Multiple factors to assist human-derived induced pluripotent stem cells to efficiently differentiate into midbrain dopaminergic neurons

Midbrain dopaminergic neurons play an important role in the etiology of neurodevelopmental and neurodegenerative diseases.They also represent a potential source of transplanted cells for therapeutic applications.In vitro differentiation of functional midbrain dopaminergic neurons provides an accessible platform to study midbrain neuronal dysfunction and can be used to examine obstacles to dopaminergic neuronal development.Emerging evidence and impressive advances in human induced pluripotent stem cells,with tuned neural induction and differentiation protocols,makes the production of induced pluripotent stem cell-derived dopaminergic neurons feasible.Using SB431542 and dorsomorphin dual inhibitor in an induced pluripotent stem cell-derived neural induction protocol,we obtained multiple subtypes of neurons,including 20%tyrosine hydroxylase-positive dopaminergic neurons.To obtain more dopaminergic neurons,we next added sonic hedgehog(SHH)and fibroblast growth factor 8(FGF8)on day 8 of induction.This increased the proportion of dopaminergic neurons,up to 75%tyrosine hydroxylase-positive neurons,with 15%tyrosine hydroxylase and forkhead box protein A2(FOXA2)co-expressing neurons.We further optimized the induction protocol by applying the small molecule inhibitor,CHIR99021(CHIR).This helped facilitate the generation of midbrain dopaminergic neurons,and we obtained 31-74%midbrain dopaminergic neurons based on tyrosine hydroxylase and FOXA2 staining.Thus,we have established three induction protocols for dopaminergic neurons.Based on tyrosine hydroxylase and FOXA2 immunostaining analysis,the CHIR,SHH,and FGF8 combined protocol produces a much higher proportion of midbrain dopaminergic neurons,which could be an ideal resource for tackling midbrain-related diseases.

PD-L1 expression and its effect on clinical outcomes of EGFRmutant NSCLC patients treated with EGFR-TKIs

Objective:Epidermal growth factor receptor(EGFR)activation was reported to upregulate programmed death-ligand 1(PD-L1)expression in lung cancer cells and subsequently contribute to immune escape,indicating its critical role in EGFR-driven lung tumors.This study characterized PD-L1 expression in patients with surgically resected EGFR-mutant non-small cell lung cancer(NSCLC).The effect of PD-L1 expression on clinical outcomes was also investigated in advanced EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors(TKIs).Methods:In total,73 patients with surgically resected NSCLC and EGFR mutations were identified.PD-L1 expression and CD8+tumor-infiltrating lymphocyte(TIL)density were assessed by immunohistochemistry.A literature review of publications that assessed the predictive and prognostic value of PD-L1 expression in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs was performed.Results:Nineteen(26.0%)patients were positive for PD-L1 expression,which was significantly associated with concomitant KRAS mutation(P=0.020)and marginally associated with higher CD8+TILs density(P=0.056).Positive PD-L1 expression was associated with markedly inferior overall survival(OS)in multivariate analysis(P=0.032).The combination of PD-L1 and CD8+TILs expression could be used to stratify the population into three groups with distinct prognoses.A meta-analysis of six publications showed that positive PD-L1 expression was not associated with OS[hazard ratio(HR)=0.90;95%confidence interval(CI),0.42–1.38]or progression-free survival(HR=1.03;95 CI,0.73–1.33)in advanced EGFR-mutant NSCLC patients receiving EGFR-TKIs.Conclusions:PD-L1 expression tended to correlate with CD8+TIL expression,concomitant KRAS mutation,and poor survival in surgically resected EGFR-mutant NSCLC.PD-L1 expression was neither the predictive nor the prognostic factor in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs.

Tooth Position and Deformation of Flexspline Assembled with Cam in Harmonic Drive Based on Force Analysis

Deformation of the flexspline is the basis of analyzing tooth trajectory and designing tooth profile.Considering the tooth influence on the position of equivalent neutral layer,a piecewise method for calculating the deformation of flexspline assembled with a cam wave generator is presented in this paper.Firstly,a mechanic model of a ring of uniform thickness in contact with a rigid cam is established.The displacements of the ring inside and outside an unknown wrapping angle are determined by the geometric constraints of the cam profile and the equilibrium rela-tionship,respectively.Meanwhile,the wrapping angle is solved according to the boundary conditions.The assembly forces are derived to investigate the circumferential elongation and strain.Then,considering the tooth effects on the neutral layer of flexspline,the tooth is positioned on the equivalent neutral layer,which is the non-elongation layer within one gear pitch but offset from the geometric mid-layer.The equivalent neutral layer is positioned by the empirical formula of the offset ratio,which is summarized by the orthogonal simulation on finite element models of racks.Finally,finite element models of a ring-shaped and a cup-shaped flexspline assembled with elliptical cam are established to verify the effectiveness and accuracy of the piecewise method.The results show that,compared with the geometric method,the tooth positioning deviation calculated by the piecewise method can be reduced by about 70%with a more accurate deformation description from the geometric condition and mechanic condition inside and outside the wrapping angle.

Regulating the growth of lithium dendrite by coating an ultra-thin layer of gold on separator for improving the fast-charging ability of graphite anode

With the ever-growing application of lithium-ion batteries(LIBs), their fast-charging technology has attracted great interests of scientists. However, growth of lithium dendrites during fast charge of the bat teries with high energy density may pose great threats to the operation and cause serious safety issues Herein, we prepared a functional separator with an ultra-thin(20 nm) layer of Au nanoparticles deposited by evaporation coating method which could regulate growth direction and morphology of the lithium dendrites, owing to nearly zero overpotential of lithium meal nucleation on lithiated Au. Once the Li den drites are about to form on the graphite anode during fast charging(or lithiation), they plate predomi nantly on the Au deposited separator rather than on the graphite. Such selective deposition does no compromise the electrochemical performance of batteries under normal cycling. More importantly, i enables the better cycling stability of batteries at fast charge condition. The Li/Graphite cells with Au nanoparticles coated separator could cycle stably with a high areal capacity retention of 90.5% over 95 cycles at the current density of 0.72 m A cm^(-2). The functional separator provides an effective strategy to adjust lithium plating position at fast charge to ensure high safety of batteries without a compromise on the energy density of LIBs.

Workflow-Based Platform Design and Implementation for Numerical Weather Prediction Models and Meteorological Data Service

In this paper, we present a set of best practices for workflow design and implementation for numerical weather prediction models and meteorological data service, which have been in operation in China Meteorological Administration (CMA) for years and have been proven effective in reliably managing the complexities of large-scale meteorological related workflows. Based on the previous work on the platforms, we argue that a minimum set of guidelines including workflow scheme, module design, implementation standards and maintenance consideration during the whole establishment of the platform are highly recommended, serving to reduce the need for future maintenance and adjustment. A significant gain in performance can be achieved through the workflow-based projects. We believe that a good workflow system plays an important role in the weather forecast service, providing a useful tool for monitoring the whole process, fixing the errors, repairing a workflow, or redesigning an equivalent workflow pattern with new components.

Coexistence of situs inversus totalis and hepatocellular carcinoma:A series of nine cases and a literature review

Hepatocellular carcinoma(HCC)is the most commonly diagnosed carcinoma and one of the leading causes of cancer-related deaths worldwide.Situs inversus totalis(SIT)is a congenital condition where in the internal organs of the abdomen and thorax lie in mirror images of their normal position.Thus far,there are very few reports on cases of SIT coexisting with HCC.Our case series is probably the largest series in world literature.The cohort of this retrospective study included a total of nine patients diagnosed with SIT-HCC and treated in our hospital between January 2013 and May 2018.Clinical characteristics,prognostic factors,and outcomes were summarized.Treatment strategies included surgery,transarterial chemoembolization,and microwave ablation.The diagnosis and treatment of patients with SIT are challenging because of organ reversion.The current treatment strategies for different stages of liver cancer are safe and feasible for patients with SIT-HCC.

Surface functionalization of SPR chip for specific molecular interaction analysis under flow condition

Surface functionalization of sensor chip for probe immobilization is crucial for the biosensing applications of surface plasmon resonance(SPR)sensors.In this paper,we report a method circulating the dopamine aqueous solution to coat polydopamine film on sensing surface for surface functionalization of SPR chip.The polydopamine film with available thickness can be easily prepared by controlling the circulation time and the biorecognition elements can be immobilized on the polydopamine film for specific molecular interaction analysis.These opera-tions are all performed under flow condition in the fuidic system,and have the advantages of easy implementation,less time consuming,and low cost,because the reagents and devices used in the operations are routinely applied in most laboratories.In this study,the specific absorption between the protein A probe immobilized on the sensing surface and human immunoglobulin G in the buffer is monitored based on this surface functionalization strategy to demonstrated its feasibility for SPR biosensing applications.

Comparison of vinorelbine plus cisplatin with vinorelbine plus capecitabine in patients with anthracyclines- and taxanes-refractory advanced breast cancer

Objective: The aim of our study was to compare the efficacy and toxicities of vinorelbine plus cisplatin(NP) regimen with that of vinorelbine plus capecitabine(NX) regimen in the treatment of anthracycline- and taxane-refractory advanced breast cancer. Methods: Forty-six patients with anthracycline- and taxane-refractory advanced breast cancer were equally randomized into a NP group(n = 23) and a NX group(n = 23). Response rates and toxicities were evaluated after 2 cycles of chemotherapy. Results: The overall response rate were 48.0% in both groups. There were no significant differences in disease control rates(78.0% vs. 83%) or 1-year survival rates(54.6% vs. 55.9%). The main adverse events were bone marrow depression and gastrointestinal reaction, and no significant difference was found in toxicities between the groups. Conclusion: For anthracycline- and taxane-refractory advanced breast cancer, NP and NX regimens exerted similar curative effects with acceptable toxicity.

Plant community dynamics during the growing season of typical ecosystems on the Tibetan Plateau

The relationships between vegetation and environmental factors have always been a core concern of ecologists.The dynamic characteristics of plant communities during the growing season can directly reflect these relation-ships,so we examined this issue for three typical ecosystems on the Tibetan Plateau.During the growing season,the dominant species remained stable while non-dominant species changed significantly in the alpine meadow and alpine steppe and a mono-dominant community was found in the temperate desert shrub.Due to the seasonal variations of temperature and soil water content,plant species diversity varied significantly during the growing season.Patrick richness,Pielou evenness and Simpson diversity indices differed significantly in the alpine meadow and alpine steppe.The total biomass of these three ecosystems was the largest during the middle growing season.Biomass was greater in the alpine meadow than the alpine steeps or temperature desert.The root-to-shoot ratio was the lowest during the middle growing season for the alpine meadow and alpine steppe and largest during the early growing season for temperate desert shrub.RDA showed the belowground and total biomass were greatly affected by soil physicochemical factors.Multiple linear stepwise regression showed the above ground biomass was greatly affected by relative atmospheric humidity and belowground and total biomass were greatly affected by soil organic carbon,total nitrogen at 0-20 cm soil depth and pH at 10-20 cm soil depth.These findings pro-vide insights into understanding the relationships between vegetation and environmental factors and promote the sustainable utilization of local grasslands on the Tibetan Plateau.

Study and Analysis of the High Performance Computing Failures in China Meteorological Field

China Meteorological Administration (CMA) has a long history of using High Performance Computing System (HPCS) for over three decades. CMA HPCS investment provides reliable HPC capabilities essential to run Numerical Weather Prediction (NWP) models and climate models, generating millions of weather guidance products daily and providing support for Coupled Model Inter-comparison Project Phase 5 (CMIP5). Monitoring the HPCS and analyzing the resource usage can improve the performance and reliability for our users, which require a good understanding of failure characteristics. Large-scale studies of failures in real production systems are scarce. This paper collects, analyzes and studies all the failures occurring during the HPC operation period, especially focusing on studying the relationship between HPCS and NWP applications. Also, we present the challenges for a more effective monitoring system development and summarize the useful maintenance strategies. This step may have considerable effects on the performance of online failure prediction of HPC and better performance in future.

Dynamic changes of autophagy during hypertrophic scar formation and the role of autophagy intervention

Background:The role of autophagy in the formation of hypertrophic scars(HS)remains unclear.This study aimed to explore the role and potential mechanism of autophagy during the development of HS.Methods:RNA and protein expression levels of Beclin-1,p62,and LC3II in normal skin tissues and HS specimens from different patients were examined.Autophagy inducers and inhibitors were used to cure established HS in rabbit ears,and the expression of Beclin-1,p62,and LC3II at the RNA and protein level was determined.Lastly,the effects of autophagy inducers and inhibitors on HS development were analyzed.Results:Compared to normal skin tissues,the expression of LC3II and Beclin-1 was higher(P<0.05),while that of p62 was lower(P<0.05)in HS tissues.In addition,the LC3II/LC3I ratio was increased during HS formation,and the altered expression of the three proteins stabilized after one year.Administration of autophagy inducers enhanced the formation of HS as well as the expression levels of LC3II and Beclin-1 but decreased p62 expression.Meanwhile,administration of autophagy inhibitors increased the expression of LC3II,Beclin-1,and p62,along with reduced HS formation.Conclusion:Autophagic activity increased during HS initiation and subsequent stabilization.In addition,autophagy inhibitors were able to inhibit HS formation by suppressing autophagy,whereas autophagy inducers promoted scar hyperplasia by enhancing autophagy。

Phosphorous and selenium tuning Co-based non-precious catalysts for electrosynthesis of H_(2)O_(2)in acidic media

Electrosynthesis of hydrogen peroxide(H2O2)is an on-site method that enables independent distribution applications in many fields due to its small-scale and sustainable features.The crucial point remains developing highly active,selective and cost-effective electrocatalysts.The electrosynthesis of H2O2 in acidic media is more practical owing to its stability and no need for further purification.We herein report a phosphorus and selenium tuning Co-based non-precious catalyst(CoPSe)toward two-electron oxygen reduction reaction(2e–ORR)to produce H2O2 in acidic media.The starting point of using both P and Se is finding a balance between strong ORR activity of CoSe and weak activity of CoP.The results demonstrated that the CoPSe catalyst exhibited the optimized 2e–ORR activity compared with CoP and CoSe.It disclosed an onset potential of 0.68 V and the H2O2 selectivity 76%-85%in a wide potential range(0–0.5 V).Notably,the CoPSe catalyst overcomes a significant challenge of a narrow-range selectivity for transitionmetal based 2e–ORR catalysts.Finally,combining with electro-Fenton reaction,an on-site system was constructed for efficient degradation of organic pollutants.This work provides a promising non-precious Co-based electrocatalyst for the electrosynthesis of H2O2 in acidic media.

Genomic correlates of the response to first-line PD-1 blockade plus chemotherapy in patients with advanced non-small-cell lung cancer

Background:Programmed death 1(PD-1)blockade plus chemotherapy has become the new first-line standard of care for patients with advanced non-small-cell lung cancer(NSCLC).Yet not all NSCLC patients benefit from this regimen.This study aimed to investigate the predictors of PD-1 blockade plus chemotherapy in untreated advanced NSCLC.Methods:We integrated clinical,genomic,and survival data from 287 patients with untreated advanced NSCLC who were enrolled in one of five registered phase 3 trials and received PD-1 blockade plus chemotherapy or chemotherapy alone.We randomly assigned these patients into a discovery cohort(n=125),a validation cohort(n=82),and a control cohort(n=80).The candidate genes that could predict the response to PD-1 blockade plus chemotherapy were identified using data from the discovery cohort and their predictive values were then evaluated in the three cohorts.Immune deconvolution was conducted using transcriptome data of 1014 NSCLC patients from The Cancer Genome Atlas dataset.Results:A genomic variation signature,in which one or more of the 15 candidate genes were altered,was correlated with significantly inferior response rates and survival outcomes in patients treated with first-line PD-1 blockade plus chemotherapy in both discovery and validation cohorts.Its predictive value held in multivariate analyses when adjusted for baseline parameters,programmed cell death ligand 1(PD-L1)expression level,and tumor mutation burden.Moreover,applying both the 15-gene panel and PD-L1 expression level produced better performance than either alone in predicting benefit from this treatment combination.Immune landscape analyses revealed that tumors with one or more variation in the 15-gene panel were associated with few immune infiltrates,indicating an immune-desert tumor microenvironment.Conclusion:These findings indicate that a 15-gene panel can serve as a negative prediction biomarker for first-line PD-1 blockade plus chemotherapy in patients with advanced NSCLC.

Outcome comparison of pyrotinib with current standard of care in the second/third line setting in advanced non-small cell lung cancer patients with HER2 mutation

To the Editor:In recent years,impressive outcomes have been achieved in patients harboring human epidermal growth factor receptor 2(HER2)mutations,which accounts for 1%to 4%of cases in non-small cell lung cancer(NSCLC).

超高度近视性白内障超声乳化术后的视功能分析

目的:分析超高度近视性白内障患者施行超声乳化吸除联合人工晶状体植入术后视功能。方法:回顾性系列病例研究。收集2015年1月至2016年1月期间上海交通大学医学院附属新华医院同一高年资医师完成的超高度近视(眼轴≥27mm)白内障手术患者53例(81眼),依据眼轴将患者分为<29mm、29~31mm、>31mm3组。在术后1周、1个月、3个月行最佳矫正远视力、裸眼近视力以及微视野检查。数据处理采用Kruskal-Wallis检验。结果:患者以核性白内障为主,其中Ⅲ、Ⅳ、Ⅴ级核患者分别占90%(73眼)、9%(7眼)、1%(1眼)。术后1周、1个月、3个月及6个月最佳矫正远视力及近视力在3组间均随着眼轴长度增加而下降,但3组间差异无统计学意义。MARA微视野检测3组患者黄斑完整度、注视稳定性术后正常眼的比例与眼轴无明显关系,但平均光敏感度阈值正常比例随着眼轴长度增加而下降。结论:超高度近视伴发白内障患者,术前、术后最佳矫正远视力、近视力及黄斑功能随着眼轴的增长,都呈下降趋势。

Mesoporous Mn-Sn bimetallic oxide nanocubes as long cycle life anodes for Li-ion half/full cells and sulfur hosts for Li-S batteries

Mesoporous Mn-Sn bimetallic oxide （BO） nanocubes with sizes of 15-30 run show outstanding stable and reversible capacities in lithium ion batteries CLIBs）, reaching 856.8 mAh.g-1 after 400 cycles at 500 mA·g^-1 and 506 mAh·g^-1 after 850 cycles at 1,000 mA·g^-1. The prelimLnary investigation of the reaction mechanism, based on X-ray diffraction measurements, indicates the occurrence of both conversion and alloying-dealloying reactions in the Mn-Sn bimetallic oxide electrode. Moreover, Mn-Sn BO//LiCoO2 Li-ion full cells were successfully assembled for the first time, and found to deliver a relatively high energy density of 176.25 Wh·kg^-1 at 16.35 W·kg^-1 （based on the total weight of anode and cathode materials）. The superior long-term stability of these materials might be attributed to their nanoscale size and unique mesoporous nanocubic structure, which provide short Li^＋ diffusion pathways and a high contact area between electrolyte and active material. In addition, the Mn-Sn BOs could be used as advanced sulfur hosts for lithium-sulfur batteries, owing to their adequate mesoporous structure and relatively strong chemisorption of lithium polysulfide. The present results thus highlight the promising potential of mesoporous Mn-Sn bimetallic oxides for application in Li-ion and Li-S batteries.

Broadband near-infrared luminescence and energy transfer of Cr^(3+),Ce^(3+) co-doped Ca_(2)LuHf_(2)Al_(3)O_(12) phosphors

Broadband near-infrared phosphors are highly desirable for food testing.Targeted Ca_(2)LuHf_(2)Al_(3)O_(12):Cr^(3+)(CLHA:Cr^(3+)) and Ca_(2)LuHf_(2)Al_(3)O_(12):Ce^(3+),Cr^(3+)(CLHA:Ce^(3+),Cr^(^(3+))) phosphors were synthesized by the conventional high-temperature solid state reaction.The CLHA:Cr^(3+)phosphor,with a good thermal stability,shows a red shift owing to radiation reabsorption and non-radiative transition with increasing Cr^(3+)content.For co-doped sample,the emission intensity of Cr^(3+)can be enhanced by three times due to the energy transfer from Ce^(3+)to Cr^(3+),which can be evidenced by a significant overlap between the PLE of Cr^(3+)single-doped phosphor and the PL of Ce^(3+)single-doped phosphor.In addition,the mechanism of energy transfer is identified as a quadrupole-quadrupole interaction according to decay Lifetime and Dexter’s energy transfer formula.The broadband NIR emission peaked at 775 nm of CLHA:Cr^(3+),Ce^(3+)phosphor shows a bright prospect in nondestructive quality-control analysis systems for food.

Cobalt and nitrogen codoped porous carbon as superior bifunctional electrocatalyst for oxygen reduction and hydrogen evolution reaction in alkaline medium

Cobalt and nitrogen codoped carbon materials(Co-N-C) were fabricated by pyrolysis of the mixture of poly(4-vinylpyridine) and cobalt chloride using SiO_2 nanoparticles as hard template, which were the first transition metal/nitrogen-codoped carbon bifunctional electrocatalyst derived from noncarbonizable polymer for ORR and HER. The as-made Co-N-C possessed hierarchical pore structure and high specific surface area, achieving excellent electrocatalytic performances for ORR and HER. Its ORR catalytic performances were comparable to those of Pt/C catalyst and its HER catalytic performances were superior to those of most doped carbon catalysts in KOH electrolyte. Moreover, its bifunctional electrocatalytic performances for ORR and HER were better than those of most bifunctional doped carbon catalysts in alkaline electrolyte.

Visualized and cascade-enhanced gene silencing by smart DNAzyme-graphene nanocomplex

BCL-2 gene as well as its products is recognized as a promising target for the molecular targeted therapy of tumors.However,due to certain defense measures of tumor cells,the therapeutic effect based on the gene silencing of BCL-2 is greatly reduced.Here we fabricate a smart response nucleic acid therapeutic that could silence the gene effectively through a dual-targeted and cascade-enhanced strategy.In brief,nano-graphene oxide(GO),working as a nano-carrier,is loaded with a well-designed DNAzyme,which can target and silence the BCL-2 mRNA.Furthermore,upon binding with the BCL-2 mRNA,the enzymatic activity of the DNAzyme can be initiated,cutting a substrate oligonucleotide to produce an anti-nucleolin aptamer AS1411.Nucleolin,a nucleolar phosphoprotein,is known as a stabilizer of BCL-2 mRNA.Via binding and inactivating the nucleolin,AS1411 can destabilize BCL-2 mRNA.By this means of simultaneously targeting mRNA and its stabilizer in an integrated system,effective silencing of the BCL-2 gene of tumor cells is achieved at both the cellular and in vivo levels.After being dosed with this nucleic acid therapeutic and without any chemotherapeutics,apoptosis of tumor cells at the cellular level and apparent shrinkage of tumors in vivo are observed.By labeling a molecular beacon on the substrate of DNAzyme,visualization of the enzymatic activity as well as the tumor in vivo can be also achieved.Our work presents a pure bio-therapeutic strategy that has positive implications for enhancing tumor treatment and avoiding side effects of chemotherapeutics.

Hierarchical flower-like cobalt phosphosulfide derived from Prussian blue analogue as an efficient polysulfides adsorbent for long-life lithium-sulfur batteries

Lithium-sulfur (Li-S) battery as one of the most attractive candidates for energy storage systems has attracted extensive interests.Herein,for the first time,hierarchical flower-like cobalt phosphosulfide architectures (defined as "CoSP") derived from Prussian blue analogue (PBA) was fabricated through the conversion of Co-based PBA in PxSy atmosphere.The as-prepared polar CoSP could effectively trap polysulfides through the formation of strong chemical bonds.In addition,after the combination of CoSP with high conductive rGO,the obtained CoSP/rGO as sulfur host material exhibits ultralow capacity decay rate of 0.046% per cycle over 900 cycles at a current density of 1 C.The excellent performance could be attributed to the shortened lithium diffusion pathways,fastened electron transport ability during polysulfide conversion,and increased much more anchor active sites to polysulfides,which is expected to be a promising material for Li-S batteries.It is believed that the as-prepared CoSP/rGO architectures will shed light on the development of novel promising materials for Li-S batteries with high cycle stability.