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Abstract Background and purpose Neurodevelopmental disorders (NDDs) are characterized by abnormalities in brain development and neurobehaviors, including autism. The maternal–fetal interface (MFI) is a highly specialized tissue through which maternal factors affect fetal brain development. However, limited research exists on restoring and maintaining MFI homeostasis and its potential impact on NDDs. This study explores the role of placental indoleamine 2,3-dioxygenase (IDO-1) in MFI homeostasis and fetal brain development. Experimental Approach The maternal-fetal barrier was disrupted by sodium valproate (VPA) in pregnant mice, whose offspring show typical autism-like behaviors. Ultrastructural analysis and flow cytometric analysis were conducted to observe the morphological and immune system changes. Behavioral tests and immunofluorescence staining was used to investigate the ability and mechanism of taprenepag to alleviate the abnormal behaviors of VPA-exposed offspring and normalize the development of serotonergic neurons. Key results In VPA-exposed pregnant mice, the downregulation of IDO-1 led to maternal immune overactivation and disruption of maternal-fetal barrier, resulting in excessive 5-HT synthesis in the placenta. This process disrupted the development of the serotonergic neuronal system in the offspring, resulting in impaired development of serotonergic neurons, thalamocortical axons, and NDDs in the progeny. However, a single injection of taprenepag at E13.5 ultimately upregulated placental IDO-1 through amplifying the positive feedback loop COX-2/PGE2/PTGER-2/IDO-1 and abolished these alterations. Conclusion Taprenepag improved autism-like behaviors in the offspring of VPA-exposed mice by addressing placental IDO-1 downregulation. This study highlights the potential of targeting IDO-1 to mitigate MFI disruption and NDD development.

The Qinghai-Xizang Plateau， distinguished by its vast array of lakes， exhibits marked seasonal lake ice coverage， which is highly responsive to climatic shifts.This ice coverage plays a crucial role in the dynamic interchange of fluxes between the lake surfaces and the atmosphere.Despite the significance of these ice phenomena， the limited availability of extensive， long-term observational data on plateau lake ice has led to a reliance on reanalyzed ice datasets， particularly ERA5-Land.This study aims to rigorously evaluate the effectiveness and potential enhancements of ERA5-Land's lake ice data in the distinct environment of the Qinghai-Xizang Plateau.Focusing on data collected from 2010 to 2022 for Qinghai Lake and Ngoring Lake， this research meticulously examines the ERA5-Land reanalysis data's ability to accurately capture the intrinsic characteristics of plateau lake ice.The study uncovered that ERA5-Land tends to overestimate the ice thickness by about 0.54~0.62 m and erroneously prolongs the freezing period by roughly 68 days per year for these lakes.This notable discrepancy necessitated an in-depth error analysis， which synthesized ERA5-Land data with direct observational data from Ngoring Lake， revealing that inaccuracies primarily originated from the FLake one-dimensional lake model within the ERA5-Land system.In an effort to address these inaccuracies， the study employed the MCD43A3 surface albedo product for both Qinghai Lake and Ngoring Lake over the same period.This innovative approach significantly refined the FLake model by incorporating both a multi-year average albedo and a dynamic daily average albedo.These methodological improvements led to a substantial reduction in the average bias of ice thickness， by 85% and 90% respectively， and narrowed the deviation in the modeled freezing period by about 6 and 8 days per year.The enhancements were particularly notable in lakes with longer periods of snow cover， where the dynamic albedo adjustment proved to be highly effective.This research has successfully identified the albedo parameter within the FLake model as a key source of error in ERA5-Land's lake ice characterizations and has implemented practical adjustments to rectify this.These enhancements have markedly increased the model's precision in simulating lake ice， thereby significantly improving the accuracy of ERA5-Land reanalyzed lake ice data.This advancement is particularly pertinent for the unique climatic and geographical conditions of Qinghai Lake and Ngoring Lake on the Qinghai-Xizang Plateau and offers invaluable insights for future research and practical applications in this domain.The findings of this study contribute profoundly to our understanding and modeling of lake ice phenomena in high-altitude regions and have broader implications for climatological research and environmental monitoring on the Qinghai-Xizang Plateau.

Lakes widely distribute in the Qinghai-Xizang Plateau， and most of them are seasonally frozen lakes.Under the background of global warming， lake ice thickness and phenology are changing significantly， which has a profound impact on regional climate evolution.However， the evolution characteristics of ice thickness and phenology on the climatological scale are not well understood at present.Therefore， in this paper， the lake ice thickness and phenological evolution characteristics of Qinghai Lake during 1979 -2017 were studied by using the field lake ice observation data from Qinghai Lake Xiashe Hydrology Station， MODIS Lake ice coverage dataset， meteorological observation data from Gangcha Meteorological Station and CMFD， combined with a quasi-steady state model of lake ice.The results show that the simulated average ice thickness is 0.31 m， which is close to the measured value of Xiashe Hydrology Station.The error in modelling breaking-up end is only 0.07 days， and the errors of the freezing-up start and the ice duration are 5.60 days and 5.67 days， respectively.The simulated maximum ice thickness decreases from 1979 to 2017 is in good agreement with the observed trend， that is， the ice thickness decreases by 0.003 m per year.In the freezing periods from 1979 to 2017， the freezing-up start of Qinghai Lake is delayed （0.23 d·a-1）， the breaking-up end is advanced （0.32 d·a-1）， and the length of the ice duration is shortened （1.02 d·a-1）， especially in the 1980s （2.2 d·a-1）.During the freezing periods of Qinghai Lake from 1979 to 2017 （from December to April of the following year）， the downward longwave radiation and air temperature （both of which showed an increasing trend） have a significant negative correlation with the average ice thickness and the maximum ice thickness， while the downward shortwave radiation （which showed a decreasing trend） has a significant positive correlation with the maximum ice thickness and the average ice thickness.The detrending sensitivity test shows that： downward longwave radiation， air temperature， downward shortwave radiation and specific humidity are the main driving factors of mean ice thickness and maximum ice thickness variability in Qinghai Lake from 1979 to 2017， contributing 42.08%， 40.93%， -36.99% and 17.45% to mean ice thickness variability， and 44.48%， 44.68%， -34.77% and 19.92% to maximum ice thickness variability， respectively.All the meteorological driving factors contribute 83.40% and 87.01% to the two factors.It can be seen that the maximum ice thickness variability of Qinghai Lake is more susceptible to the influence of meteorological conditions than the average ice thickness variability.The results of this study provide an understanding of the long-term evolution trend of lake ice in the cryosphere， and provide a reference for the study of other lakes in the Tibetan Plateau in the cold season.

Abstract Background Standardized patients (SPs) simulation training models have been widely used in various fields, the study of using SPs in Traditional Chinese medicine (TCM) is still a new filed. Previous studies have demonstrated the effectiveness of occupational SP for TCM (OSP-TCM), which has an increasingly problem of high time and financial costs. The faculty SPs for TCM (FSP-TCM) simulation training model may provide a better alternative. This study aims to test and determine whether FSP-TCM simulations are more cost-effective than OSP-TCM and traditional educational models to improve the clinical competence of TCM students. Methods This study was a single-blind, prospective, randomized controlled trial conducted between February 2023 and October 2023. The participants were randomized into FSP-TCM group, OSP-TCM group and traditionally taught group (TT group) in the ratio of 1:1:1. The duration of this training program was 12 weeks (36 credit hours). Formative and summative assessments were integrated to evaluate the effectiveness of teaching and learning. Three distinct questionnaires were utilized to collect feedback from students, SPs, and teachers at the conclusion of the course. Additionally, analysis of cost comparisons between OSP-TCM and FSP-TCM were performed in the study. Results The study comprised a total of 90 students, with no dropouts during the research. In the formative evaluation, students assigned to both the FSP-TCM and OSP-TCM groups demonstrated higher overall scores compared to those in the TT group. Notably, their performance in “physical examination” (P a = 0.01, P b = 0.04, P c = 0.93) and “comprehensive ability” (P a = 0.01, P b = 0.006, P c = 0.96) significantly exceeded that of the TT group. In the summary evaluation, both SP-TCM groups students outperforms TT group in the online systematic knowledge test (P a = 0.019, P b = 0.04, P c = 0.97), the application of TCM technology (P a = 0.01, P b = 0.03, P c = 0.93) and real-time assessment (P a= 0.003, P b = 0.01, P c = 0.93). The feedback questionnaire demonstrated that both SP-TCM groups showed higher levels of agreement for this course in “satisfaction with the course” (P a = 0.03; P b = 0.02) and “enhanced TCM clinical skills” (P a = 0.02; P b = 0.03) than TT group. The SP questionnaire showed that more FSPs than OSPs in “provided professional feedback” (FSPs: strongly agree 30%, agree 50% vs. OSPs: strongly agree 20%, agree 40%. P = 0.69), and in “gave hints” during the course (FSPs: strongly agree 10%, agree 30% vs. OSPs: strongly agree 0%, agree 10%. P = 0.42). It is noteworthy that FSP-TCM was significantly lower than the OSP-TCM in overall expense (FSP-TCM $7590.00 vs. OSP-TCM $17415.60), and teachers have a positive attitude towards the FSP-TCM. Conclusion FSP-TCM training mode showed greater effectiveness than traditional teaching method in improving clinical competence among TCM students. It was feasible, practical, and cost-effective, and may serve as an alternative method to OSP-TCM simulation.

Qinghai Lake is not only the largest lake in China but also an important part of the national ecological security strategy.Under the background of global warming， the water level of Qinghai Lake changes rapidly， which has great effects on the surrounding traffic facilities， residents' safety and the development of animal husbandry， etc.Therefore， it is necessary to study the water level evolution characteristics of Qinghai Lake and its water balance under climate change.Based on the hydrological data of Buha River hydrology station and Xiashe hydrology station， meteorological data of Gangcha meteorological station and CMFD， and water balance equation， this paper first analyzes the inter-annual and intra-year water level evolution characteristics of Qinghai Lake from 1956 to 2020， and the water balance components， such as runoff into the lake （Rs）， precipitation （P） and evaporation （E）.The second reveals that the changes in water level values calculated in the same months are synchronized with the changes in Rs， P， and E.Finally， the ridge regression method is employed to quantitatively calculate the contribution rates of Rs， P， and E to the water level change of Qinghai Lake based on calculations made for December.The results show that the annual average water level declined at a rate of 0.8 m·（10a）-1 from 1956 to 2004， of which the main reason for the decrease between 1979 and 2004 was that E exceeded the sum of P and Rs.However， from 2004 to 2020， the water level increased at a rate of 1.9 m·（10a）-1， of which the main reason for the increase between 2004 and 2018 was the increase of P and Rs.Qinghai Lake exhibits evident intra-annual variations， with the water level starting to rise in May and reaching its peak in September， which aligns with the monthly variations of Rs， P， and E.Furthermore， the impact of the current year's P， Rs， and E changes on the annual water level change for the same months of September to December is greater than that of the previous year.Specifically， the contributions of the current year's P， Rs， and E changes to the water level change calculated based on December data are 10%， 70%， and 20%， respectively.

Many lakes are widely and densely distributed on the Qinghai-Tibet Plateau.Due to the high altitude， the lakes seasonally freeze with a long ice-covered period.Lake ice can significantly affect the local and regional climate and the sub-glacial aquatic ecosystem by changing the transfer process of radiation energy on and in the lakes.However， their characteristics during the ice-covered period still remain unclear.Therefore， from February 6 to 28， 2022， we conducted a systematic observation of water ice air in Qinghai Lake， the largest lake on the Qinghai-Tibet Plateau.Using field observation data， video images and the precipitation data of peripheral observation stations， the influence of different ice cover conditions on the radiation and temperature of the water-ice-atmosphere on Qinghai Lake during the ice-covered period was analyzed.Results showed that different weather processes such as snowfall， sand and gale could remarkably change the property of cover on the ice， leading to variations of ice thickness on Qinghai Lake.Furthermore， the discrepancies of solar radiation absorption and reflection of different covers result in energy equilibrium that directly dictate ice surface temperature at water-ice-atmosphere interface.Bare ice with low albedo and low absorption induced the relatively strong net solar radiation and the correspondingly large diurnal variations of ice temperature.Compared to bare ice， the high reflection of snow cover and the strong absorption of sand and dust make the ability of net short-wave radiation to penetrate ice weaker， and the diurnal variation of lake ice temperature is smaller.

Lake ice is sensitive to climate change.Under the background of global warming， lake ice is generally declining， and even some lakes in the Northern Hemisphere may not freeze in the future.Lakes are widely distributed in the Qinghai-Xizang Plateau， but there are few studies on lake ice simulation.In addition， the understanding of lake ice characteristics and its freezing coefficients on the Qinghai-Xizang Plateau is still relatively limited.The freezing coefficient A0 of Qinghai Lake was calculated by the degree-day approach for ice growth， using the lake ice thickness measurement data from fly-by-wire radar， meteorological observation data of Qinghai Lake， ERA5-Land reanalysis data， MODIS land surface temperature data and Aqua/MODIS satellite remote sensing images.The results show that A0 has spatial and temporal heterogeneity in Qinghai Lake， and the former is more obvious than the latter.Both the degree-day approach and the energy balance-based analytical model are applied to simulate the lake ice evolution of Qinghai Lake on the Qinghai-Xizang Plateau.The results show that， compared with the degree-day method， the simulations of the start of ice formation， the end of melting and the thickness of lake ice for the 2018 -2019 ice season of Qinghai Lake by the energy balance-based analytic Model are more consistent with the observations.The analytical model is a better method than the degree-day method for simulating the ice of Qinghai Lake.It incorporates the effects of radiation， energy exchange， meteorological elements， lake depth and other factors， thus improving the physical processes and compensating for the fact that the accuracy of the degree-day method of simulation depends on the first date of freezing and cannot simulate the melting process.

Abstract 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.

Lakes on the Qinghai Tibet Plateau (QTP) are widely distributed spatially, and they are mostly seasonally frozen. Due to global warming, the thickness and phenology of the lake ice has been changing, which profoundly affects the regional climate evolution. There are a few studies about lake ice in alpine regions, but the understanding of climatological characteristics of lake ice on the QTP is still limited. Based on a field experiment in the winter of 2022, the thermal conductivity of Qinghai Lake ice was determined as 1.64 W·m−1·°C−1. Airborne radar ice thickness data, meteorological observations, and remote sensing images were used to evaluate a quasi-steady ice model (Leppäranta model) performance of the lake. This is an analytic model of lake ice thickness and phenology. The long-term (1979–2017) ice history of the lake was simulated. The results showed that the modeled mean ice thickness was 0.35 m with a trend of −0.002 m·a−1, and the average freeze-up start (FUS) and break-up end (BUE) were 30 December and 5 April, respectively, which are close to the field and satellite observations. The simulated trend of the maximum ice thickness from 1979 to 2017 (0.004 m·a−1) was slightly higher than the observed result (0.003 m·a−1). The simulated trend was 0.20 d·a−1 for the FUS, −0.34 d·a−1 for the BUE, and −0.54 d·a−1 for the ice duration (ID). Correlation and detrending analysis were adopted for the contribution of meteorological factors. In the winters of 1979–2017, downward longwave radiation and air temperature were the two main factors that had the best correlation with lake ice thickness. In a detrending analysis, air temperature, downward longwave radiation, and solar radiation contributed the most to the average thickness variability, with contributions of 42%, 49%, and −48%, respectively, and to the maximum thickness variability, with contributions of 41%, 45%, and −48%, respectively. If the six meteorological factors (air temperature, downward longwave radiation, solar radiation, wind speed, pressure, and specific humidity) are detrending, ice thickness variability will increase 83% on average and 87% at maximum. Specific humidity, wind, and air pressure had a poor correlation with ice thickness. The findings in this study give insights into the long-term evolutionary trajectory of Qinghai Lake ice cover and serve as a point of reference for investigating other lakes in the QTP during cold seasons.

Cities and lakes have obvious influences on regional precipitation， but their single or interaction effects on reginal heavy rain process remain to be quantified.To reveal the effects of interactions between cities and lakes on the process of heavy rain， this study focuses on a process of typical heavy rain induced by low-level shear line occurred on 27 June 2015 during Yangtze-Huaihe Meiyu period in East China， and conducts a serial of sensitivity experiments to explore the role of Lake Taihu and its nearby cities played in the heavy rain process.Through the contrast of elements in simulation results， it can be concluded that the coexistence of Lake Taihu and its nearby cities enhances the total precipitation of the study area， and the effects of nearby cities on increasing precipitation are more significant than Lake Taihu.The temperature differences between Lake Taihu and city area and the other areas cause the surface wind convergences around the cities， and then introduce strong convection.The strong surface convergence line can affect the form of low-level shear line as well， and it will adjust and enhance the low-level shear line with its movement.In conclusion， the interactions of Lake Taihu and its nearby cities have important influences on the formation and intensity of the surface wind convergence and low-level shear line， and then influence the location and strength of the heavy rain.

The Tibetan Plateau (TP) is distributed with large areas of permafrost, which have received increasing attention as the climate warms. Accurately modeling the extent of permafrost and permafrost changes is now an important challenge for climate change research and climate modeling in this region. Uncertainty in land use and land cover (LULC), which is important information characterizing surface conditions, directly affects the accuracy of the simulation of permafrost changes in land surface models. In order to investigate the effect of LULC uncertainty on permafrost simulation, we conducted simulation experiments on the TP using the Community Land Model, version 5 (CLM5) with five high-resolution LULC products in this study. Firstly, we evaluated the simulation results using shallow soil temperature data and deep borehole data at several sites. The results show that the model performs well in simulating shallow soil temperatures and deep soil temperature profiles. The effect of different land use products on the shallow soil temperature and deep soil temperature contours is not obvious due to the small differences in land use products at these sites. Although there is little difference in the simulating results of different land use products when compared to the permafrost distribution map, the differences are noticeable for the simulation of the active layer. Land cover had a greater impact on soil temperature simulations in regions with greater land use inconsistency, such as at the junction of bare soil and grassland in the northwestern part of the TP, as well as in the southeast region with complex topography. The main way in which this effect occurs is that land cover affects the net surface radiation, which in turn causes differences in soil temperature simulations. In addition, we discuss other factors affecting permafrost simulation results and point out that increasing the model plant function types as well as carefully selecting LULC products is one of the most important ways to improve the simulation performance of land-surface models in permafrost regions.

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.

Abstract 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 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 and Kdi induce 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 of Kdi. The ice thickness and frozen days vary little with Kdw, but increasing Kdw can decrease the water temperature. Compared with the ice albedo, the Kdi and 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.

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.

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.

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.

Abstract 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 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

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.

Myocardial infarction (MI) may cause heart failure and seriously harm human health. During the genesis of cardiac fibrosis after MI, the proliferation and migration of cardiac fibroblasts contribute to secretion and maintenance of extracellular matrix (ECM) components. Many miRNAs have been highly implicated in the processes of cardiac fibrosis after MI. However, the molecular mechanisms for how miRNAs involve in cardiac fibrosis remain largely unexplored. Based on MI model in miniature pigs, the potential miRNAs involved in MI were identified by using small RNA sequencing. Using human cardiac fibroblasts (HCFs) as a cellular model, EdU, Transwell, and the expression of ECM-related proteins were applied to investigate the cell proliferation, migration and collagen synthesis. In this study, using MI model based on miniature pigs, 84 miRNAs were identified as the differentially expressed miRNAs between MI and control group, and miR-144-3p, one of differentially expressed miRNAs, was identified to be higher expressed in infarct area. The cell proliferation, migration activity, and the mRNA and protein levels of the ECM-related genes were significantly increased by miR-144-3p mimic but significantly decreased by miR-144-3p inhibitor in cardiac fibroblasts. Furthermore, miR-144-3p was observed to repress transcription and translation of PTEN, and interfering with the expression of PTEN up-regulated the mRNAs and proteins levels of α-SMA, Col1A1, and Col3A1, and promoted the proliferation and migration of cardiac fibroblasts, which was in line with that of miR-144-3p mimics, but this observation could be reversed by miR-144-3p inhibitor. Collectively, miR-144-3p promotes cell proliferation, migration, and collagen production by targeting PTEN in cardiac fibroblasts, suggesting that miR-144-3p-mediated-PTEN regulation might be a novel therapeutic target for cardiac fibrosis after MI.

To gain more understanding of lake ice melting process, field research was carried out in an arctic tundra lake, Kilpisjärvi (surface area 37.1 km2, maximum depth 57 m) in the melting periods of 2013 and 2014. The heat budget of the ice cover was dominated by the radiation balance; turbulent heat fluxes were large in 2013 due to warm air advection but small in 2014. Transmittance of solar radiation through ice was 0.25 in 2013 and 0.10 in 2014, snow-ice was absent in 2013 but in 2014 accounted for 50% of the ice cover. The melting rate was 4.4 cm d-1 in 2013, 1.9 cm d-1 in 2014. The portions of surface, bottom and internal melting were, respectively, 2.9, 1.0 and 0.5 cm d-1 in 2013 and 0.8, 1.0 and 0.1 cm d-1 in 2014. Internal melting was realized in increase of ice porosity. In 2013 a rapid ice breakage event completed the ice breakup in short time when ice porosity had reached 40-50%. A lake ice melting model should include the thickness and porosity of ice, with porosity connected to an ice strength criterion.

The Tibetan Plateau (TP) is covered by thousands of lakes which affect the regional and global heat and mass budget with important implications for the current and future climate change. However, the heat and mass budget of TP lakes and the performance of contemporary lake models over TP have not been quantified to date. We utilise 3-yr observations from Ngoring Lake, the largest lake in the Yellow River source region of TP, to investigate the typical properties of the lake–air boundary layer and to evaluate the performance of a simplified lake scheme from the Community Land Model version 4.5 (SLCLM) as one of the most popular lake parameterization schemes in atmospheric models. The strong boundary layer instability during the entire open-water period is a distinguishing feature of the air–lake exchange, similar to the situation over tropical and subtropical lakes, while contrasting to the generally stable atmospheric conditions commonly observed over ice-free temperate and boreal lakes from spring to summer. The rather simple algorithm of SLCLM demonstrated good performance in these conditions. A series of sensitivity simulations with SLCLM revealed strong shortwave solar radiation and cold air temperatures because of high altitude as the primary factors causing the boundary layer instability. The outcomes of the study (1) demonstrate the role of TP lakes as accumulators of shortwave solar radiation releasing the heat into the atmosphere during the entire open-water period; (2) justify the use of simple lake models for the Tibetan highlands, while revealing remarkable uncertainties in the estimations of the latent heat flux; (3) qualify the strong cool-skin effect on the lake surface which results from permanent negative air–lake temperature difference, and should be taken into account when interpreting remote sensing data from highland areas.

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.

The Tibetan Plateau harbors thousands of lakes; however few studies focus on impacts of lakes on local climate in the region. To investigate and quantify impacts of the two biggest lakes (Ngoring Lake and Gyaring Lake) of the Yellow River source region in the Tibetan Plateau on local climate, two simulations (with and without the two large lakes) from May 2010 to July 2011 are performed and analyzed using the WRF-CLM model (the weather research and forecasting model coupled with the community land model). Differences between simulated results show that the WRF-CLM model could provide realistic reproduction of surface observations and has better simulation after considering lakes. Lakes mostly reduce the maximum temperature all year round and increase the minimum temperature except in March due to the large heat capacity that makes lakes absorb (release) more energy for the same temperature change compared to land. Lakes increase precipitation over the lake area and in the nearby region, mostly during 02–14 BT (Beijing Time) of July to October when the warm lake surface induces the low level horizontal convergence and updraft over lake and provides energy and vapor to benefit the development of the convection for precipitation.

In the study, the weather research and forecasting model coupled with the community land model (WRF-CLM) is used to investigate impacts of the GSL and its salinity from October 2001 to April 2002. A salinity parameterization scheme is incorporated into the lake scheme of CLM. The WRF-CLM model with the salinity parameterization scheme can better simulate temperature and precipitation compared to that without considering the salinity effects. The improvement of simulation is especially significant under cold weather condition. The precipitation caused by the GSL effect is always positive over the downwind area of the GSL during the study period. Increased precipitation is largely attributed to the warm lake surface temperature and high latent heat flux over the GSL, which are favorable for the development of strong convective activity and horizontal wind and moisture convergence. Such kind of GSL-induced forcing is the primary mechanism for the downstream GSL effect precipitation. The GSL effect precipitation is largely contributed by fresh water effect when the temperature is close to or higher than 0°C. However, with lower temperature, the salinity effect becomes dominant for the GSL effect precipitation.