Nano transdermal system combining mitochondria-targeting cerium oxide nanoparticles with all-trans retinoic acid for psoriasis

Psoriasis is an inflammatory skin disease that is intricately linked to oxidative stress.Antioxidation and inhibition of abnormal proliferation of keratinocytes are pivotal strategies for psoriasis.Delivering drugs with these effects to the site of skin lesions is a challenge that needs to be solved.Herein,we reported a nanotransdermal delivery system composed of all-trans retinoic acid(TRA),triphenylphosphine(TPP)-modified cerium oxide(CeO2)nanoparticles,flexible nanoliposomes and gels(TCeO_(2)-TRA-FNL-Gel).The results revealed that TCeO_(2)synthesized by the anti-micelle method,with a size of approximately 5 nm,possessed excellent mitochondrial targeting ability and valence conversion capability related to scavenging reactive oxygen species(ROS).TCeO_(2)-TRA-FNL prepared by the film dispersion method,with a size of approximately 70 nm,showed high drug encapsulation efficiency(>96%).TCeO_(2)-TRA-FNL-Gel further showed sustained drug release behaviors,great transdermal permeation ability,and greater skin retention than the free TRA.The results of in vitro EGF-induced and H2O2-induced models suggested that TCeO_(2)-TRA-FNL effectively reduced the level of inflammation and alleviated oxidative stress in HaCat cells.The results of in vivo imiquimod(IMQ)-induced model indicated that TCeO_(2)-TRA-FNL-Gel could greatly alleviate the psoriasis symptoms.In summary,the transdermal drug delivery system designed in this study has shown excellent therapeutic effects on psoriasis and is prospective for the safe and accurate therapy of psoriasis.

Important population viability analysis parameters for giant pandas(Aliuropoda melanoleuca)

Population viability analysis(PVA) is a tool to evaluate the risk of extinction for endangered species and aid conservation decision-making.The quality of PVA output is dependent on parameters related to population dynamics and life-history;however,it has been difficult to collect this information for the giant panda(Aliuropoda melanoleuca),a rare and endangered mammal native to China,confined to some 30 fragmented habitat patches.Since giant pandas are long-lived,mature late,have lower reproductive rates,and show little sexual dimorphism,obtaining data to perform adequate PVA has been difficult.Here,we develop a parameter sensitivity index by modeling the dynamics of six giant panda populations in the Minshan Mountains,in order to determine the parameters most influential to giant panda populations.Our data shows that the giant panda populations are most sensitive to changes in four female parameters:initial breeding age,reproductive rate,mortality rate between age 0 and 1,and mortality rate of adults.The parameter sensitivity index strongly correlated with initial population size,as smaller populations were more sensitive to changes in these four variables.This model suggests that demographic parameters of females have more influence on the results of PVA,indicating that females may play a more important role in giant panda population dynamics than males.Consequently,reintroduction of female individuals to a small giant panda population should be a high priority for conservation efforts.Our findings form a technical basis for the coming program of giant panda reintroduction,and inform which parameters are crucial to successfully and feasibly monitoring wild giant panda populations.

Important population viability analysis parameters for giant pandas(Aliuropoda melanoleuca)

Population viability analysis(PVA)is a tool to evaluate the risk of extinction for endangered species and aid conservation decision-making.The quality of PVA output is dependent on parameters related to population dynamics and life-history;however,it has been difficult to collect this information for the giant panda(Aliuropoda melanoleuca),a rare and endangered mammal native to China,confined to some 30 fragmented habitat patches.Since giant pandas are long-lived,mature late,have lower reproductive rates,and show little sexual dimorphism,obtaining data to perform adequate PVA has been difficult.Here,we develop a parameter sensitivity index by modeling the dynamics of six giant panda populations in the Minshan Mountains,in order to determine the parameters most influential to giant panda populations.Our data shows that the giant panda populations are most sensitive to changes in four female parameters:initial breeding age,reproductive rate,mortality rate between age 0 and 1,and mortality rate of adults.The parameter sensitivity index strongly correlated with initial population size,as smaller populations were more sensitive to changes in these four variables.This model suggests that demographic parameters of females have more influence on the results of PVA,indicating that females may play a more important role in giant panda population dynamics than males.Consequently,reintroduction of female individuals to a small giant panda population should be a high priority for conservation efforts.Our findings form a technical basis for the coming program of giant panda reintroduction,and inform which parameters are crucial to successfully and feasibly monitoring wild giant panda populations.

Estimation of Drought Change Trends in Northeast China in 2020-2050 and Its Impact on Maize Yield

Based on the results of nine Coupled Model Intercomparison Project Phase 5 (CMIP5) coupling models, the temperature and precipitation data of 114 stations in Northeast China were compared and analyzed. The simulation effect of CMIP5 model on precipitation and temperature in Northeast China was evaluated. The research shows that the Geophysical Fluid Dynamics Laboratory Earth System Models (GGFDL-ESM2G) have the best simulation effect on precipitation and temperature in Northeast China. Based on the SPEI index, the relationship between the drought trend of maize growing season and the yield change rate of maize in Northeast China was analyzed, and the future drought (2020-2050) and corn yield in Northeast China were estimated. The cumulative Standardized Precipitation Evapotranspiration Index (SPEI) analysis of the northeast maize growing season (May-September) shows that the drought in the northeastern region showed an intensifying trend from 1980 to 2010, especially in the first ten years of the 21st century. The cumulative SPEI index has a significant positive correlation with the yield of maize in Northeast China, and has a certain indicator effect on the yield of maize in Northeast China. The three scenarios of GFDL-ESM2G model show that under the three scenarios of Representative Concentration Pathways (RCP), the warming in Northeast China is significant;under the RCP4.5 scenario, the precipitation in Northeast China is increasing;in the RCP2.6 and RCP8.5 climate scenarios, precipitation is presented and reduces the trend of drought. Estimates of drought trends in Northeast China show that under the RCP4.5 climate scenario, the drought in Northeast China showed a slowing trend from 2020 to 2050. Under the RCP2.6 and RCP8.5 climate scenarios, the drought in Northeast China showed an increasing trend. Under the RCP2.6 and RCP8.5 climate scenarios, the yield change rate of maize in Northeast China showed a downward trend, indicating that climate warming caused the drought in Northeast China to increase, which had a negative impact on corn yield increase. In severe drought years, drought may cause northeast corn production seriously reduced. However, under the RCP4.5 scenario, drought has little effect on corn yield.

μ-opioid receptor agonist facilitates circulating tumor cell formation in bladder cancer via the MOR/AKT/Slug pathway:a comprehensive study including randomized controlled trial

Background:μ-opioid receptor agonists(MORAs)are indispensable for analgesia in bladder cancer(BC)patients,both during surgery and for chronic pain treatment.Whether MORAs affect BC progression and metastasis remains largely unknown.This study focused on the effects of MORAs on the formation of circulating tumor cells(CTCs)in BC and aimed to provide potential therapeutic targets,which would retain the pain-relieving effects of MORAs in BC patients without sacrificing their long-term prognosis.Methods:Different preclinical models were used to identify the effects of MORAs on the progression of BC.A novel immunocapture microfluidic chip was utilized to analyze whether MORAs affected the number of CTCs in mouse models and clinical BC patients.Bioinformatic analyses,total transcriptome sequencing,and molecular biology methods were then used to investigate the underlying mechanisms in these models and in BC cell lines.Results:Mouse models of hematogenous metastasis and in situ BC demonstrated that tumor metastasis was significantly increased after MORA treatment.A significant increase in the number of mesenchymal and/or epithelial CTCs was detected after MORA treatment in both the mouse models and clinical trial patients.Mechanistically,MORAs facilitated the formation of CTCs by activating the MOR/PI3K/AKT/Slug signaling pathway,hereby promoting the epithelialmesenchymal transition(EMT)of BC cells,as knockdown of MOR,Slug or blockade of PI3K inhibited the EMT process and CTC formation.Conclusion:MORAs promoted BC metastasis by facilitating CTC formation.The EMT-CTC axis could be targeted for preventive measures during MORA treatment to inhibit the associated tumormetastasis or recurrence in BC patients.

基于微流控技术的循环肿瘤细胞分析研究进展

癌症的精准诊疗是提高癌症患者生存率和生存质量的重要手段.液体活检通过采用非侵入采样方式,获取肿瘤病人全面、准确、实时的基因组、转录组及蛋白组等生物学信息,是一种新兴的癌症诊断技术,对癌症精确诊断、个体化治疗、预后评估等方面具有重要意义.循环肿瘤细胞(CTC)是一种从实体瘤组织脱落进入外周血的肿瘤细胞,因能提供完整的细胞生物学信息,是最具应用前景的液体活检靶标.然而, CTC的数量极其稀少、异质性强、所处外周血环境复杂等特点,给CTC的富集和分析带来了巨大的技术挑战.本文将总结本课题组近年来发展的基于CTC液体活检策略,着重讨论在CTC识别、富集与单细胞分析等方面的研究进展.

Life history pattern and fitness of an endangered Hainan Eld’s deer population

Understanding life history patterns,individual fitness and population fitness can assist with conservation of endangered species.Field data on life history traits(i.e.age specific fecundity,age specific mortality,age at first reproduction,litter size and adult life expectancy)were collected from 121 Hainan Eld’s deer(Cervus eldi hainanus Thomas,1918),an in situ herd of an endemic,rare and endangered cervid inhabiting Bangxi Natural Reserve of Hainan Island,from 1990 to 2002.First,we constructed a dynamic life table to analyze the life history pattern of the population,which showed that the difference between the average lifespan of males and females was not significant(P>0.05),and that the difference between the average lifespan of the whole Hainan Eld’s deer population and that of other Eld’s deer populations living in South Asia(P>0.05),North America(P>0.05)and Europe(P>0.05)was not significant.Second,we used individual reproductive success or number of offspring of a male over its lifetime to estimate male individual fitness.Statistic analysis showed that male individual fitness was not significantly correlated with total antler velvet mass.Third,we used the population intrinsic rate of increase to measure population fitness,and population fitness of Hainan Eld’s deer was compared with similar indexes of 5 other cervid species.Hainan Eld’s deer population fitness index was 0.012,the second lowest value relative to other cervids.Results indicated that this rare species is still endangered and is in need of additional protection.

Antibody-engineered red blood cell interface for high-performance capture and release of circulating tumor cells

Circulating tumor cells(CTCs),as important liquid biopsy target,can provide valuable information for cancer progress monitoring and individualized treatment.However,current isolation platforms incapable of balancing capture efficiency,specificity,cell viability,and gentle release have restricted the clinical applications of CTCs.Herein,inspired by the structure and functional merits of natural membrane interfaces,we established an antibody-engineered red blood cell(RBC-Ab)affinity interface on microfluidic chip for high-performance isolation and release of CTCs.The lateral fluidity,pliability,and anti-adhesion property of the RBC microfluidic interface enabled efficient CTCs capture(96.5%),high CTCs viability(96.1%),and high CTCs purity(average 4.2-log depletion of leukocytes).More importantly,selective lysis of RBCs by simply changing the salt concentration was utilized to destroy the affinity interface for efficient and gentle release of CTCs without nucleic acid contamination.Using this chip,CTCs were successfully detected in colon cancer samples with 90%sensitivity and 100%specificity(20 patients and 10 healthy individuals).After the release process,KRAS gene mutations of CTCs were identified from all the 5 cancer samples,which was consistent with the results of tissue biopsy.We expect this RBC interface strategy will inspire further biomimetic interface construction for rare cell analysis.

Integrated microfluidic devices for in vitro diagnostics at point of care

Given the continuous and growing demand for point of care(POC)diagnostic tests,attention has been shifted toward integration and miniaturization of laboratory protocols into“sample-in-answer-out”devices.Microfluidic technologies have been considered an ideal solution to address the requirements of POC diagnostics since many laboratory functions can be miniaturized and incorporated onto a single integrated chip.In this review,we summarize the advances of integrated microfluidic devices for POC diagnostics in the last 3 years.Particularly,we summarize current materials used for microfluidic chip fabrication,discuss the innovation of versatile integrated microfluidic devices,especially the strategies for simplifying sample preparation in manual or self-driven systems,and new detection methods of microfluidic chips.In addition,we describe new integrated microfluidic devices for POC diagnostics of protein-targeted immunodiagnostics,nucleic acid molecular tests,and small molecule metabolites analysis.We also provide future perspectives and current challenges for clinical translation and commercialization of these microfluidic technologies.

Amplified visualization and function exploration of exosomal protein-specific glycosylation using hybridization chain reaction from non-functional epitope

Exosomal glycoproteins play significant roles in many physiological and pathological procedures. However, the current methods for studying exosomal glycoproteins have low sensitivity or can affect exosomal biological function. Herein, we developed a proximity dual-tagging strategy using an induced hybridization chain reaction(HCR) from the target’s non-functional epitope for amplified visualization and functional exploration of exosomal protein-specific glycosylation. This strategy leverages dualtagging based on the aptamer with little influence on target function and metabolic glycan labelling, and the rigid product and high sensitivity of HCR. The method improves the signal of visualizing exosomal PD-L1(exo PD-L1) by 7.7-fold compared with the signal without HCR amplification without affecting the natural exo PD-L1/PD-1 interaction. As a result, we verified that the interaction between exo PD-L1 and PD-1 positive cells is positively correlated to the glycosylation level of exo PD-L1. Overall,we have developed a sensitive method with little functional influence to visualize exosomal protein-specific glycosylation in situ,offering a powerful tool for studying the biological implications of exosomal glycoproteins.

Crosstalk-free colloidosomes for high throughput single-molecule protein analysis

Droplet microfluidics is a powerful platform for high-throughput single-molecule protein analysis.However,the issues of coalescence and crosstalk of droplets compromise the accuracy of detection and hinder its wide application.To address these limitations,a novel colloidosome-based method was presented by combining a Pickering emulsion with droplet microfluidics for single-molecule protein analysis.Utilizing the self-assembly of easily synthesized colloidal surfactant F-SiO2 NPs at the water/oil interface,the colloidosomes are rigidly stabilized and can effectively avoid the leakage of fluorescent molecules.The crosstalk-free colloidosomes enable high-throughput single-molecule protein analysis,including heterogenous dynamic studies and digital detection.As a robust and accurate method,colloidosome-based microfluidics is promising as a powerful tool for a wide variety of applications,such as directed enzyme evolution,digital enzyme-linked immunosorbent assay(ELISA),and screening of antibiotics.

Dispen-Seq: a single-microparticle dispenser based strategy towards flexible cell barcoding for single-cell RNA sequencing

Single-cell RNA sequencing(sc RNA-seq)has become one of the most powerful tools to understand the heterogeneity of biological systems.While barcoding strategies have revolutionized the field of high-throughput sc RNA-seq,it is still challenging to achieve highly efficient,direct and universal cell barcoding with cost-effectiveness and minimal sample loss.Herein,a single micro-particle dispenser approach for rapid single barcode bead/cell manipulation and pairing,enabling highly efficient cell barcoding for sc RNA-seq(Dispen-Seq)was developed.Notably,Dispen-Seq provides a versatile platform which can enrich cell subgroups of interest while unlimited by input sample amounts,and can respond to changes in sample composition with high resolution and reproducibility.It is anticipated that Dispen-Seq will increase the scope of sc RNA-seq from academic research to practical applications.