of P-CSSO/p53 complexes (77.1%) significantly increased, which was higher than CSSO/p53 complexes (69.9%). The present study indicates that tumor microenvironment sensitive and macrophages uptake suppressive P-CSSO/p53 is a powerful in vivo gene delivery system for enhanced anticancer therapy.

Holocene environment change in the Gobi Desert of Mongolia and northwestern China is of global significance as it is one of the key dust source areas of the world. The Juyanze Basin, located in the central Gobi Desert of southern Mongolian Plateau, is one of the three terminal basins of the Heihe River that flows north from the Qilian Mountain. A series of geomorphic shorelines at different elevations around the basin indicate that large lake levels fluctuated during the past. In this study, we measured the exact elevation of shorelines in the Juyanze Basin using Digital Global Positioning System and found seven shorelines at ~37, ~36, ~34, ~30, ~28, ~24, and ~22 m above modern basin floor (a.m.b.f.). Optically stimulated luminescence dating was employed to date the deposition of beach sand and gravel sequences at these shorelines. Results indicate a paleolake developed in the basin at ~5 ka when lake levels reached ~26 m a.m.b.f.. The lake level then gradually increased to ~29 m a.m.b.f. at ~3.3 ka and reached its highest Holocene level of~37 m a.m.b.f. at ~2.7 ka. The lake environment during 1.1–0.8 ka was characterized by frequent lake-level fluctuations at ~30 m a.m.b.f. The lake disappeared from both East and West Juyanze Basin after ~0.6 ka. This sequence is out-of-phase with other regional Holocene lake records which indicate Holocene high stands occurred during the early to middle Holocene. We suggest that out-of-phase lake high stands at ~5–1 ka in the Juyanze Basin are related to geomorphological shifts of the Heihe River channels across its fan/delta, feeding the three sub-basins of the Ejina at different times. Using paleolake shorelines in this region to reconstruct the climate changes needs to be very careful.

Loess deposits surrounding the high mountainous regions of arid central Asia (ACA) play an important role in understanding environmental changes in Eurasia on orbital and sub-orbital time scales. However, problems with dating loess in ACA have limited the interpretation of climatic and environmental data, especially Holocene data. We selected a typical loess/paleosol sequence (LJW10) on the northern slope of the Tianshan Mountains in ACA consisting of 280 cm of loess with multiple paleosols formed in the upper 170 cm of the section. We applied quartz OSL dating to coarse-grained (63–90 μm) fractions, and newly developed K-feldspar pIRIR dating protocols to both coarse-grained and medium-grained (38–63 μm) fractions of the samples from LJW10 section. Internal checks of the quartz OSL dating indicate that the single-aliquot regenerative-dose protocol on large aliquots (5 mm) is appropriate for equivalent dose (De) determinations and that the quartz ages of the loess samples are likely to be reliable. Luminescence characteristics and internal checks of the pIRIR dating indicate the pIRIR signal at a 170 °C stimulation temperature with a 200 °C preheat can be used for both coarse-grained and medium-grained De determinations. Anomalous fading tests for the pIRIR 170 °C signal indicate the pIRIR signals are stable and the anomalous fading of the pIRIR 170 °C signal can be ignored. Sunlight bleaching tests of the loess indicate the residual dose for the pIRIR 170 °C signal can also be ignored as it corresponds to only ∼9 years for the medium-grained K-feldspar and ∼85 years for the coarse-grained K-feldspar. The pIRIR ages of five medium-grained and coarse-grained K-feldspar samples are consistent with coarse-grained quartz OSL ages, and both the medium-grained and coarse-grained ages increase uniformly with depth, indicating these pIRIR ages are reliable. Based on the coarse-grained quartz OSL ages, and on coarse-grained and medium-grained K-feldspar pIRIR ages, an age-depth model for the paleosol-loess sequence was established by using a Bacon age-depth model. This model suggests eolian loess deposition began by at least ∼16 ka ago and that paleosol development on these eolian loess deposits began ∼5.5 ka, continuing to the present, with periods of high effective moisture at 5.5–4.9, 4.6–4.1, and 3.4–3.1 ka. This sequence suggests overall relative aridity during the early Holocene and an increase in effective moisture beginning ∼5.5 ka during the mid-late Holocene in ACA.

A persistent unstable atmospheric boundary layer was observed over Lake Ngoring, caused by higher temperature on the water surface compared with the overlying air. Against this background, the eddy covariance flux data collected from Lake Ngoring were used to analyse the variation of transfer coefficients and roughness lengths for momentum, heat and moisture. Results are discussed and compared with parameterization schemes in a lake model. The drag coefficient and momentum roughness length rapidly decreased with increasing wind velocity, reached a minimum value in the moderate wind velocity and then increased slowly as wind velocity increased further. Under weak wind conditions, the surface tension or small scale capillary wave becomes more important and increases the surface roughness. The scalar roughness length ratio was much larger than unity under weak wind conditions, and it decreased to values near unity as wind velocity exceeded 4.0 m s−1. The lake model could not reproduce well the variation of drag coefficient, or momentum roughness length, versus wind velocity in Lake Ngoring, but it did simulate well the sensible heat and latent heat fluxes, as a result of complementary opposite errors.

In this paper, we introduced parameterizations of the salinity effects (on heat capacity, thermal conductivity, freezing point and saturated vapor pressure) in a lake scheme integrated in the Weather Research and Forecasting model coupled with the Community Land Model (WRF-CLM). This was done to improve temperature simulation over and in a saline lake and to test the contributions of salinity effects on various water properties via sensitivity experiments. The modified lake scheme consists of the lake module in the CLM model, which is the land component of the WRF-CLM model. The Great Salt Lake (GSL) in the USA was selected as the study area. The simulation was performed from September 3, 2001 to September 30, 2002. Our results show that the modified WRF-CLM model that includes the lake scheme considering salinity effects can reasonably simulate temperature over and in the GSL. This model had much greater accuracy than neglecting salinity effects, particularly in a very cold event when that effect alters the freezing point. The salinity effect on saturated vapor pressure can reduce latent heat flux over the lake and make it slightly warmer. The salinity effect on heat capacity can also make lake temperature prone to changes. However, the salinity effect on thermal conductivity was found insignificant in our simulations.

It remains unclear what are the characteristics of the surface energy budget and the radiation balance over the lake at high altitudes. Here we report a nearly two-year ice-free time measurement (2011–2012) of energy flux and radiation balance using the eddy covariance method over Lake Ngoring, Tibetan Plateau. A persistent unstable atmospheric boundary layer was maintained over the lake, caused by a higher water surface temperature compared with the overlying atmosphere. As a result, the positive sensible heat (H) and latent heat (LE) fluxes almost lasted throughout the entire observation period. The heat storage period of the lake could last until September, and the strongest heating occurred in October from the lake to the atmosphere. Compared with the subtropical lake, Bowen ratios were larger in Lake Ngoring, caused by a large temperature difference and a small specific humidity difference between the water surface and the overlying air. The patterns of H versus the atmospheric stability differed from those of LE. H was large under unstable stratification conditions and significantly decreased in the nearly neutral and stable atmospheric stratification. By contrast, the large LE concentrated in the weak unstable to the nearly neutral atmospheric stratification, and clearly declined with increased atmospheric instability. Overall, the vertical specific humidity difference contributed more to LE than the wind speed. As regards H, the major contributors varied with the atmospheric stability. The intrusion of dry, cold air with strong wind could result in significant increases in H and LE (approximately 2.0–4.5 times as much as those of normal days); during this period, the stored energy in water dramatically decreased and even could provide 70% of the energy for H and LE.

Increased flooding caused by global warming threatens the safety of coastal and river basin dwellers, but the relationship of flooding frequency, human settlement and climate change at long time scales remains unclear. Paleolithic, Neolithic and Bronze Age cultural deposits interbedded with flood sediments were found at the Shalongka site near the north bank of the upper Yellow River, northeastern Tibetan Plateau. We reconstruct the history of overbank flooding and human occupation at the Shalongka site by application of optically stimulated luminescence and radiocarbon dating, grain size, magnetic susceptibility and color reflectance analysis of overbank sediment and paleosols. The reliability of OSL dating has been confirmed by internal checks and comparing with independent C-14 ages; alluvial OSL ages have shown a systematic overestimation due to poor bleaching. Our results indicate that the Yellow River episodically overflowed and reached the Shalongka site from at least similar to 6 ka and lasting until similar to 3 ka. Soil development and reduced flooding occurred at similar to 15, similar to 8.3-5.4, and after similar to 3 ka, and prehistoric populations spread to the Shalongka site area at similar to 83, similar to 5.4, and similar to 3 ka. We suggest that climate change influenced the overbank flooding frequency and then affected prehistoric human occupation of the Shalongka site. (C) 2014 University of Washington. Published by Elsevier Inc. All rights reserved.