The crosstalk between megakaryocytic lineage cells and the skeletal system has just begun to be explored but remains largely elusive.Using conditional gene knockout mouse models,we demonstrated that loss of Beclin 1(B...The crosstalk between megakaryocytic lineage cells and the skeletal system has just begun to be explored but remains largely elusive.Using conditional gene knockout mouse models,we demonstrated that loss of Beclin 1(Becn1),a major regulator of mammalian autophagy,exclusively in the megakaryocytic lineage disrupted autophagy in platelets but did not compromise megakaryopoiesis or the formation and function of platelets.Unexpectedly,conditional Becn1 deletion in male mice led to a remarkable increase in bone mass with improved bone quality,in association with a decrease in sex hormone binding globulin(SHBG)and an increase in free testosterone(FT).In vivo Becn1 overexpression in megakaryocytic lineage-specific cells reduced bone mass and quality,along with an increase in SHBG and a decrease in FT.Transplantation of wild-type bone marrow cells into megakaryocytic lineage Becn1-deficient male mice restored bone mass and normalized SHBG and FT.Furthermore,bilateral orchiectomy of Becn1^(f/f);Pf4-iCre mice,which are crippled with the production of testosterone,resulted in a reduction in bone mass and quality,whereas in vivo overexpression of SHBG,specifically in the liver of Becn1^(f/f);Pf4-iCre mice,decreased FT and reduced bone mass and quality.In addition,metformin treatment,which induces SHBG expression,reduced FT and normalized bone mass in Becn1^(f/f);Pf4-iCre mice.We thus concluded that Becn1 of the megakaryocytic lineage is dispensable locally for platelet hemostasis but limits bone mass by increasing SHBG,which in turn reduces the FT of male mice.Our findings highlight a mechanism by which Becn1 from megakaryocytic lineage cells distally balances bone growth.展开更多
Soybean(Glycine max)is a globally important crop that serves as a primary source of edible oil and protein for both humans and animals.Cultivated soybean varieties exhibit considerable genetic diversity depending on t...Soybean(Glycine max)is a globally important crop that serves as a primary source of edible oil and protein for both humans and animals.Cultivated soybean varieties exhibit considerable genetic diversity depending on their geographical origin.Heinong 531(HN531)is an elite cultivar that was released in China in June 2021 with 22.34%seed oil,high resistance to soybean cyst nematode(SCN)race 3,and enhanced yield.However,the genetic basis for these desirable agronomic traits is unclear.In this study,we generated a high-quality genome assembly for HN531 and used it to systematically analyze genes related to agronomic traits such as resistance to SCN.The assembled genome spans 981.20 Mb,featuring a contig N50 of 19.47 Mb,and contains 58,151 predicted gene models.Pan-genomic comparison with 27 previously reported soybean genomes revealed 95,071 structural variants(SVs)of>50 bp,of which 602 were HN531-specific.Furthermore,we identified a copy number variation at rhg1 that underlies resistance to SCN,and we found elite alleles of functional genes underlying important agronomic traits such as seed oil content,adaptability,and yield.This high-quality HN531 genome can be used to explore the genetic basis for the excellent agronomic traits of this cultivar,and is a valuable resource for breeders aiming to improve HN531 and related cultivars.展开更多
To achieve high power rating and low current harmonics of motor drive,this paper develops a dual three-phase open-winding permanent magnet synchronous motor(DTP-OW-PMSM)drive with the DC-link voltage ratio of 2:1:1.Ba...To achieve high power rating and low current harmonics of motor drive,this paper develops a dual three-phase open-winding permanent magnet synchronous motor(DTP-OW-PMSM)drive with the DC-link voltage ratio of 2:1:1.Based on this topology,this paper proposes a DTP four-level space vector pulse width modulation(DTP-FL SVPWM)strategy.First,two identical three-phase four-level space vector diagrams are constructed and divided.Then,three adjacent vectors nearest to the reference vector in each diagram are selected for the vector synthesis to guarantee high modulation precision and low switching frequency.Furthermore,to avoid the modulation error caused by the voltage deviation,the proposed DTP-FL SVPWM strategy is further optimized through unified duty ratio compensation(UDRC).The effectiveness of the proposed strategy is verified through experiments.展开更多
The pollution status and characteristics of PAEs（phthalate esters） were investigated in indoor air of offices, and PAEs of both gas-phase and particulate-phase were detected in all the samples. The concentration（su...The pollution status and characteristics of PAEs（phthalate esters） were investigated in indoor air of offices, and PAEs of both gas-phase and particulate-phase were detected in all the samples. The concentration（sum of the gas phase and the particulate phase） was4748.24 ng/m3, ranging between 3070.09 and 6700.14 ng/m3. Diethyl phthalate, dibutyl phthalate, and di（2-ethylhexyl） phthalate were the most abundant compounds, together accounting for 70% of the ∑ 6PAEs. Dividing the particulate-phase PAEs into four size ranges（〈 2.5, 2.5–5, 5–10, 〉 10 μm）, the result indicated that PAEs in PM2.5were the most abundant,with the proportion of 72.64%. In addition, the PAE concentration in PM2.5correlated significantly with the total particulate-phase PAEs（R2= 0.85）. Thus, the amount of PAEs in PM2.5can be estimated from the total amount of particulate-phase PAEs using this proportion. In a comparison between the offices and a newly decorated study room, it was found that pollution characteristics were similar between these two places. Thus, it is implied that the PAE concentration decreased by 50% 2 yr after decorating.展开更多
Phthalate esters（PAEs） are widely used as plasticizers in consumer products. PAEs are a group of environmental hormone which disrupts human and animals＇ endocrine systems. Different occupational groups are exposed ...Phthalate esters（PAEs） are widely used as plasticizers in consumer products. PAEs are a group of environmental hormone which disrupts human and animals＇ endocrine systems. Different occupational groups are exposed to various levels of PAEs. In the present study, four typical occupational groups were chosen, including doctors, college teachers, college students, and drivers who worked in public traffic system. In order to understand the exposure levels to PAEs via inhalation, air samples were collected from multiple microenvironments including indoor and outdoor in Hangzhou to measure the gas and particle concentrations of six PAEs, together with time spent in different microenvironments of these four groups. A comprehensive PAEs exposure model was built to estimate the daily PAEs exposure through inhalation, oral and dermal pathways. The Monte Carlo simulation results show that doctors were exposed to the highest level of PAEs, and consequently had the highest health risk among these four occupational groups. In contrast, college students had the lowest health risk. By setting the exposure level of staying in residences as the baseline, doctors and drivers were two occupations exposed to high PAEs health risk. Di-（2-ethylhexyl） phthalate（DEHP） was the largest contributor among the six phthalates, posing moderate health risk（10-5–10-6） to every occupation. For traffic microenvironments alone, the total exposure levels for different transportation modes were in the descending order of busses, cars, cabs, tubes, motor bikes, and walking.展开更多
Currently,the cancer immunotherapy has made great progress while antitumor vaccine attracts substantial attention.Still,the selection of adjuvants as well as antigens are always the most crucial issues for better vacc...Currently,the cancer immunotherapy has made great progress while antitumor vaccine attracts substantial attention.Still,the selection of adjuvants as well as antigens are always the most crucial issues for better vaccination.In this study,we proposed a biomimetic antitumor nanovaccine based on biocompatible nanocarriers and tumor cell membrane antigens.Briefly,endogenous calcium pyrophosphate nanogranules with possible immune potentiating effect are designed and engineered,both as delivery vehicles and adjuvants.Then,these nanocarriers are coated with lipids and B16-OVA tumor cell membranes,so the biomembrane proteins can serve as tumor-specific antigens.It was found that calcium pyrophosphate nanogranules themselves were compatible and possessed adjuvant effect,while membrane proteins including tumor associated antigen were transferred onto the nanocarriers.It was demonstrated that such a biomimetic nanovaccine could be well endocytosed by dendritic cells,promote their maturation and antigen-presentation,facilitate lymph retention,and trigger obvious immune response.It was confirmed that the biomimetic vaccine could induce strong T-cell response,exhibit excellent tumor therapy and prophylactic effects,and simultaneously possess nice biocompatibility.In general,the present investigation might provide insights for the further design and application of antitumor vaccines.展开更多
Reducing oxidative stress and hepatoprotective effect of Pu-erh tea water extracts on rats fed with high-fat diet were researched for explaining health care of Pu-erh tea.Fifty SD rats were divided into five groups.Th...Reducing oxidative stress and hepatoprotective effect of Pu-erh tea water extracts on rats fed with high-fat diet were researched for explaining health care of Pu-erh tea.Fifty SD rats were divided into five groups.The body weight was measured once a day.The malondialdehyde(MDA)and glucose(Glu)levels and the activities of alanine aminotransferase(ALT),aspartate aminotransferase(AST),nitric oxide synthase(NOS),and pyruvate kinase(PK)in serum were determined.Furthermore,the hepatic glycogen level(HGL)and the activities of hepatic total superoxide dismutase(T-SOD),catalase(CAT),and glutathione peroxidase(GSH-Px)were also measured after continuous administration for 12 weeks.The result demonstrated that Pu-erh extract caused the decreases in body weight,fat index,MDA and NOS levels,and the increases in hepatic T-SOD,CAT and GSH-Px activities,indicating that the extract may be due to inhibiting the increases of body weight and fat index,reducing oxidant stress state and inhibiting lipid peroxidation,thus decreasing the activities of ALT and AST,and protecting the liver in rat.Meanwhile,the extracts could increase the production of hepatic glycogen and the activity of PK,and reduce glucose level,protecting the liver from the diseases associated with type II diabetes.展开更多
Small GTPase is a kind of GTP-binding protein commonly found in eukaryotic cells.It plays an important role in cytoskeletal reorganization,cell polarity,cell cycle progression,gene expression and many other significan...Small GTPase is a kind of GTP-binding protein commonly found in eukaryotic cells.It plays an important role in cytoskeletal reorganization,cell polarity,cell cycle progression,gene expression and many other significant events in cells,such as the interaction with foreign particles.Therefore,it is of great scientific significance to understand the biological properties of small GTPases as well as the GTPase-nano interplay,since more and more nanomedicine are supposed to be used in biomedical field.However,there is no review in this aspect.This review summarizes the small GTPases in terms of the structure,biological function and its interaction with nanoparticles.We briefly introduced the various nanoparticles such as gold/silver nanoparticles,SWCNT,polymeric micelles and other nano delivery systems that interacted with different GTPases.These current nanoparticles exhibited different pharmacological effect modes and various target design concepts in the small GTPases study.This will help to elucidate the conclusion that the therapeutic strategy targeting small GTPases might be a new research direction.It is believed that the in-depth study on the functional mechanism of GTPases can provide insights for the design and study of nanomedicines.展开更多
Sympatric reptiles are the ideal system for investigating temperature-driven coexistence. Understanding thermally physiological responses of sympatric lizards is necessary to reveal the physiological mechanisms that u...Sympatric reptiles are the ideal system for investigating temperature-driven coexistence. Understanding thermally physiological responses of sympatric lizards is necessary to reveal the physiological mechanisms that underpin the sympatric occurrence of reptiles. In this study, we used three lizard species, Eremias argus, E. multiocellata, and Phrynocephalus przewalskii, which are sympatric in the Inner Mongolia desert steppe, as a study system. By comparing their resting metabolic rates(RMR) and locomotion at different body temperatures, we aimed to better understand their physiological responses to thermal environments, which may explain the sympatric occurrence of these lizards. Our results showed that E. argus had significantly higher RMR and sprint speed than E. multiocellata, and higher RMR than P. przewalskii. In addition, the optimal temperature that maximized metabolic rates and locomotion for E. argus and E. multiocellata was 36°C, whereas for P. przewalskii it was 39°C. Our study revealed the physiological responses to temperatures that justify the sympatric occurrence of these lizards with different thermal and microhabitat preferences and active body temperatures. Eremias argus and E. multiocellata, which have lower body temperatures than P. przewalskii, depend on higher RMR and locomotion to compensate for their lower body temperatures in field conditions. Our study also highlights the importance of using an integrative approach, combining behavior and physiology, to explore the basis of sympatric occurrence in ectothermic species.展开更多
Objective:Therapy for hepatocellular carcinoma(HCC)is a major challenge,and targeted therapies provide only a modest benefit in terms of overall survival.Treatment with antibodies to programmed cell death protein 1(PD...Objective:Therapy for hepatocellular carcinoma(HCC)is a major challenge,and targeted therapies provide only a modest benefit in terms of overall survival.Treatment with antibodies to programmed cell death protein 1(PD-1)/PD-L1 can restore the functions of tumor-infiltrating T cells in HCC and has shown clinical efficacy in 20%of patients with advanced HCC.Novel approaches are urgently needed to treat HCC and to augment the efficacy of immunotherapy.Methods:Tumor-bearing mice were treated with Agrocybe aegerita galectin(AAGL)alone or in combination with anti-PD-1,and the tumor sizes and lifespans of mice were determined.Transcriptome analysis,cytokine analysis,flow cytometry analysis of the number and proportion of immune cell subsets in the liver and spleen,and molecular and cellular analyses of tumors were used to define the underlying mechanisms.Results:AAGL significantly inhibited the growth of liver tumors in a dose-dependent manner.Furthermore,AAGL increased the expression of multiple cytokines and chemokines in tumor-bearing mouse livers;this effect was associated with the activation and migration of T cells and macrophages,in agreement with the in vitro results.Importantly,the aggregation of T cells and macrophages induced by AAGL in tumor-bearing mouse livers clearly enhanced the response to PD-1 blockade immunotherapy.Conclusions:The results showed that AAGL induced the activation and migration of lymphocytes to the liver,and that the combination of AAGL and anti-PD-1 may be a promising strategy for HCC treatment.展开更多
The combination regimen of trastuzumab(Tras)plus Nab-paclitaxel(Nab)is recommended to treat HER2-positive(HER2+)cancers.However,they exert effects in different mechanisms:Tras need to stay on cell membranes,while Nab ...The combination regimen of trastuzumab(Tras)plus Nab-paclitaxel(Nab)is recommended to treat HER2-positive(HER2+)cancers.However,they exert effects in different mechanisms:Tras need to stay on cell membranes,while Nab need to be endocytosed,therefore the concurrent combination regimen may not be the best one in HER2+tumors treatment.Caveolin-1(Cav-1)is a key player in mediating their endocytosis and is associated with their efficacy,but few researches noticed the opposite effect of Cav-1 expression on the combination efficacy.Herein,we systematically studied the Cav-1 expression level on the combination efficacy and proposed an optimized and clinically feasible combination regimen for HER2+Cav-1 High tumor treatment.In the regimen,lovastatin(Lova)was introduced to modulate the Cav-1 expression and the results indicated that Lova could downregulate Cav-1 expression,increase Tras retention on cell membrane and enhance the in vitro cytotoxicity of Tras in HER2+Cav-1 High cells but not in HER2+Cav-1 Low cells.Therefore,by exchanging the dosing sequence of Nab and Tras,and by adding Lova at appropriate time points,the precise three-drug-sequential regimen(PTDS,Nab(D1)-Lova(D2)-Lova&Tras(D2+12 h))was established.Compared with the concurrent regimen,the PTDS regimen exhibited a higher in vitro cytotoxicity and a stronger tumor growth inhibition in HER2+Cav-1 High tumors,which might be a promising combination regimen for these patients in clinics.展开更多
Based on previous research, the sampling and analysis methods for phthalate esters （PAEs） were improved by increasing the sampling flow of indoor air from 1 to 4 L/min, shortening the sampling duration from 8 to 2 h...Based on previous research, the sampling and analysis methods for phthalate esters （PAEs） were improved by increasing the sampling flow of indoor air from 1 to 4 L/min, shortening the sampling duration from 8 to 2 hr. Meanwhile, through the optimization of chromatographic conditions, the concentrations of 9 additional PAE pollutants in indoor air were measured. The optimized chromatographic conditions required a similar amount of time for analysis as before, but gave high responsivity, the capability of simultaneously distinguishing 15 kinds of PAEs, and a high level of discrimination between individual sample peaks, as well as stable peak generation. The recovery rate of all gas-phase and particle-phase samples of the 15 kinds of PAEs ranged from 91.26% to 109.42%, meeting the quantitative analysis requirements for indoor and outdoor air sampling and analysis. For the first time, investigation of the concentration levels as well as characteristics of 15 kinds of PAEs in the indoor air from four different traffic micro-environments （private vehicles, busses, taxis and subways） was carried out, along with validation of the optimized sampling and analytical method. The results show that all the 9 additional PAEs could be detected at relatively high pollution levels in the indoor air from the four traffic micro-environments. As none of the pollution levels of the 15 kinds of PAEs in the indoor air from the 4 traffic micro-environments should be neglected, it is of great significance to increase the types of PAEs able to be detected in indoor air.展开更多
The cost of highway is affected by many factors.Its composition and calculation are complicated and have great ambiguity.Calculating the cost of highway according to the traditional highway engineering estimation meth...The cost of highway is affected by many factors.Its composition and calculation are complicated and have great ambiguity.Calculating the cost of highway according to the traditional highway engineering estimation method is a completely tedious task.Constructing a highway cost prediction model can forecast the value promptly and improve the accuracy of highway engineering cost.This work sorts out and collects 60 sets of measured data of highway engineering;establishes an expressway cost index system based on 10 factors,including main route mileage,roadbed width,roadbed earthwork,and number of bridges;and processes the data through principal component analysis(PCA)and hierarchical cluster analysis.Particle swarm optimization(PSO)is used to obtain the optimal parameter combination of the regularization parameter c and the kernel function width coefficientin least squares support vector machine(LSSVM).Results show that the average relative and mean square errors of the PCA-PSO-LSSVM model are 0.79%and 10.01%,respectively.Compared with BP neural networks and unoptimized LSSVM model,the PCA-PSO-LSSVM model has smaller relative errors,better generalization ability,and higher prediction accuracy,thereby providing a new method for highway cost prediction in complex environments.展开更多
The concentrations of phthalate esters（PAEs） in Chinese hospitals were investigated by simultaneously determining concentrations of gas- and particle-phase PAEs. PAEs were detected in two third-class first-grade hos...The concentrations of phthalate esters（PAEs） in Chinese hospitals were investigated by simultaneously determining concentrations of gas- and particle-phase PAEs. PAEs were detected in two third-class first-grade hospitals, two second-class first-grade hospitals, and a community health service center. Hospital drugstores had the highest concentration（24.19 μg/m3）, which was 1.54 times that of newly decorated houses. The second highest concentration was found in the transfusion rooms, averaging 21.89 μg/m3; this was followed by the concentrations of PAEs in the nurse＇s workstations, the wards, and the doctor＇s offices, with mean concentrations of 20.66, 20.0, and 16.92 μg/m3, respectively. The lowest concentrations were found in the hallways（16.30 μg/m3）. Of the six different kinds of PAEs found, major pollutants included diethyl phthalates, dibutyl phthalates, butylbenzyl phthalates and di（2-ethylhexyl） phthalates, comprising more than 80% of all PAEs present.Meanwhile, a comparison between different wards showed that PAE concentrations in the maternity wards were 1.63 times higher than in the main wards. Based on known health hazards, our results suggest that the PAEs seriously influence the health of the pregnant women and babies; therefore, it is of great importance to take the phthalate concentrations in hospitals into consideration. In addition, hospital indoor air was more seriously contaminated than the air of newly decorated houses.展开更多
In order to realize the combination of chemotherapy and immunotherapy,a reduction-responsive paclitaxel(PTX)prodrug PEG-SS-PTX was synthesized and used as a carrier to encapsulate IDO inhibitor CY-1-4 for preparing PE...In order to realize the combination of chemotherapy and immunotherapy,a reduction-responsive paclitaxel(PTX)prodrug PEG-SS-PTX was synthesized and used as a carrier to encapsulate IDO inhibitor CY-1-4 for preparing PEG-SS-PTX/CY-1-4 NPs.PEG-SS-PTX/CY-1-4 NPs were evaluated by cytotoxicity,immunogenic cell death(ICD)induction ability and anti-tumor efficacy.Dynamic light scattering(DLS)results showed that the size of PEG-SS-PTX/CY-1-4 NPs was about 149 nm.In vitro experiments indicated that its cytotoxicity was in a concentration-dependent manner,and it induced the ICD of B16-F10 cells.In vivo studies in melanoma mouse model indicated that PEG-SS-PTX/CY-1-4 NPs significantly inhibited the tumor growth and reduced the expression of IDO in tumor tissues.Moreover,it increased the rate of CD8+T cells in the spleen.In summary,PEG-SS-PTX/CY-1-4 NPs achieved good anti-tumor effects and reduced the dose of chemotherapy drugs,which was a safe and effective combined delivery system.展开更多
The application of nanomedicines in oral drug delivery effectively promotes the drug absorption and transportation through enterocytes.Nevertheless,the absence of mechanism studies on efficacy and safety limits their ...The application of nanomedicines in oral drug delivery effectively promotes the drug absorption and transportation through enterocytes.Nevertheless,the absence of mechanism studies on efficacy and safety limits their final translation in humans.Although the vesicular trafficking has been verified as the general character for transport of nanomedicines,the deeper mechanism in molecular mechanism is still unclear.Moreover,the cellular transport of nanomedicines is a dynamic process involved by different organelles and components.However,most of existing studies just pay attention to the static location of nanomedicines,but neglect the dynamic biological effects on cells caused by them.Here,we prepared gold nanoparticles(Au NPs)as the model and cultured epithelial cell monolayer to explore the nano-bio interactions at the molecular level.The traditional pharmacological inhibition strategy and subcellular imaging technology elucidated the macropinocytosis/endosome/MVB/lysosome pathway during the transportation of Au NPs.Proteomics strategy based on mass spectrometry(MS)was utilized to identify and quantify proteins involved in the cellular transport of nanomedicines.Multiple proteins related to subcellular structure,signal transduction,energy transformation and metabolism regulation were demonstrated to be regulated by nanoparticle transport.These alterations of protein expression clarified the effects of intracellular proteins and verified the conventional findings.More importantly,it revealed a feedback mechanism of cells to the nano-trafficking.We believed that these new regulatory mechanisms provided new insights into the efficient transport of nanomedicines through epithelial barriers.展开更多
The interplay among diverse cell populations in the tumor microenvironment contributes to tumor progression.Targeting to different cell populations might result in improved therapeutic effects on malignant tumors.Inte...The interplay among diverse cell populations in the tumor microenvironment contributes to tumor progression.Targeting to different cell populations might result in improved therapeutic effects on malignant tumors.Integrins high express on many kinds of tumor cells,and VEGF has a strong effect on tumor angiogenesis.Therefore,based on tumor cells and angiogenesis,we fabricated integrin-targeting cRGD-DOX nanoparticles and combined them with the anti-VEGF antibody bevacizumab.We evaluated the antitumor effect of this combination therapy in an integrin-overexpressing MDA-MB-231 tumor model.The cRGD-DOX nanoparticles were effectively uptake by MDA-MB-231 cells and the uptake was related to the expression of integrinin;cRGD-DOX nanoparticles showed less cytotoxic than free DOX;Bevacizumab did not show significant cytotoxicity against MDA-MB-231 cells at concentrations less than 1 mg/mL.The in vivo results showed that bevacizumab could reduce tumor interstitial fluid pressure;the combination of bevacizumab and cRGD-DOX nanoparticles showed enhanced antitumor effects compared with the corresponding single-agent treatments.These findings suggested the combination of angiogenesis antibody and integrin-targeting nanoparticle loaded with a cytotoxic drug was a promising cancer treatment regimen.展开更多
基金supported in part by grants from the National Natural Science Foundation of China(No.81673093,No.82170227,No.91649113,No.82470165,No.82000121,No.31771640)the Jiangsu Science and Technology Department(No.SBK20200191)+1 种基金the State Key Laboratory of Radiation Medicine and Protection of Soochow University(No.GZC00201)a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘The crosstalk between megakaryocytic lineage cells and the skeletal system has just begun to be explored but remains largely elusive.Using conditional gene knockout mouse models,we demonstrated that loss of Beclin 1(Becn1),a major regulator of mammalian autophagy,exclusively in the megakaryocytic lineage disrupted autophagy in platelets but did not compromise megakaryopoiesis or the formation and function of platelets.Unexpectedly,conditional Becn1 deletion in male mice led to a remarkable increase in bone mass with improved bone quality,in association with a decrease in sex hormone binding globulin(SHBG)and an increase in free testosterone(FT).In vivo Becn1 overexpression in megakaryocytic lineage-specific cells reduced bone mass and quality,along with an increase in SHBG and a decrease in FT.Transplantation of wild-type bone marrow cells into megakaryocytic lineage Becn1-deficient male mice restored bone mass and normalized SHBG and FT.Furthermore,bilateral orchiectomy of Becn1^(f/f);Pf4-iCre mice,which are crippled with the production of testosterone,resulted in a reduction in bone mass and quality,whereas in vivo overexpression of SHBG,specifically in the liver of Becn1^(f/f);Pf4-iCre mice,decreased FT and reduced bone mass and quality.In addition,metformin treatment,which induces SHBG expression,reduced FT and normalized bone mass in Becn1^(f/f);Pf4-iCre mice.We thus concluded that Becn1 of the megakaryocytic lineage is dispensable locally for platelet hemostasis but limits bone mass by increasing SHBG,which in turn reduces the FT of male mice.Our findings highlight a mechanism by which Becn1 from megakaryocytic lineage cells distally balances bone growth.
基金supported by National Natural Science Foundation of China(32201759,32172002)Inner Mongolia Innovation Center of Biological Breeding Technology,National Key Research and Development Program of China(2021YFD1201600)+1 种基金Earmarked Fund for CARS(CARS-04-PS01)Agricultural Science and Technology Innovation Program(ASTIP).
文摘Soybean(Glycine max)is a globally important crop that serves as a primary source of edible oil and protein for both humans and animals.Cultivated soybean varieties exhibit considerable genetic diversity depending on their geographical origin.Heinong 531(HN531)is an elite cultivar that was released in China in June 2021 with 22.34%seed oil,high resistance to soybean cyst nematode(SCN)race 3,and enhanced yield.However,the genetic basis for these desirable agronomic traits is unclear.In this study,we generated a high-quality genome assembly for HN531 and used it to systematically analyze genes related to agronomic traits such as resistance to SCN.The assembled genome spans 981.20 Mb,featuring a contig N50 of 19.47 Mb,and contains 58,151 predicted gene models.Pan-genomic comparison with 27 previously reported soybean genomes revealed 95,071 structural variants(SVs)of>50 bp,of which 602 were HN531-specific.Furthermore,we identified a copy number variation at rhg1 that underlies resistance to SCN,and we found elite alleles of functional genes underlying important agronomic traits such as seed oil content,adaptability,and yield.This high-quality HN531 genome can be used to explore the genetic basis for the excellent agronomic traits of this cultivar,and is a valuable resource for breeders aiming to improve HN531 and related cultivars.
基金supported in part by the National Natural Science Foundation of China under Grant 62303333in part by the Project of Hetao Shenzhen-Hong Kong Science and Technology Innovation Cooperation Zone under Grant HZQB-KCZYB-2020083.
文摘To achieve high power rating and low current harmonics of motor drive,this paper develops a dual three-phase open-winding permanent magnet synchronous motor(DTP-OW-PMSM)drive with the DC-link voltage ratio of 2:1:1.Based on this topology,this paper proposes a DTP four-level space vector pulse width modulation(DTP-FL SVPWM)strategy.First,two identical three-phase four-level space vector diagrams are constructed and divided.Then,three adjacent vectors nearest to the reference vector in each diagram are selected for the vector synthesis to guarantee high modulation precision and low switching frequency.Furthermore,to avoid the modulation error caused by the voltage deviation,the proposed DTP-FL SVPWM strategy is further optimized through unified duty ratio compensation(UDRC).The effectiveness of the proposed strategy is verified through experiments.
基金supported by the National Natural Science Foundation of China (No. 20977075)the National High Technology Research and Development Program of China (863) (Nos. 2010AA064901, 2010AA064902)
文摘The pollution status and characteristics of PAEs（phthalate esters） were investigated in indoor air of offices, and PAEs of both gas-phase and particulate-phase were detected in all the samples. The concentration（sum of the gas phase and the particulate phase） was4748.24 ng/m3, ranging between 3070.09 and 6700.14 ng/m3. Diethyl phthalate, dibutyl phthalate, and di（2-ethylhexyl） phthalate were the most abundant compounds, together accounting for 70% of the ∑ 6PAEs. Dividing the particulate-phase PAEs into four size ranges（〈 2.5, 2.5–5, 5–10, 〉 10 μm）, the result indicated that PAEs in PM2.5were the most abundant,with the proportion of 72.64%. In addition, the PAE concentration in PM2.5correlated significantly with the total particulate-phase PAEs（R2= 0.85）. Thus, the amount of PAEs in PM2.5can be estimated from the total amount of particulate-phase PAEs using this proportion. In a comparison between the offices and a newly decorated study room, it was found that pollution characteristics were similar between these two places. Thus, it is implied that the PAE concentration decreased by 50% 2 yr after decorating.
基金supported by the National Key Research and Development Program of China(No.2016YFC0207103)the National Natural Science Foundation of China(No.21607127)Koninklijke Philips N.V.(No.BB3-2016-01)
文摘Phthalate esters（PAEs） are widely used as plasticizers in consumer products. PAEs are a group of environmental hormone which disrupts human and animals＇ endocrine systems. Different occupational groups are exposed to various levels of PAEs. In the present study, four typical occupational groups were chosen, including doctors, college teachers, college students, and drivers who worked in public traffic system. In order to understand the exposure levels to PAEs via inhalation, air samples were collected from multiple microenvironments including indoor and outdoor in Hangzhou to measure the gas and particle concentrations of six PAEs, together with time spent in different microenvironments of these four groups. A comprehensive PAEs exposure model was built to estimate the daily PAEs exposure through inhalation, oral and dermal pathways. The Monte Carlo simulation results show that doctors were exposed to the highest level of PAEs, and consequently had the highest health risk among these four occupational groups. In contrast, college students had the lowest health risk. By setting the exposure level of staying in residences as the baseline, doctors and drivers were two occupations exposed to high PAEs health risk. Di-（2-ethylhexyl） phthalate（DEHP） was the largest contributor among the six phthalates, posing moderate health risk（10-5–10-6） to every occupation. For traffic microenvironments alone, the total exposure levels for different transportation modes were in the descending order of busses, cars, cabs, tubes, motor bikes, and walking.
基金supported by the National Key R&D Program of China(2017YFA0205600)the National Natural Science Foundation of China(81690264,81821004).
文摘Currently,the cancer immunotherapy has made great progress while antitumor vaccine attracts substantial attention.Still,the selection of adjuvants as well as antigens are always the most crucial issues for better vaccination.In this study,we proposed a biomimetic antitumor nanovaccine based on biocompatible nanocarriers and tumor cell membrane antigens.Briefly,endogenous calcium pyrophosphate nanogranules with possible immune potentiating effect are designed and engineered,both as delivery vehicles and adjuvants.Then,these nanocarriers are coated with lipids and B16-OVA tumor cell membranes,so the biomembrane proteins can serve as tumor-specific antigens.It was found that calcium pyrophosphate nanogranules themselves were compatible and possessed adjuvant effect,while membrane proteins including tumor associated antigen were transferred onto the nanocarriers.It was demonstrated that such a biomimetic nanovaccine could be well endocytosed by dendritic cells,promote their maturation and antigen-presentation,facilitate lymph retention,and trigger obvious immune response.It was confirmed that the biomimetic vaccine could induce strong T-cell response,exhibit excellent tumor therapy and prophylactic effects,and simultaneously possess nice biocompatibility.In general,the present investigation might provide insights for the further design and application of antitumor vaccines.
文摘Reducing oxidative stress and hepatoprotective effect of Pu-erh tea water extracts on rats fed with high-fat diet were researched for explaining health care of Pu-erh tea.Fifty SD rats were divided into five groups.The body weight was measured once a day.The malondialdehyde(MDA)and glucose(Glu)levels and the activities of alanine aminotransferase(ALT),aspartate aminotransferase(AST),nitric oxide synthase(NOS),and pyruvate kinase(PK)in serum were determined.Furthermore,the hepatic glycogen level(HGL)and the activities of hepatic total superoxide dismutase(T-SOD),catalase(CAT),and glutathione peroxidase(GSH-Px)were also measured after continuous administration for 12 weeks.The result demonstrated that Pu-erh extract caused the decreases in body weight,fat index,MDA and NOS levels,and the increases in hepatic T-SOD,CAT and GSH-Px activities,indicating that the extract may be due to inhibiting the increases of body weight and fat index,reducing oxidant stress state and inhibiting lipid peroxidation,thus decreasing the activities of ALT and AST,and protecting the liver in rat.Meanwhile,the extracts could increase the production of hepatic glycogen and the activity of PK,and reduce glucose level,protecting the liver from the diseases associated with type II diabetes.
基金supported by the National Natural Science Foundation of China[81690264]the National Basic Research Program of China[2015CB932100,2017YFA0205600]the Innovation Team of the Ministry of Education[BMU20110263]。
文摘Small GTPase is a kind of GTP-binding protein commonly found in eukaryotic cells.It plays an important role in cytoskeletal reorganization,cell polarity,cell cycle progression,gene expression and many other significant events in cells,such as the interaction with foreign particles.Therefore,it is of great scientific significance to understand the biological properties of small GTPases as well as the GTPase-nano interplay,since more and more nanomedicine are supposed to be used in biomedical field.However,there is no review in this aspect.This review summarizes the small GTPases in terms of the structure,biological function and its interaction with nanoparticles.We briefly introduced the various nanoparticles such as gold/silver nanoparticles,SWCNT,polymeric micelles and other nano delivery systems that interacted with different GTPases.These current nanoparticles exhibited different pharmacological effect modes and various target design concepts in the small GTPases study.This will help to elucidate the conclusion that the therapeutic strategy targeting small GTPases might be a new research direction.It is believed that the in-depth study on the functional mechanism of GTPases can provide insights for the design and study of nanomedicines.
基金Animal Ethics Committees at the Institute of Zoology, Chinese Academy of Sciences approved the ethics and protocol (IOZ14001) for the collection, handling, and husbandry of the study animalsBI J. H. (No.31660615) and SUN B. J. (No. 31870391 and 31500324) are supported by grants from the National Natural Science Foundation of China
文摘Sympatric reptiles are the ideal system for investigating temperature-driven coexistence. Understanding thermally physiological responses of sympatric lizards is necessary to reveal the physiological mechanisms that underpin the sympatric occurrence of reptiles. In this study, we used three lizard species, Eremias argus, E. multiocellata, and Phrynocephalus przewalskii, which are sympatric in the Inner Mongolia desert steppe, as a study system. By comparing their resting metabolic rates(RMR) and locomotion at different body temperatures, we aimed to better understand their physiological responses to thermal environments, which may explain the sympatric occurrence of these lizards. Our results showed that E. argus had significantly higher RMR and sprint speed than E. multiocellata, and higher RMR than P. przewalskii. In addition, the optimal temperature that maximized metabolic rates and locomotion for E. argus and E. multiocellata was 36°C, whereas for P. przewalskii it was 39°C. Our study revealed the physiological responses to temperatures that justify the sympatric occurrence of these lizards with different thermal and microhabitat preferences and active body temperatures. Eremias argus and E. multiocellata, which have lower body temperatures than P. przewalskii, depend on higher RMR and locomotion to compensate for their lower body temperatures in field conditions. Our study also highlights the importance of using an integrative approach, combining behavior and physiology, to explore the basis of sympatric occurrence in ectothermic species.
基金This work was supported by the National Natural Science Foundation of China(Grant No.81670531)Hubei Key Laboratory of Edible Wild Plants Conservation and Utilization(Grant No.EWPL201804).
文摘Objective:Therapy for hepatocellular carcinoma(HCC)is a major challenge,and targeted therapies provide only a modest benefit in terms of overall survival.Treatment with antibodies to programmed cell death protein 1(PD-1)/PD-L1 can restore the functions of tumor-infiltrating T cells in HCC and has shown clinical efficacy in 20%of patients with advanced HCC.Novel approaches are urgently needed to treat HCC and to augment the efficacy of immunotherapy.Methods:Tumor-bearing mice were treated with Agrocybe aegerita galectin(AAGL)alone or in combination with anti-PD-1,and the tumor sizes and lifespans of mice were determined.Transcriptome analysis,cytokine analysis,flow cytometry analysis of the number and proportion of immune cell subsets in the liver and spleen,and molecular and cellular analyses of tumors were used to define the underlying mechanisms.Results:AAGL significantly inhibited the growth of liver tumors in a dose-dependent manner.Furthermore,AAGL increased the expression of multiple cytokines and chemokines in tumor-bearing mouse livers;this effect was associated with the activation and migration of T cells and macrophages,in agreement with the in vitro results.Importantly,the aggregation of T cells and macrophages induced by AAGL in tumor-bearing mouse livers clearly enhanced the response to PD-1 blockade immunotherapy.Conclusions:The results showed that AAGL induced the activation and migration of lymphocytes to the liver,and that the combination of AAGL and anti-PD-1 may be a promising strategy for HCC treatment.
基金by the National Natural Science Foundation of China(Nos.81872809,82073786)the Beijing Natural Science Foundation(L212013).
文摘The combination regimen of trastuzumab(Tras)plus Nab-paclitaxel(Nab)is recommended to treat HER2-positive(HER2+)cancers.However,they exert effects in different mechanisms:Tras need to stay on cell membranes,while Nab need to be endocytosed,therefore the concurrent combination regimen may not be the best one in HER2+tumors treatment.Caveolin-1(Cav-1)is a key player in mediating their endocytosis and is associated with their efficacy,but few researches noticed the opposite effect of Cav-1 expression on the combination efficacy.Herein,we systematically studied the Cav-1 expression level on the combination efficacy and proposed an optimized and clinically feasible combination regimen for HER2+Cav-1 High tumor treatment.In the regimen,lovastatin(Lova)was introduced to modulate the Cav-1 expression and the results indicated that Lova could downregulate Cav-1 expression,increase Tras retention on cell membrane and enhance the in vitro cytotoxicity of Tras in HER2+Cav-1 High cells but not in HER2+Cav-1 Low cells.Therefore,by exchanging the dosing sequence of Nab and Tras,and by adding Lova at appropriate time points,the precise three-drug-sequential regimen(PTDS,Nab(D1)-Lova(D2)-Lova&Tras(D2+12 h))was established.Compared with the concurrent regimen,the PTDS regimen exhibited a higher in vitro cytotoxicity and a stronger tumor growth inhibition in HER2+Cav-1 High tumors,which might be a promising combination regimen for these patients in clinics.
基金support by the Hi-Tech Research and Development Program(863) of China(No.2010AA064902)the National Key Technologies R&D Program(No.2016YFC0207100)+1 种基金the National Natural Science Foundation of China(No.21207116)the Brain Bridge project with Philips(No.BB3-2016-01)
文摘Based on previous research, the sampling and analysis methods for phthalate esters （PAEs） were improved by increasing the sampling flow of indoor air from 1 to 4 L/min, shortening the sampling duration from 8 to 2 hr. Meanwhile, through the optimization of chromatographic conditions, the concentrations of 9 additional PAE pollutants in indoor air were measured. The optimized chromatographic conditions required a similar amount of time for analysis as before, but gave high responsivity, the capability of simultaneously distinguishing 15 kinds of PAEs, and a high level of discrimination between individual sample peaks, as well as stable peak generation. The recovery rate of all gas-phase and particle-phase samples of the 15 kinds of PAEs ranged from 91.26% to 109.42%, meeting the quantitative analysis requirements for indoor and outdoor air sampling and analysis. For the first time, investigation of the concentration levels as well as characteristics of 15 kinds of PAEs in the indoor air from four different traffic micro-environments （private vehicles, busses, taxis and subways） was carried out, along with validation of the optimized sampling and analytical method. The results show that all the 9 additional PAEs could be detected at relatively high pollution levels in the indoor air from the four traffic micro-environments. As none of the pollution levels of the 15 kinds of PAEs in the indoor air from the 4 traffic micro-environments should be neglected, it is of great significance to increase the types of PAEs able to be detected in indoor air.
文摘The cost of highway is affected by many factors.Its composition and calculation are complicated and have great ambiguity.Calculating the cost of highway according to the traditional highway engineering estimation method is a completely tedious task.Constructing a highway cost prediction model can forecast the value promptly and improve the accuracy of highway engineering cost.This work sorts out and collects 60 sets of measured data of highway engineering;establishes an expressway cost index system based on 10 factors,including main route mileage,roadbed width,roadbed earthwork,and number of bridges;and processes the data through principal component analysis(PCA)and hierarchical cluster analysis.Particle swarm optimization(PSO)is used to obtain the optimal parameter combination of the regularization parameter c and the kernel function width coefficientin least squares support vector machine(LSSVM).Results show that the average relative and mean square errors of the PCA-PSO-LSSVM model are 0.79%and 10.01%,respectively.Compared with BP neural networks and unoptimized LSSVM model,the PCA-PSO-LSSVM model has smaller relative errors,better generalization ability,and higher prediction accuracy,thereby providing a new method for highway cost prediction in complex environments.
基金supported by a grant from the National Science Foundation of China (No. 20977075)the National High Technology Research and Development Program of China (863) (No. 2010AA064902)
文摘The concentrations of phthalate esters（PAEs） in Chinese hospitals were investigated by simultaneously determining concentrations of gas- and particle-phase PAEs. PAEs were detected in two third-class first-grade hospitals, two second-class first-grade hospitals, and a community health service center. Hospital drugstores had the highest concentration（24.19 μg/m3）, which was 1.54 times that of newly decorated houses. The second highest concentration was found in the transfusion rooms, averaging 21.89 μg/m3; this was followed by the concentrations of PAEs in the nurse＇s workstations, the wards, and the doctor＇s offices, with mean concentrations of 20.66, 20.0, and 16.92 μg/m3, respectively. The lowest concentrations were found in the hallways（16.30 μg/m3）. Of the six different kinds of PAEs found, major pollutants included diethyl phthalates, dibutyl phthalates, butylbenzyl phthalates and di（2-ethylhexyl） phthalates, comprising more than 80% of all PAEs present.Meanwhile, a comparison between different wards showed that PAE concentrations in the maternity wards were 1.63 times higher than in the main wards. Based on known health hazards, our results suggest that the PAEs seriously influence the health of the pregnant women and babies; therefore, it is of great importance to take the phthalate concentrations in hospitals into consideration. In addition, hospital indoor air was more seriously contaminated than the air of newly decorated houses.
基金The National Natural Science Foundation of China(Grants No.31671017,81872809)the National Key Research and Development Program of China(Grants No.2017YFA0205600)Beijing Natural Science Foundation(Grants No.7162108)。
文摘In order to realize the combination of chemotherapy and immunotherapy,a reduction-responsive paclitaxel(PTX)prodrug PEG-SS-PTX was synthesized and used as a carrier to encapsulate IDO inhibitor CY-1-4 for preparing PEG-SS-PTX/CY-1-4 NPs.PEG-SS-PTX/CY-1-4 NPs were evaluated by cytotoxicity,immunogenic cell death(ICD)induction ability and anti-tumor efficacy.Dynamic light scattering(DLS)results showed that the size of PEG-SS-PTX/CY-1-4 NPs was about 149 nm.In vitro experiments indicated that its cytotoxicity was in a concentration-dependent manner,and it induced the ICD of B16-F10 cells.In vivo studies in melanoma mouse model indicated that PEG-SS-PTX/CY-1-4 NPs significantly inhibited the tumor growth and reduced the expression of IDO in tumor tissues.Moreover,it increased the rate of CD8+T cells in the spleen.In summary,PEG-SS-PTX/CY-1-4 NPs achieved good anti-tumor effects and reduced the dose of chemotherapy drugs,which was a safe and effective combined delivery system.
基金The National Key R&D Program of China(Grant No.2017YFA0205600)the National Natural Science Foundation of China(Grant No.81690264,81573359 and 81703441)。
文摘The application of nanomedicines in oral drug delivery effectively promotes the drug absorption and transportation through enterocytes.Nevertheless,the absence of mechanism studies on efficacy and safety limits their final translation in humans.Although the vesicular trafficking has been verified as the general character for transport of nanomedicines,the deeper mechanism in molecular mechanism is still unclear.Moreover,the cellular transport of nanomedicines is a dynamic process involved by different organelles and components.However,most of existing studies just pay attention to the static location of nanomedicines,but neglect the dynamic biological effects on cells caused by them.Here,we prepared gold nanoparticles(Au NPs)as the model and cultured epithelial cell monolayer to explore the nano-bio interactions at the molecular level.The traditional pharmacological inhibition strategy and subcellular imaging technology elucidated the macropinocytosis/endosome/MVB/lysosome pathway during the transportation of Au NPs.Proteomics strategy based on mass spectrometry(MS)was utilized to identify and quantify proteins involved in the cellular transport of nanomedicines.Multiple proteins related to subcellular structure,signal transduction,energy transformation and metabolism regulation were demonstrated to be regulated by nanoparticle transport.These alterations of protein expression clarified the effects of intracellular proteins and verified the conventional findings.More importantly,it revealed a feedback mechanism of cells to the nano-trafficking.We believed that these new regulatory mechanisms provided new insights into the efficient transport of nanomedicines through epithelial barriers.
基金National Natural Science Foundation of China(Grant No.81690264)the National Key Research and Development Program of China(Grant No.2017YFA0205600)Beijing Natural Science Foundation(Grant No.7162108)
文摘The interplay among diverse cell populations in the tumor microenvironment contributes to tumor progression.Targeting to different cell populations might result in improved therapeutic effects on malignant tumors.Integrins high express on many kinds of tumor cells,and VEGF has a strong effect on tumor angiogenesis.Therefore,based on tumor cells and angiogenesis,we fabricated integrin-targeting cRGD-DOX nanoparticles and combined them with the anti-VEGF antibody bevacizumab.We evaluated the antitumor effect of this combination therapy in an integrin-overexpressing MDA-MB-231 tumor model.The cRGD-DOX nanoparticles were effectively uptake by MDA-MB-231 cells and the uptake was related to the expression of integrinin;cRGD-DOX nanoparticles showed less cytotoxic than free DOX;Bevacizumab did not show significant cytotoxicity against MDA-MB-231 cells at concentrations less than 1 mg/mL.The in vivo results showed that bevacizumab could reduce tumor interstitial fluid pressure;the combination of bevacizumab and cRGD-DOX nanoparticles showed enhanced antitumor effects compared with the corresponding single-agent treatments.These findings suggested the combination of angiogenesis antibody and integrin-targeting nanoparticle loaded with a cytotoxic drug was a promising cancer treatment regimen.
