靶向紧密连接蛋白6的药物在癌症治疗中的研究进展

紧密连接蛋白6(Claudin6,CLDN6)是紧密连接蛋白(Claudins,CLDNs)家族的一员,在卵巢癌、睾丸癌、子宫颈内膜癌、肝癌和肺腺癌等多种癌症中特异性高表达,而在成人正常组织中几乎不表达。其能够激活多条通路参与肿瘤发生的多个过程,包括促进肿瘤生长、迁移和侵袭,且促进肿瘤化疗耐药。近年来,CLDN6作为癌症治疗的新靶点引起了研究人员的广泛关注,针对CLDN6靶点开发了多种类型的抗癌药物,包括抗体偶联药物(antibody-drug conjugate,ADC)、单克隆抗体、双特异性抗体和嵌合抗原受体T细胞免疫疗法(chimeric antigen receptor T-cell immunotherapy,CAR-T)。本文简要概述了CLDN6的蛋白结构、表达分布以及在肿瘤中的功能,并对其作为药靶开发的抗癌药物研发现状和研发思路进行了综述。     

Interactive effects of aphid feeding and virus infection on host gene expression and volatile compounds in salt-stressed soybean, <Emphasis Type="Italic">Glycine max</Emphasis> (L.) Merr.

Saline soils are becoming an important limiting factor in production agriculture. Soybean cultivars [Glycine max (L.) Merr.] differ in their ability to tolerate salt stress with those that cannot limit ion uptake into leaves being salt sensitive. Those that can partially limit ion uptake into leaves are generally more salt tolerant. Soybean mosaic virus (SMV) is an important viral pathogen of soybean worldwide and is commonly transmitted by the soybean aphid, Aphis glycines Matsumura. In this study, we investigate the interaction of salt stress in soybean with SMV infection and infestation by the soybean aphid by measuring aphid populations in a no-choice assay, gene expression levels, and the induction of volatile organic compounds using static headspace GC–MS analysis. Salt stress and SMV infection both reduced total aphid populations, though SMV did not reduce the total number of aphids per gram of fresh weight. Aphid suppression of a calcium EF hand gene and OPR1 was lost when salt-sensitive soybean plants were salt stressed and when salt-tolerant plants were subjected to all three stressors. The relative levels of SMV in aphid-infested soybeans were increased by salt stress in the salt-sensitive cultivar, whereas SMV levels decreased in the salt-tolerant cultivar. Static headspace collection of volatile organic compounds revealed that salt stress and SMV infection had suppressive activities on aphid-induced terpenes. These results suggest that although salt stress has a negative impact on aphid population size, the changes in volatiles and SMV levels could alter the incidence of SMV in salt-stressed fields.     

Association analysis of salt tolerance in cowpea (<Emphasis Type="Italic">Vigna unguiculata</Emphasis> (L.) Walp) at germination and seedling stages

Key message

This is the first report on association analysis of salt tolerance and identification of SNP markers associated with salt tolerance in cowpea.

Abstract

Cowpea (Vigna unguiculata (L.) Walp) is one of the most important cultivated legumes in Africa. The worldwide annual production in cowpea dry seed is 5.4 million metric tons. However, cowpea is unfavorably affected by salinity stress at germination and seedling stages, which is exacerbated by the effects of climate change. The lack of knowledge on the genetic underlying salt tolerance in cowpea limits the establishment of a breeding strategy for developing salt-tolerant cowpea cultivars. The objectives of this study were to conduct association mapping for salt tolerance at germination and seedling stages and to identify SNP markers associated with salt tolerance in cowpea. We analyzed the salt tolerance index of 116 and 155 cowpea accessions at germination and seedling stages, respectively. A total of 1049 SNPs postulated from genotyping-by-sequencing were used for association analysis. Population structure was inferred using Structure 2.3.4; K optimal was determined using Structure Harvester. TASSEL 5, GAPIT, and FarmCPU involving three models such as single marker regression, general linear model, and mixed linear model were used for the association study. Substantial variation in salt tolerance index for germination rate, plant height reduction, fresh and dry shoot biomass reduction, foliar leaf injury, and inhibition of the first trifoliate leaf was observed. The cowpea accessions were structured into two subpopulations. Three SNPs, Scaffold87490_622, Scaffold87490_630, and C35017374_128 were highly associated with salt tolerance at germination stage. Seven SNPs, Scaffold93827_270, Scaffold68489_600, Scaffold87490_633, Scaffold87490_640, Scaffold82042_3387, C35069468_1916, and Scaffold93942_1089 were found to be associated with salt tolerance at seedling stage. The SNP markers were consistent across the three models and could be used as a tool to select salt-tolerant lines for breeding improved cowpea tolerance to salinity.

     

Mapping and confirmation of loci for salt tolerance in a novel soybean germplasm,Fiskeby III

Key message

The confirmation of a major locus associated with salt tolerance and mapping of a new locus, which could be beneficial for improving salt tolerance in soybean.

Abstract

Breeding soybean for tolerance to high salt conditions is important in some regions of the USA and world. Soybean cultivar Fiskeby III (PI 438471) in maturity group 000 has been reported to be highly tolerant to multiple abiotic stress conditions, including salinity. In this study, a mapping population of 132 F₂ families derived from a cross of cultivar Williams 82 (PI 518671, moderately salt sensitive) and Fiskeby III (salt tolerant) was analyzed to map salt tolerance genes. The evaluation for salt tolerance was performed by analyzing leaf scorch score (LSS), chlorophyll content ratio (CCR), leaf sodium content (LSC), and leaf chloride content (LCC) after treatment with 120 mM NaCl under greenhouse conditions. Genotypic data for the F₂ population were obtained using the SoySNP6K Illumina Infinium BeadChip assay. A major allele from Fiskeby III was significantly associated with LSS, CCR, LSC, and LCC on chromosome (Chr.) 03 with LOD scores of 19.1, 11.0, 7.7 and 25.6, respectively. In addition, a second locus associated with salt tolerance for LSC was detected and mapped on Chr. 13 with an LOD score of 4.6 and an R ² of 0.115. Three gene-based polymorphic molecular markers (Salt-20, Salt14056 and Salt11655) on Chr.03 showed a strong predictive association with phenotypic salt tolerance in the present mapping population. These molecular markers will be useful for marker-assisted selection to improve salt tolerance in soybean.

     

Erysiphe abbreviata on cherry bark oak--morphology, phylogeny and taxonomy

Powdery mildew on cherry bark oak (Quercus falcate var. pagodifolia) collected in Tennessee, USA, was determined to be Erysiphe abbreviata, a species confined to North America. The diagnostically important anamorph of this species is described for the first time. Sequence analyses of the rDNA ITS region and D1/D2 domains of the 28S rDNA were used to obtain phylogenetic data for and taxonomic conclusions about this species. The structure of the anamorph (Oidium subgen. Pseudoidium) and the molecular data support the placement of this species in Erysiphe emend. (including Microsphaera) as a species separate from the Eurasian Erysiphe alphitoides.     

Mapping of quantitative trait loci for canopy-wilting trait in soybean (Glycine max L. Merr)

Drought stress adversely affects [Glycine max (L.) Merr] soybean at most developmental stages, which collectively results in yield reduction. Little information is available on relative contribution and chromosomal locations of quantitative trait loci (QTL) conditioning drought tolerance in soybean. A Japanese germplasm accession, PI 416937, was found to possess drought resistance. Under moisture-deficit conditions, PI 416937 wilted more slowly in the field than elite cultivars and has been used as a parent in breeding programs to improve soybean productivity. A recombinant inbred line (RIL) population was derived from a cross between PI 416937 and Benning, and the population was phenotyped for canopy wilting under rain-fed field conditions in five distinct environments to identify the QTL associated with the canopy-wilting trait. In a combined analysis over environments, seven QTL that explained 75?% of the variation in canopy-wilting trait were identified on different chromosomes, implying the complexity of this trait. Five QTL inherited their positive alleles from PI 416937. Surprisingly, the other two QTL inherited their positive alleles from Benning. These putative QTL were co-localized with other QTL previously identified as related to plant abiotic stresses in soybean, suggesting that canopy-wilting QTL may be associated with additional morpho-physiological traits in soybean. A locus on chromosome 12 (Gm12) from PI 416937 was detected in the combined analysis as well as in each individual environment, and explained 27?% of the variation in canopy-wilting. QTL identified in PI 416937 could provide an efficient means to augment field-oriented development of drought-tolerant soybean cultivars.     

Genetic confirmation of 2 independent genes for resistance to soybean mosaic virus in J05 soybean using SSR markers

J05 soybean was previously identified to carry 2 independent genes, Rsv1 and Rsv3, for "soybean mosaic virus" (SMV) resistance by inheritance and allelism studies. The objective of this research was to confirm the 2 genes in J05 using molecular markers so that a marker-assisted selection can be implemented. The segregation of F(2) plants from J05 x Essex exhibited a good fit to a 3:1 ratio when inoculated with SMV G1. Three simple sequence repeat (SSR) markers near Rsv1, Satt114, Satt510, and Sat_154, amplified polymorphic DNA fragments between J05 and Essex and were closely linked to the gene on soybean molecular linkage group (MLG) F, thus verifying the presence of Rsv1 in J05 for resistance to SMV G1. The presence of Rsv3 in J05 was confirmed by 2 closely linked SSR markers on MLG B2, Satt726 and Sat_424, in F(2:3) lines that were derived from the SMV G1-susceptible F(2) plants and segregated in a 1:2:1 ratio for reaction to SMV G7. Two closely linked markers for Rsv4, Satt296 and Satt542, segregated independently of SMV resistance, indicating the absence of Rsv4 in J05. These SSR markers for Rsv1 and Rsv3 can serve as a useful molecular tool for selection and pyramiding of genes in J05 for SMV resistance.     

Meta-analysis to refine map position and reduce confidence intervals for delayed-canopy-wilting QTLs in soybean

Slow canopy wilting in soybean has been identified as a potentially beneficial trait for ameliorating drought effects on yield. Previous research identified QTLs for slow wilting from two different biparental populations, and this information was combined with data from three other populations to identify nine QTL clusters for slow wilting on Gm02, Gm05, Gm11, Gm 14, Gm17, and Gm19. The QTL cluster on Gm14 was eliminated because these QTLs appeared to be false positives. In the present research, QTLs from these remaining eight clusters were compiled onto the soybean consensus map for meta-QTL analysis. Five model selection criteria were used to determine the most appropriate number of meta-QTLs at these eight chromosomal regions. For a QTL cluster on Gm02, two meta-QTLs were identified, whereas for the remaining seven QTL clusters the single meta-QTL model was most appropriate. Thus, the analysis identified nine meta-QTLs associated with slow wilting. Meta-analysis decreased the confidence intervals from an average of 21.4 cM for the eight QTL clusters to 10.8 cM for the meta-QTLs. Averaged R² values of the nine meta-QTLs in eight QTL clusters were 0.13 and ranged from 0.09 to 0.22. Meta-QTLs on Gm11 and Gm19 had the highest R² values (0.22 and 0.20, respectively).     

Characterization of the fan1 locus in soybean line A5 and development of molecular assays for high-throughput genotyping of FAD3 genes

Soybean is one of the most important oil crops worldwide, and reducing the linolenic acid content of soybean oil will provide increased stability of the oil to consumers and limit the amount of trans fat in processed foods. The linolenic content in soybean seed is controlled by three fatty acid desaturase (FAD) three enzymes, FAD3A, B, and C. The soybean lines with 1 % linolenic acid content which are widely used in breeding for reduced linolenic acid in the USA have mutations in each of the three FAD genes derived from lines A5 (deletion of FAD3A), A26, and A23 (missense mutations in FAD3B and C, respectively). Although soybean line A5 has been released for 30 years, the extent and definition of the deletion of the FAD3A gene has not been characterized, which has prevented researchers from designing robust molecular markers for effective marker-assisted selection (MAS). Using a PCR-based genomic strategy, we have identified a 6.4-kbp deletion of the FAD3A gene in A5 and developed a TaqMan detection assay by targeting the deletion junction in A5, which could be used to distinguish the homozygotes and heterozygotes of the gene. In addition, based on mutant single nucleotide polymorphisms in FAD3B and FAD3C identified in A26 and A23, respectively, we have also developed TaqMan assays for high-throughput MAS. The TaqMan assays have proven to be a very effective platform for detecting the mutant FAD3 alleles and thus will greatly facilitate high-throughput MAS for development of soybean lines with reduced linolenic acid content.