Ⅰ期-Ⅲ期非转移性非小细胞肺癌的系统性治疗演变

早期肺癌患者的治疗是以治愈为目标的。针对手术可切除性和可操作性的多学科讨论模式决定了最终的局部治疗方式(手术或放疗)和相关的系统性治疗方案,从而进一步提高患者治愈的可能性。研究证据支持以顺铂为基础的辅助化疗用于切除术后,或与放疗同步使用。共识指南支持以新辅助化疗代替辅助化疗,并支持对不符合顺铂治疗条件的患者采用基于卡铂的治疗方案。由于研究设计效率低下,需要长时间随访来评估生存终点以及对晚期疾病的持续关注,将新药物(现在是IV期肺癌患者的标准药物)纳入以治愈为目标的治疗范式的工作一直滞后。目前正在研究中的替代性终点(例如病理缓解)将可能缩短研究的时间。2018年,抗程序性死亡配体(programmed cell death ligand 1,PD-L1)抗体度伐利尤单抗获批用于治疗同步放、化疗后的Ⅲ期肺癌患者,自那时起,针对早期肺癌患者的靶向治疗和免疫治疗的研究迅速发展。在本篇综述中,我们介绍了对于目前早期肺癌患者治疗方案的考虑因素,探讨并展望非转移性肺癌系统性治疗的临床研究现状和未来。

Plasma membrane-localized SlSWEET7a and SlSWEET14 regulate sugar transport and storage in tomato fruits

Sugars,especially glucose and fructose,contribute to the taste and quality of tomato fruits.These compounds are translocated from the leaves to the fruits and then unloaded into the fruits by various sugar transporters at the plasma membrane.SWEETs,are sugar transporters that regulate sugar efflux independently of energy or pH.To date,the role of SWEETs in tomato has received very little attention.In this study,we performed functional analysis of SlSWEET7a and SlSWEET14 to gain insight into the regulation of sugar transport and storage in tomato fruits.SlSWEET7a and SlSWEET14 were mainly expressed in peduncles,vascular bundles,and seeds.Both SlSWEET7a and SlSWEET14 are plasma membrane-localized proteins that transport fructose,glucose,and sucrose.Apart from the resulting increase in mature fruit sugar content,silencing SlSWEET7a or SlSWEET14 resulted in taller plants and larger fruits(in SlSWEET7a-silenced lines).We also found that invertase activity and gene expression of some SlSWEET members increased,which was consistent with the increased availability of sucrose and hexose in the fruits.Overall,our results demonstrate that suppressing SlSWEET7a and SlSWEET14 could be a potential strategy for enhancing the sugar content of tomato fruits.

Phenylfluorenamine-functionalized poly(N-vinylcarbazole)s as dopant-free polymer hole-transporting materials for inverted quasi-2D perovskite solar cells

In order to improve the efficiency and stability of inverted three-dimensional(3D) or quasi-2D perovskite solar cells(PSCs) for future commercialization, exploring high efficient dopant-free polymer holetransporting materials(HTMs) is still desired and meaningful. One simple and efficient way to achieve high performance dopant-free HTMs is to synthesize novel non-conjugated side-chain polymers via rational molecular design. In this work, N-(4-methoxyphenyl)-9,9-dimethyl-9H-fluoren-2-amine(FMeNPh) groups are introduced into the poly(N-vinylcarbazole)(PVK) side chains to afford two nonconjugated polymers PVCz-DFMeNPh and PVCz-FMeNPh as dopant-free HTMs in inverted quasi-2D PSCs. Benefited from the flexible properties of polyethylene backbone and excellent optoelectronic natures of FMeNPh side-chain groups, PVCz-DFMeNPh with more FMeNPh units exhibited excellent thermal stability, well-matched energy levels and improved charge mobility as compared to PTAA and PVCzFMeNPh. Moreover, the morphologies investigation of quasi-2D perovskite on PVCz-DFMeNPh shows more compact and homogeneous perovskite films than those on PTAA and PVCz-FMeNPh. As a result,the dopant-free PVCz-DFMeNPh based inverted quasi-2D PSCs deliver power conversion efficiency(PCE) up to 18.44% as well as negligible hysteresis and favorable long-term stability, which represents as excellent performance reported to date for inverted quasi-2D PSCs. The results demonstrate the great potentials of constructing non-conjugated side-chain polymer HTMs based on phenylfluorenamine-func tionalized PVK for the development of high efficient and stable inverted 3D or quasi-2D PSCs.

Piezoelectric nanofoams with the interlaced ultrathin graphene confining Zn–N–C dipoles for efficient piezocatalytic H_(2) evolution under low-frequency vibration

Unique nanofoams consisting of interweaved ultrathin graphene confining Zn–N–C dipoles (ZnNG) are constructed via calcination of Zn-coordinated precursor.Due to the introduction of local polar Zn–N–C configurations,with hypersensitivity for mechanical stress,the piezoelectricity is created on the nonpiezoelectric graphene,and the hierarchical ZnNG exhibits obvious piezocatalytic activity of water splitting for H_(2) production even under mild agitation.The corresponding rate of H_(2) production is about 14.65 μmol g^(-1)h^(-1).It triggers a breakthrough in piezocatalytic H_(2) evolution under low-frequency vibration,and takes a significant step forward for piezocatalysis towards practical applications.Furthermore,the presented concept of confining atomic polar configuration for engineering piezoelectricity would open up new horizon for constructing new-type piezoelectrics based on both piezoelectric and nonpiezoelectric materials.

The association between craniofacial gene and oncogene

As early as 2000 years ago,ancient Chinese medical records had described the relationship between diseases and appearance in detail.Moreover,modern medicine has also constantly studied the relationship between facial features and health in evolutionary terms.It is well known that many hereditary diseases involve certain abnormal facial features and gene mutations.The tumor is also considered as genetic disorder to some extent,so what is the relationship between cancer genetics and congenital development of facial features?Here,we reviewed some clues to the appearance-gene-tumor relation,which might become the targets in the early prevention or gene therapy of cancer in the future.This summary provided us a new strategy for the cancer genetic screening and a new research direction for genetic diagnosis of the potential disease.

Nonvolatile and reconfigurable two-terminal electro-optic duplex memristor based on III-nitride semiconductors

With the fast development of artificial intelligence(AI),Internet of things(IOT),etc,there is an urgent need for the technology that can efficiently recognize,store and process a staggering amount of information.The AlScN material has unique advantages including immense remnant polarization,superior temperature stability and good latticematch to other III-nitrides,making it easy to integrate with the existing advanced III-nitrides material and device technologies.However,due to the large band-gap,strong coercive field,and low photo-generated carrier generation and separation efficiency,it is difficult for AlScN itself to accumulate enough photo-generated carriers at the surface/interface to induce polarization inversion,limiting its application in in-memory sensing and computing.In this work,an electro-optic duplex memristor on a GaN/AlScN hetero-structure based Schottky diode has been realized.This twoterminal memristor shows good electrical and opto-electrical nonvolatility and reconfigurability.For both electrical and opto-electrical modes,the current on/off ratio can reach the magnitude of 104,and the resistance states can be effectively reset,written and long-termly stored.Based on this device,the“IMP”truth table and the logic“False”can be successfully reproduced,indicating the huge potential of the device in the field of in-memory sensing and computing.

Characterization of Panax ginseng UDP- Glycosyltransferases Catalyzing Protopanaxatriol and Biosyntheses of Bioactive Ginsenosides F1 and Rhl in Metabolically Engineered Yeasts

Ginsenosides, the main pharmacologically active natural compounds in ginseng （Panax ginseng）, are mostly the glycosylated products of protopanaxadiol （PPD） and protopanaxatriol （PPT）. No uridine diphosphate glycosyltransferase （UGT）, which catalyzes PPT to produce PPT-type ginsenosides, has yet been reported. Here, we show that UGTPgl, which has been demonstrated to regio-specifically glycosylate the C20-OH of PPD, also specifically glycosylates the C20-OH of PPT to produce bioactive ginsenoside FI. We report the characterization of four novel UGT genes isolated from P. ginseng, sharing high deduced amino acid identity （〉84%） with UGTPgl. We demonstrate that UGTPgl00 specifically glycosylates the C6-OH of PPT to produce bioactive ginsenoside Rhl, and UGTPgl01 catalyzes PPT to produce F1, followed by the generation of ginsenoside Rgl from FI. However, UGTPgl02 and UGTPgl03 were found to have no detectable activity on PPT. Through structural modeling and site-directed mutagenesis, we identified several key amino acids of these UGTs that may play important roles in determining their activities and substrate regio-specificities. Moreover, we constructed yeast recombinants to biosynthesize F1 and Rhl by introducing the genetically engineered PPT-producing pathway and UGTPgl or UGTPgl00. Our study reveals the possible biosynthetic pathways of PPT-type ginsenosides in Panax plants, and provides a sound manufacturing approach for bioactive PPT-type ginsenosides in yeast via synthetic biology strategies.

pUGTdb:A comprehensive database of plant UDP-dependent glycosyltransferases

Dear Editor,Plant UDP-dependent glycosyltransferases(UGTs),belonging to the carbohydrate-active enzyme glycosyltransferase 1 family(Louveau and Osbourn,2019),not only play important roles in adaptation to various environments(Cai et al.,2020;Pastorczyk-Szlenkier and Bednarek,2021)but also endow plant natural products with great pharmaceutical and ecological significance(Margolin et al.,2020).In recent years,an increasing number of plant UGTs have been characterized to function in the biosynthesis of many bioactive compounds such as ginsenosides(Wei et al.,2015),breviscapine(Liu et al.,2018),and rubusoside(Xu et al.,2022).

GPIBase:A comprehensive resource for geminivirus-plant-insect research

Dear Editor,As one of the most widespread and destructive families of plant viruses,Geminiviridae,named for the twinned icosahedral particles of virus members in the family,poses a serious threat to agricultural production worldwide.Transmitted by various homopterans insects such as whiteflies,leafhoppers,aphids,and treehoppers,geminiviruses infect,in addition to wild plants,vegetable,root,and fiber crops,thus causing important losses around the globe(Hanley-Bowdoin et al.,2013;Li et al.,2022).

Prime editing-mediated precise knockin of protein tag sequences in the rice genome

Dear Editor,Accurately labeling proteins in living plant cells has long been a challenge and can be addressed by targeted insertion of tag sequences in a given locus.Recent optimized plant prime editors(PEs)enable efficient programmable installation of small insertions or deletions,including insertions of short sequences(Li et al.,2022a,2022b;Jiang et al.,2022;Xu et al.,2022;Zong et al.,2022;Zou et al.,2022).To investigate whether prime editing can be used to tag endogenous proteins in rice,we made use of the enpPE2 system described in our previous report(Li et al.,2022b).

Establishment of an efficient haploid identification system by engineering anthocyanin accumulation in the wheat embryo

Dear Editor,Bread wheat(Triticum aestivum)is one of the most important food crops and provides approximately 20%of the food calories for human consumption.A 70%increase in wheat production is needed by 2050 to keep pace with the growing global population(International Wheat Genome Sequencing,2014).Developing superior cultivars is an efficient way to improve yield.Nevertheless,conventional breeding is time consuming,as more than eight generations are needed to develop new plant varieties.Using doubled haploid(DH)technology,homozygous lines can be produced in only two generations,dramatically accelerating the breeding process.In wheat,haploids can be obtained by cross pollination with corn pollen followed by embryo rescue(Laurie and Bennett,1988).In maize,haploids can be induced by haploid inducer lines derived from Stock6(Liu et al.,2022).The cloning of two genes that control haploid induction(HI)in maize,MATL/ZmPLA1/NLD and ZmDMP,paved the way for DH breeding in more crop species(Jacquier et al.,2020).Further studies have shown that loss of function of TaPLAs triggers wheat HI with an efficiency of 5.88%to 31.6%(Liu et al.,2020a,2020b);this would be a promising approach for establishing a new,simple,and more efficient DH breeding method in wheat.

In situ Injectable Tetra-PEG Hydrogel Bioadhesive for Sutureless Repair of Gastrointestinal Perforation

Hydrogel bioadhesives represent promising and efficient alternatives to sutures or staples for gastrointestinal(GI)perforation management.However,several concerns remain for the existing bioadhesives including slow and/or weak adhesive,poor mechanical strength,low biocompatibility,and poor biodegradability,which largely limit their clinical application in GI perforation repair.In this work,we introduce an in situ injectable Tetra-PEG hydrogel bioadhesive(SS)composed of tetra-armed poly(ethylene glycol)amine(Tetra-PEG-NH2)and tetra-armed poly(ethylene glycol)succinimidyl succinate(Tetra-PEG-SS)for the sutureless repair of GI defects.The SS hydrogel exhibits rapid gelation behavior and high burst pressure and is capable of providing instant robust adhesion and fluid-tight sealing in the ex vivo porcine intestinal and gastric models.Importantly,the succinyl ester linkers in the SS hydrogel endow the bioadhesive with suitable in vivo degradability to match the new GI tissue formation.The in vivo evaluation in the rat GI injured model further demonstrates the successful sutureless sealing and repair of the intestine and stomach by the SS hydrogel with the advantages of neglectable postsurgical adhesion,suppressed inflammation,and enhanced angiogenesis.Together,our results support potential clinical applications of the SS bioadhesive for the high-efficient repair of GI perforation.

Insights into the evolution and spatial chromosome architecture of jujube from an updated gapless genome assembly

Dear Editor,Jujube(Ziziphus jujuba Mill.),commonly called Chinese jujube,is a vital member of the Rhamnaceae family.It is famous for its tolerance to dry,barren,and saline-alkali soils,and its fruit has important nutritional and medicinal value.Recent fundamental research on jujube has involved assembly of draft genome sequences for the fresh-eating cultivar‘Dongzao’(Liu et al.,2014),dry-eating cultivar‘Junzao’(Huang et al.,2016),and wild sour jujube‘Suanzao’(Shen et al.,2021).

Mutation-independent gene knock-in therapy targeting 5′UTR for autosomal dominant retinitis pigmentosa

Dear Editor,Retinitis pigmentosa(RP)is an inherited photoreceptor degeneration disease with high genetic heterogeneity(>90 disease-causing genes according to RetNet:https://web.sph.uth.edu/RetNet/sumdis.htm).Taking a single RP disease gene RHO as an example,there are more than two hundred loss-of-function and gain-of-function mutations identified.1 While gene supplementation therapy has emerged as the most promising treatment for autosomal recessive RP(arRP)and X-linked RP(ClinicalTrials identifier:NCT01482195,NCT03328130,NCT03116113,NCT03252847,NCT03316560),therapeutic approaches to treat autosomal dominant RP(adRP)fall behind due to the low efficiency to disrupt mutant alleles specifically and a broad spectrum of the gain-of-function mutations.

From Golden Rice to aSTARice:Bioengineering Astaxanthin Biosynthesis in Rice Endosperm

Carotenoids are important phytonutrients with antioxidant properties,and are widely used in foods and feedstuffs as Supplements.Astaxanthin,a red-colored ketocarotenoid,has strong antioxidant activity and thus can benefit human health.However,astaxanthin is not produced in most higher plants.Here we report the bioengineering of astaxanthin biosynthesis in rice endosperm by introducing four synthetic genes,sZmPSY1,sPaCrtl,sCrBKT,and sHpBHY,which encode the enzymes phytoene synthase,phytoene desaturase,β-carotene ketolase,and β-carotene hydroxylase,respectively.Transgneic overexpression of two (sZmPSY1 and sPaCrtl),three (sZmPSY1,sPaCrtl and sCrBKT),and all these four genes driven by rice endosperm-specific promoters established the Carotenoid/ketocarotenoid/astaxanthin biosynthetic pathways in the endosperm and thus resulted in various types of germplasm,from the yellow-grained β-caro- tene-enriched Golden Rice to orange-red-grained Canthaxanthin Rice and Astaxanthin Rice,respectively. Grains Of Astaxanthin Rice were enriched with astaxanthin in the endosperm and had higher antioxidant activity.These results proved that introduction of a minimal set of four transgenes enables de novo biosynthesis of astaxanthin in therice endosperm.This work provides a Successful example for synthetic biology in plants and biofortification in crops;the biofortified rice products generated by this study could be consumed as health-promoting foods and processed tO produce dietary supplements.

Two Faces of One Seed： Hormonal Regulation of Dormancy and Germination

Seed plants have evolved to maintain the dormancy of freshly matured seeds until the appropriate time for germination. Seed dormancy and germination are distinct physiological processes, and the transition from dormancy to germination is not only a critical developmental step in the life cycle of plants but is also impor- tant for agricultural production. These processes are precisely regulated by diverse endogenous hormones and environmental cues. Although ABA （abscisic acid） and GAs （gibberellins） are known to be the primary phytohormones that antagonistically regulate seed dormancy, recent findings demonstrate that another phytohormone, auxin, is also critical for inducing and maintaining seed dormancy, and therefore might act as a key protector of seed dormancy. In this review, we summarize our current understanding of the sophisticated molecular networks involving the critical roles of phytohormones in regulating seed dormancy and germination, in which AP2-domain-containing transcription factors play key roles. We also discuss the interactions （crosstalk） of diverse hormonal signals in seed dormancy and germination, focusing on the ABA/GA balance that constitutes the central node.

BZR1 Positively Regulates Freezing Tolerance via CBF-Dependent and CBF-Independent Pathways in Arabidopsis

Cold stress is a major environmental factor that adversely affects plant growth and development. The C-repeat binding factor/DRE binding factor 1 （CBF/DREB1） transcriptional regulatory cascade has been shown to play important roles in plant response to cold. Here we demonstrate that two key components of brassinosteroid （BR） signaling modulate freezing tolerance of Arabidopsis plants. The loss-of-function mutant of the GSK3-1ike kinases involved in BR signaling, bin2-3 bill bil2, showed increased freezing tolerance, whereas overexpression of BIN2 resulted in hypersensitivity to freezing stress under both non-acclimated and acclimated conditions. By contrast, gain-of-function mutants of the transcription factors BZR1 and BES1 displayed enhanced freezing tolerance, and consistently cold treatment could induce the accumulation of dephosphorylated BZR1. Biochemical and genetic analyses showed that BZR1 acts upstream of CBF1 and CBF2 to directly regulate their expression. Moreover, we found that BZR1 also regulated other COR genes uncoupled with CBFs, such as WKRY6, PYL6, SOCl, JMT, and SAG21, to modulate plant response to cold stress. Consistently, wrky6 mutants showed decreased freezing tolerance. Taken together, our results indicate that BZR1 positively modulates plant freezing tolerance through CBF-dependent and CBF-independent pathways.

A Rare Allele of GS2 Enhances Grain Size anc Grain Yield in Rice

Grain size determines grain weight and affects grain quality. Several major quantitative trait loci （QTLs） regulating grain size have been cloned; however, our understanding of the underlying mechanism that regulates the size of rice grains remains fragmentary. Here, we report the cloning and characterization of a dominant QTL, GRAIN SIZE ON CHROMOSOME 2 （GS2）, which encodes Growth-Regulating Factor 4 （OsGRF4）, a transcriptional regulator. GS2 localizes to the nucleus and may act as a transcription activator. A rare mutation of GS2 affecting the binding site of a microRNA, OsmiR396c, causes elevated expression of GS2/OsGRF4. The increase in GS2 expression leads to larger cells and increased numbers of cells, which thus enhances grain weight and yield. The introduction of this rare allele of GS2/OsGRF4 into rice cultivars could significantly enhance grain weight and increase grain yield, with possible applications in breeding high-yield rice varieties.

TRICHOMEAND ARTEMISININ REGULATOR 1 Is Required for Trichome Development and Artemisinin Biosynthesis in Artemisia annua

Trichomes, small protrusions on the surface of many plant species, can produce and store various secondary metabolic products. Artemisinin, the most famous and potent medicine for malaria, is synthesized, stored, and secreted by Artemisia annua trichomes. However, the molecular basis regulating the biosynthesis of artemisinin and the development of trichomes in A. annua remains poorly understood. Here, we report that an AP2 transcription factor, TRICHOME AND ARTEMISININ REGULATOR 1 （TAR1）, plays crucial roles in regulating the development of trichomes and the biosynthesis of artemisinin in A. annua. TAR1, which encodes a protein specially located in the nucleus, is mainly expressed in young leaves, flower buds, and some trichomes. In TAR1-RNAi lines, the morphology of trichomes and the composition of cuticular wax were altered, and the artemisinin content was dramatically reduced, which could be significantly increased by TAR1 oeverexpression. Expression levels of several key genes that are involved in artemisinin biosynthesis were altered when TAR1 was silenced or overexpressed. By the electrophoretic mobility shift, yeast one-hybrid and transient transformation β-glucuronidase assays, we showed that ADS and CYP71AV1, two key genes in the biosynthesis pathway of artemisinin, are likely the direct targets of TAR1. Taken together, our results indicate that TAR1 is a key component of the molecular network regulating trichome development and artemisinin biosynthesis in A. annua.

ABF2, ABF3, and ABF4 Promote ABA-Mediated Chlorophyll Degradation and Leaf Senescence by Transcriptional Activation of Chlorophyll Catabolic Genes and Senescence-Associated Genes in Arabidopsis

Chlorophyll （Chl） degradation is an integral process of leaf senescence, and NYE1/SGR1 has been demonstrated as a key regulator of Chl catabolism in diverse plant species. In this study, using yeast one-hybrid screening, we identified three abscisic acid （ABA）-responsive element （ABRE）-binding transcription factors, ABF2 （AREB1）, ABF3, and ABF4 （AREB2）, as the putative binding proteins of the NYE1 promoter. Through the transactivation analysis, electrophoretic mobility shift assay, and chromatin immunoprecipitation, we demonstrated that ABF2, ABF3, and ABF4 directly bound to and activated the NYE1 promoter in vitro and in vivo. ABA is a positive regulator of leaf senescence, and exogenously applied ABA can accelerate Chl degradation. The triple mutant of the ABFs, abf2abf3abf4, as well as two ABA-insensitive mutants, abil-1 and snrk2.2/2.3/2.6, exhibited stay-green phenotypes after ABA treatment, along with decreased induction of NYE1 and NYE2 expression. In contrast, overexpression of ABF4 accelerated Chl degradation upon ABA treatment. Interestingly, ABF2/3/4 could also activate the expression of two Chl catabolic enzyme genes, PAO and NYCl, by directly binding to their promoters. In addition, abf2abf3abf4 exhibited a functional stay-green phenotype, and senescence-associated genes （SAGs）, such as SAG29 （SWEET15）, might be directly regulated by the ABFs. Taken together, our results suggest that ABF2, ABF3, and ABF4 likely act as key regulators in mediating ABA-triggered Chl degradation and leaf senescence in general in Arabidopsis.