Integrating phosphorus management and cropping technology for sustainable maize production

Achieving high maize yields and efficient phosphorus(P)use with limited environmental impacts is one of the greatest challenges in sustainable maize production.Increasing plant density is considered an effective approach for achieving high maize yields.However,the low mobility of P in soils and the scarcity of natural P resources have hindered the development of methods that can simultaneously optimize P use and mitigate the P-related environmental footprint at high plant densities.In this study,meta-analysis and substance flow analysis were conducted to evaluate the effects of different types of mineral P fertilizer on maize yield at varying plant densities and assess the flow of P from rock phosphate mining to P fertilizer use for maize production in China.A significantly higher yield was obtained at higher plant densities than at lower plant densities.The application of single superphosphate,triple super-phosphate,and calcium magnesium phosphate at high plant densities resulted in higher yields and a smaller environmental footprint than the application of diammonium phosphate and monoammonium phosphate.Our scenario analyses suggest that combining the optimal P type and application rate with a high plant density could increase maize yield by 22%.Further,the P resource use efficiency throughout the P supply chain increased by 39%,whereas the P-related environmental footprint decreased by 33%.Thus,simultaneously optimizing the P type and application rate at high plant densities achieved multiple objectives during maize production,indicating that combining P management with cropping techniques is a practical approach to sustainable maize production.These findings offer strategic,synergistic options for achieving sustainable agricultural development.

尿囊素促进破骨细胞缺陷斑马鱼骨折修复

骨折愈合是一个由多细胞介导的多步骤的严密有序的过程,其中破骨细胞介导的骨重塑在骨折愈合中具有关键作用,其生成减少或者功能障碍不仅导致骨折的易发生,还会引起骨折愈合障碍。但是,目前关于破骨细胞缺陷所致的骨折愈合障碍的研究较少,并且临床上尚缺乏针对破骨细胞缺陷所致骨折愈合障碍的治疗药物。斑马鱼(Danio rerio)骨骼系统中的细胞类型和调节途径与哺乳动物高度相似,使得其被广泛地运用于骨骼相关的研究。为了研究破骨细胞缺陷所致的骨折愈合障碍过程以及寻找有潜力的治疗药物,本研究使用前期建立的fms基因突变斑马鱼(fmsj4e1)构建了体内破骨细胞缺陷骨折模型,结果发现功能性破骨细胞减少可在骨折早期影响骨折的愈合;使用离体鳞片培养系统用于筛选破骨细胞靶向药物,获得了可以激活破骨细胞的小分子化合物尿囊素(allantoin,ALL);随后,在体内fmsj4e1骨折缺陷模型中验证了ALL对破骨细胞的激活作用以及对骨折修复的促进作用;最后,通过对破骨细胞生成和成熟过程的分析,发现ALL可能通过调节RANKL/OPG来促进破骨细胞的成熟,从而促进fmsj4e1骨折愈合。本研究为未来改善破骨细胞缺陷引起的骨折愈合障碍提供了潜在的新方法。

Clay minerals and elemental composition of sediments on different sedimentary units in the northern East China Sea shelf:provenance tracing and genetic mechanism analysis

The composition,provenance,and genetic mechanism of sediment on different sedimentary units of the East China Sea(ECS)shelf are essential for understanding the depositional dynamics environment in the ECS.The sediments in the northern ECS shelf are distributed in a ring-shaped distribution centered on the southwestern Cheju Island Mud.From the inside to the outside,the grain size goes from fine to coarse.Aside from the“grain size effect”,hydrodynamic sorting and mineral composition are important restrictions on the content of rare earth elements(REEs).Based on the grain size,REEs,and clay mineral composition of 300 surface sediments,as well as the sedimentary genesis,the northern ECS shelf is divided into three geochemical zones:southwestern Cheju Island Mud Area(ZoneⅠ),Changjiang Shoal Sand Ridges(ZoneⅡ-1),Sand Ridges of the East China Sea shelf(ZoneⅡ-2).The northern ECS shelf is mostly impacted by Chinese mainland rivers(the Changjiang River and Huanghe River),and the provenance and transport mechanism of sediments of different grain sizes is diverse.The bulk sediments come primarily from the Changjiang River,with some material from the Huanghe River carried by the Yellow Sea Coastal Current and the North Jiangsu Coastal Current,and less from Korean rivers.Among them,surface sediments in the southwestern Cheju Island Mud Area(ZoneⅠ)come mostly from the Changjiang River and partly from the Huanghe River.It was formed by the counterclockwise rotating cold eddies in the northern ECS shelf,which caused the sedimentation and accumulation of the fine-grained sediments of the Changjiang River and the Huanghe River.The Changjiang Shoal Sand Ridges(ZoneⅡ-1)were developed during the early-middle Holocene sea-level highstand.It is the modern tidal sand ridge sediment formed by intense hydrodynamic action under the influence of the Yellow Sea Coastal Current,North Jiangsu Coastal Current,and Changjiang Diluted Water.The surface sediments mainly originate from the Changjiang River and Huanghe River,with the Changjiang River dominating,and the Korean River(Hanjiang River)influencing just a few stations.Sand Ridges of the East China Sea shelf(ZoneⅡ-2)are the relict sediments of the paleo-Changjiang River created by sea invasion at the end of the Last Deglaciation in the Epipleistocene.The clay mineral composition of the surface sediments in the study area is just dominated by the Changjiang River,with the North Jiangsu Coastal Current and the Changjiang Diluted Water as the main transporting currents.

An Improved Coupled Dynamic Modelling for Exploring Gearbox Vibrations Considering Local Defects

Gearbox is a key part in machinery,in which gear,shaft and bearing operate together to transmit motion and power.The wide usage and high failure rate of gearbox make it attract much attention on its health monitoring and fault diagnosis.Dynamic modelling can study the mechanism under different faults and provide theoretical foundation for fault detection.However,current commonly used gear dynamic model usually neglects the influence of bearing and shaft,resulting in incomplete understanding of gearbox fault diagnosis especially under the effect of local defects on gear and shaft.To address this problem,an improved gear-shaft-bearing-housing dynamic model is proposed to reveal the vibration mechanism and responses considering shaft whirling and gear local defects.Firstly,an eighteen degree-of-freedom gearbox dynamic model is proposed,taking into account the interaction among gear,bearing and shaft.Secondly,the dynamic model is iteratively solved.Then,vibration responses are expounded and analysed considering gear spalling and shaft crack.Numerical results show that the gear mesh frequency and its harmonics have higher amplitude through the spectrum.Vibration RMS and the shaft rotating frequency increase with the spalling size and shaft crack angle in general.An experiment is designed to verify the rationality of the proposed gearbox model.Lastly,comprehensive analysis under different spalling size and shaft crack angle are analysed.Results show that when spalling size and crack angle are larger,RMS and the amplitude of shaft rotating frequency will not increase linearly.The dynamic model can accurately simulate the vibration of gear transmission system,which is helpful for gearbox fault diagnosis.

印染外排废水中溶解性有机质的荧光特性

通过三维荧光(EEM)光谱技术,结合平行因子分析(PARAFAC)及荧光区域积分法(FRI),对我国珠三角的五家印染废水处理厂外排废水的溶解性有机质(DOM)进行定性及定量表征。五组水样DOM的EEM光谱中类蛋白荧光峰最为明显,结合荧光指数(FI),自生源指标(BIX)及腐殖化指标(HIX),发现DOM的腐殖质主要来源于微生物的活动。基于PARAFAC的结果发现印染外排废水DOM的构成组分可分为类蛋白荧光组分C1(Em/Ex=320/275 nm)和C2(Em/Ex=350/225,275 nm),及类腐殖质荧光组分C3(Em/Ex=460/250,300 nm)。不同组分之间的显著相关性表明他们具有同源或同结构相似性,其中C2与C3之间相关性最高(r=0.7949),其次是C1与C2(r=0.7936),而C1与C3之间相关性不显著(P>0.05)。结合FRI,发现外排废水中DOM的有机物构成以溶解性微生物代谢产物和芳香性蛋白类为主,类腐殖质的含量相对较低。三维荧光光谱结合平行因子分析和荧光区域积分法,能有效监测及分析外排废水中低浓度有机物的具体信息,可以作为一种有效的水质监测手段。

Identification of the four rearranged hopane series in geological bodies and their geochemical significances

Saturated fractions in a total of 23 oil samples and hydrocarbon source rocks from the Songliao, Tarim,and Ordos Basins have been analyzed by GC–MS and GC–MS–MS. According to the relative retention, mass spectral characteristics, and comparison with existing literature, a complete carbon number distribution ranging from C27 to C35(without C28) in the 17a(H)-diahopane series and early-eluting rearranged hopane series is identified. Compounds in the 18a(H)-neohopane series(Ts and C29Ts) and21-methyl-28-nor-hopane series(29Nsp and 30Nsp) are also noted. These four series of rearranged hopanes seem to occur in both brackish-saline lacustrine and coal measure environments. However, the coal measure and swamp environments being under an oxic condition, compared with brackish-saline lacustrines, are presumably more helpful to the formation of 30 E. Diversity in the content and distribution patterns indicate that rearranged hopanes could serve as good indicators of organic facies, depositional environment and maturity in petroleum geology.

Liquid chromatography–tandem mass spectrometry method for simultaneous determination of valproic acid and its ene-metabolites in epilepsy patient plasma

A simple and high throughput method was developed and validated for simultaneous determination of valproic acid and its two toxicant ene-metabolites, 2-enevalproic acid and 4-enevalproic acid in epilepsy patient plasma using liquid chromatography-tandem mass spectrometry. Probenecid was used as in- ternal standard and solid-phase extraction was selected for sample preparation. A chromatographic separation was performed on an Agilent Poroshell SB-C18 column （50 mm × 4.6 mm i.d., 2.7μm） by an optimized gradient elution at a flow rate of 0.9 mL/min. The total run time was 7 rain. Electrospray ionization was used in negative ion mode by multiple reaction monitoring of the precursor-to-product ion transitions at m/z 143.0→143.0 for valproic acid, m/z 140.9 →140.9 for 2-enevalproic acid and 4-enevalproic acid for their poor fragments, and m/z 283.9→239,9 for probenecid. The results showed good linearity ofvalproic acid, 2-enevalproic acid and 4-enevalproic acid in their respective linear ranges. The correlation coefficients were more than 0.998, The intra- and inter-day precision of the assay was less than 11.0% and the accuracy ranged from 2% to 12%. This analytical method was successfully applied to assay plasma concentrations of valproic acid and its two ene-metabolites in epilepsy patient plasma and used for therapeutic drug monitoring.

Discrimination of aqueous and vinegary extracts of Shixiao San using metabolomics coupled with multivariate data analysis and evaluation of antihyperlipidemic effect

A novel study using LCeMS(Liquid chromatography tandem mass spectrometry)coupled with multivariate data analysis and bioactivity evaluation was established for discrimination of aqueous extract and vinegar extract of Shixiao San.Batches of these two kinds of samples were subjected to analysis,and the datasets of sample codes,tR-m/z pairs and ion intensities were processed with principal component analysis(PCA).The result of score plot showed a clear classification of the aqueous and vinegar groups.And the chemical markers having great contributions to the differentiation were screened out on the loading plot.The identities of the chemical markers were performed by comparing the mass fragments and retention times with those of reference compounds and/or the known compounds published in the literatures.Based on the proposed strategy,quercetin-3-Oneohesperidoside,isorhamnetin-3-O-neohespeeridoside,kaempferol-3-O-neohesperidoside,isorhamnetin-3-O-rutinoside and isorhamnetin-3-O-(2G-a-l-rhamnosyl)-rutinoside were explored as representative markers in distinguishing the vinegar extract from the aqueous extract.The anti-hyperlipidemic activities of two processed extracts of Shixiao San were examined on serum levels of lipids,lipoprotein and blood antioxidant enzymes in a rat hyperlipidemia model,and the vinegary extract,exerting strong lipid-lowering and antioxidative effects,was superior to the aqueous extract.Therefore,boiling with vinegary was predicted as the greatest processing procedure for anti-hyperlipidemic effect of Shixiao San.Furthermore,combining the changes in the metabolic profiling and bioactivity evaluation,the five representative markers may be related to the observed antihyperlipidemic effect.

Development of a UPLC–MS/MS method for determination of pimavanserin tartrate in rat plasma: Application to a pharmacokinetic study

A simple, rapid and sensitive method based on an ultra-performance liquid chromatography tandem mass spectrometry （UPLC-MS/MS） has been developed and validated for the determination of pimavanserin in rat plasma. The analyte was extracted by protein precipitation with methanol and separated on an ACQUITY BEH C18 column （100 mm × 2.1 mm, 1.7μm; Waters, USA）, with an isocratic elution of acetonitrile-water containing 10 mM ammonium acetate （70：30, v/v）, at a flow rate of 0.2 mL/min for 2.5 rain. The analyte and clarithromyein （the internal standard） were detected and quantified in positive ion mode using multiple reaction monitoring transitions at m/z 428.2 - 223.0 for pimavanserin and m/z 748.5 - 589.5 for clarithromycin. Relative coefficient （r） for the calibration curve was more than 0.9980. The intra-day and inter-day precisions （relative standard deviation, RSD%） were less than 13.3% and 10.5%, respectively, and the accuracy （relative error, RE%） was within ± 11.5%. The analytical method was successfully applied to a routine pharmacokinetic study of pimavanserin in rats after oral administration at the dose of 10 mg/kg.

Influence of pretreatment of piperazine ferulate on pharmacokinetic parameters of methotrexate in methotrexate-induced renal injury model rats by HPLC-MS

The present study was designed to investigate the influence of the pretreatment of piperazine ferulate on pharmacokinetic parameters of methotrexate in methotrexate-induced renal injury rats.A simple and efficient high performance liquid chromatography coupled with mass spectrometry(HPLC-MS)method was developed to determine methotrexate in rat plasma.Methotrexate and syringic acid(internal standard)were extracted from rat plasma samples by protein precipitation with acetonitrile.The analysis was performed on a CAPCELL PAK C18column(150 mm×4.6 mm,5μm)with acetonitrile and 5 mmol/l ammonium acetate aqueous(10:90,v/v).The linear range was 5.0×10-2to 100.0μg/ml for methotrexate.Other parameters were all within the acceptance criteria.The validated method was successfully applied the pharmacokinetic study of methotrexate between two methotrexate treated groups(with and without the pretreatment of piperazine ferulate).Compared with the methotrexate treated alone group,the pharmacokinetic parameters in the methotrexate with the pretreatment of piperazine ferulate group showed significantly lower MRT(0-t),MRT(0-∞) and T1/2.Results suggested that methotrexate can be rapidly eliminated,cleared or metabolized in rat blood,which might be related to the pretreatment of piperazine ferulate.The method provided deeper insights into rational clinical use of methotrexate with the pretreatment of piperazine ferulate on cancer patients with renal dysfunction.

Metabolomics provide insights into the endogenous mechanism of strobilation in the scyphozoan jellyfi sh Rhopilema esculentum

Strobilation is a well-organized metamorphosis process in scyphozoan jellyfi sh,through which the benthic polyp develops into the pelagic medusa.So far,knowledge on the molecular mechanisms behind the drastic morphological and physiological changes remains limited.In the present study,the metabolic profi les in polyp and strobila stages of jellyfi sh Rhopilema esculentum were examined using ultra-performance liquid chromatography coupled to a mass spectrometer.A total of 3071 metabolites with putative annotation were detected,of which 167 were identifi ed as diff erential metabolites between the polyp and strobila.Among the metabolites,31 signifi cantly decreased and 136 signifi cantly increased in abundance in the strobila.Thyroxin,one of the previously proposed strobilation inducer of Aurelia,was not detected in this study.The indole-containing compounds are known for triggering strobilation in Discomedusae.Two indole derivatives and an indole-isomer containing metabolite were detected among the most signifi cantly increased metabolites,which may be potential endogenous molecules for strobilation initiation.The membrane-associated phospholipids and the infl ammation and oxidative stress-related eicosanoids were found to have signifi cant changes.Although the functions of these metabolites in strobilation are not yet completely known,they provide some clues to the induction of the process of strobilation and metabolic responses that take place during strobilation.

SQoE KQIs Anomaly Detection in Cellular Networks: Fast Online Detection Framework with Hourglass Clustering

The explosive growth of data volume in mobile networks makes fast online diagnose a pressing search problem. In this paper, an object-oriented detection framework with a two-step clustering, named as Hourglass Clustering, is given. Where three object parameters are chosen as Synthetical Quality of Experience(SQo E) Key Quality Indicators(KQIs) to reflect accessibility, integrality, and maintainability of networks. Then, we choose represented Key Performance Indicators(r KPIs) as cause parameters with correlation analysis. For these two kinds of parameters, a hybrid algorithm combining the self-organizing map(SOM)

Degradation kinetics of larotaxel and identification of its degradation products in alkaline condition

Larotaxel, a new taxane compound prepared by partial synthesis from 10-deacetyl baccatin III, is active against tumors. In this research, a selective LC–MS method was developed and validated for the study of degradation kinetics of larotaxel, which was carried out in aqueous solutions with different pH（1.5, 3.0, 5.0, 6.5, 7.4, 9.0, 10 and 11.0） and temperature（0, 25, 37 and 45 °C）. The linear range was 0.5–25 μg/mL, the intra-and inter-day precisions were less than 7.0%, and accuracy ranged from 97.4–104.5% for each analyte. The observed rate obtained by measuring the remaining intact larotaxel was shown to follow first-order kinetics. The activation energies for degradation were 126.7 and 87.01 k J/mol at pH 1.5 and 11, respectively. Although larotaxel was stable in pH 5, 6.5 and 7.4 buffers at 37 °C for 24 h during our study, increasing or decreasing the pH of the solutions would decrease its stabilities. Moreover, three main degradation products in alkaline condition were separated by HPLC and identified by Q–TOF–MS. The three degradation products were confirmed as 10-deacetyl larotaxel, 7, 8-cyclopropyl baccatin Ⅲ and 10-deacetyl-7, 8-cyclopropyl baccatin Ⅲ.

Determination of 6258-70,a new semi-synthetic taxane,in rat plasma and tissues:Application to the pharmacokinetics and tissue distribution study

Cancer is the leading cause of death all over the world.Among the chemotherapy drugs,taxanes play an important role in cancer treatment.6258-70 is a new semi-synthetic taxane which has a broad spectrum of antitumor activity.A fast and reliable high performance liquid chromatography-tandem mass spectrometry（HPLC-MS/MS） method was developed for quantification of 6258-70 in rat plasma and tissues in this paper.After extraction by liquid-liquid extraction method with methyl tert-butyl ether,the samples were separated on a Kinetex C_（18） column（50 mm × 2.1 mm,2.6 μm,Phenomenex,USA） within3 min.The method was fully validated with the matrix effect between 87.7%and 99.5%and the recovery ranging from 80.3%to 90.1%.The intra- and inter-day precisions were less than 9.5%and the accuracy ranged from-3.8%to 6.5%.The reliable method was successfully applied to the pharmacokinetics and tissue distribution studies of 6258-70 after intravenous administration in rats.The pharmacokinetic results indicated that the pharmacokinetic behavior of 6258-70 in rats was in accordance with linear features within tested dosage of 1 to 4 mg/kg,and there was no significant difference between the two genders.The tissue distribution study showed that 6258-70 had an effective penetration,spread widely and rapidly and could cross blood-brain barrier.The results of pharmacokinetics and tissue distribution may provide a guide for future study.

Phase separation of Nur77 mediates XS561-induced apoptosis by promoting the formation of Nur77/Bcl-2 condensates

The orphan nuclear receptor Nur77 is a critical regulator of the survival and death of tumor cells.The pro-death effect of Nur77 can be regulated by its interaction with Bcl-2,resulting in conversion of Bcl-2 from a survival to killer.As Bcl-2 is overexpressed in various cancers preventing them from apoptosis and promoting their resistance to chemotherapy,targeting the apoptotic pathway of Nur77/Bcl-2 may lead to new cancer therapeutics.Here,we report our identification of XS561 as a novel Nur77 ligand that induces apoptosis of tumor cells by activating the Nur77/Bcl-2 pathway.In vitro and animal studies revealed an apoptotic effect of XS561 in a range of tumor cell lines including MDA-MB-231 triple-negative breast cancer(TNBC)and MCF-7/LCC2 tamoxifen-resistant breast cancer(TAMR)in a Nur77-dependent manner.Mechanistic studies showed XS561 potently induced the translocation of Nur77 from the nucleus to mitochondria,resulting in mitochondria-related apoptosis.Interestingly,XS561-induced accumulation of Nur77 at mitochondria was associated with XS561 induction of Nur77 phase separation and the formation of Nur77/Bcl-2 condensates.Together,our studies identify XS561 as a new activator of the Nur77/Bcl-2 apoptotic pathway and reveal a role of phase separation in mediating the apoptotic effect of Nur77 at mitochondria.

不同土壤氮水平下C_(3)和C_(4)植物之间的菌根网络及氮传递

丛枝菌根真菌(AMF)的菌丝在土壤中通常可以链接相同或不同物种的植物根系,所形成的菌根网络可以将养分从一种植物传递到另一种植物。然而,土壤中的氮(N)含量对不同植物物种之间通过菌根网络进行养分转移的影响尚未实验验证。为了定量研究不同土壤氮水平下羊草(LC)和糙隐子草(CS)之间通过菌根网络的养分转移,本研究建立了两个分室盆栽系统,即CS–LC系统(CS和LC分别为供体和受体)和LC–CS系统(LC和CS分别为供体和受体),设置了3种土壤氮添加水平,即不添加氮对照(N0)、添加7 mg/kg(N1)和添加14 mg/kg(N2)。通过在供体植物一侧土壤添加稳定同位素^(15)N,示踪并量化不同物种植物幼苗之间通过菌根网络传递的氮。在CS–LC系统中,AMF侵染率、菌丝密度和植物生物量在N1水平最高;而在LC–CS系统,AMF侵染率、菌丝密度和植物生物量在N2水平达到最大。此外,在CS–LC系统中,^(15)N转移率介于16%到61%之间,在N1水平最大。对于LC–CS系统,^(15)N传输速率相对较低,最大值出现在N0水平。这些发现表明,土壤中的氮含量能够调控供体植物和受体植物之间经由菌根网络传递的氮养分。

A knowledge-based approach for estimating the distribution of urban mixed land use

Estimating the proportion of land-use types in different regions is essential to promote the organization of a compact city and reduce energy consumption.However,existing research in this area has a few limitations:(1)lack of consideration of land-use distribution-related factors other than POIs;(2)inability to extract complex relations from heterogeneous information;and(3)overlooking the correlation between land-use types.To overcome these limitations,we propose a knowledge-based approach for estimating land-use distributions.We designed a knowledge graph to display POIs and other related heterogeneous data and then utilized a knowledge embedding model to directly obtain the region embedding vectors by learning the complex and implicit relations present in the knowledge graph.Region embedding vectors were mapped to land-use distributions using a label distribution learning method integrating the correlation between land-use types.To prove the reliability and validity of our approach,we conducted a case study in Jinhua,China.The results indicated that the proposed model outperformed other algorithms in all evaluation indices,thus illustrating the potential of this method to achieve higher accuracy land-use distribution estimates.

Erianin,a novel dibenzyl compound in Dendrobium extract,inhibits lung cancer cell growth and migration via calcium/calmodulin-dependent ferroptosis

Ferroptosis,a novel form of programmed cell death,is characterized by iron-dependent lipid peroxidation and has been shown to be involved in multiple diseases,including cancer.Stimulating ferroptosis in cancer cells may be a potential strategy for cancer therapy.Therefore,ferroptosis-inducing drugs are attracting more attention for cancer treatment.Here,we showed that erianin,a natural product isolated from Dendrobium chrysotoxum Lindl,exerted its anticancer activity by inducing cell death and inhibiting cell migration in lung cancer cells.Subsequently,we demonstrated for the first time that erianin induced ferroptotic cell death in lung cancer cells,which was accompanied by ROS accumulation,lipid peroxidation,and GSH depletion.The ferroptosis inhibitors Fer-1 and Lip-1 but not Z-VAD-FMK,CQ,or necrostatin-1 rescued erianin-induced cell death,indicating that ferroptosis contributed to erianin-induced cell death.Furthermore,we demonstrated that Ca^(2+)/CaM signaling was a critical mediator of erianin-induced ferroptosis and that blockade of this signaling significantly rescued cell death induced by erianin treatment by suppressing ferroptosis.Taken together,our data suggest that the natural product erianin exerts its anticancer effects by inducing Ca^(2+)/CaMdependent ferroptosis and inhibiting cell migration,and erianin will hopefully serve as a prospective compound for lung cancer treatment.

PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death

5-Fluorouracil(5-FU)is known as a first-line chemotherapeutic agent against colorectal cancer(CRC),but drug resistance occurs frequently and significantly limits its clinical success.Our previous study showed that the protocadherin 17(PCDH17)gene was frequently methylated and functioned as a tumor suppressor in CRC.However,the relationship between PCDH17 and 5-FU resistance in CRC remains unclear.Here,we revealed that PCDH17 was more highly expressed in 5-FU-sensitive CRC tissues than in 5-FU-resistant CRC tissues,and high expression of PCDH17 was correlated with high BECN1 expression.Moreover,this expression profile contributed to superior prognosis and increased survival in CRC patients.Restoring PCDH17 expression augmented the 5-FU sensitivity of CRC in vitro and in vivo by promoting apoptosis and autophagic cell death.Furthermore,autophagy played a dominant role in PCDH17-induced cell death,as an autophagy inhibitor blocked cell death to a greater extent than the pancaspase inhibitor Z-VAD-FMK.PCDH17 inhibition by siRNA decreased the autophagy response and 5-FU sensitivity.Mechanistically,we showed that c-Jun NH2-terminal kinase(JNK)activation was a key determinant in PCDH17-induced autophagy.The compound SP600125,an inhibitor of JNK,suppressed autophagy and 5-FU-induced cell death in PCDH17-reexpressing CRC cells.Taken together,our findings suggest for the first time that PCDH17 increases the sensitivity of CRC to 5-FU treatment by inducing apoptosis and JNK-dependent autophagic cell death.PCDH17 may be a potential prognostic marker for predicting 5-FU sensitivity in CRC patients.

Cyanation and cyanomethylation of trimethylammonium salts via electrochemical cleavage of C–N bonds

We have developed a practical and mild electrochemical protocol for cyanation and cyanomethylation of trimethylammonium salts through a pathway involving C–N bond cleavage without the need for an exter-nal stoichiometric reducing agent or a sacrificial anode.The reaction employs tosyl cyanide(TsCN)or azido allyl alcohol as the cyanation or cyanomethylation reagent,respectively.It shows high functional group compatibility and can be applied for the cyanation of natural product derivatives.Preliminary mechanistic studies indicate the involvement of a radical addition pathway.