In light of the pressing global challenges of climate change,declining crop resilience,and hidden hunger,it is imperative to overcome the limitations of conventional crop breeding to enhance both the nutritional quali...In light of the pressing global challenges of climate change,declining crop resilience,and hidden hunger,it is imperative to overcome the limitations of conventional crop breeding to enhance both the nutritional quality and stress tolerance of crops.Synthetic metabolic engineering presents innovative strategies for the precision modification and de novo design of metabolic pathways.This approach generally encompasses three essential steps:identifying key metabolites through metabolomics,integrating multi-omics technologies to investigate the synthesis and regulation of these metabolites,and utilizing gene editing or de novo design to modify crop metabolic pathways associated with desirable agronomic traits.This review underscores the vital role of plant metabolite diversity in enhancing crop nutritional quality and stress resilience.Integrated multi-omics analyses facilitate the metabolic engineering by identifying key genes,transporters,and transcription factors that regulate metabolite biosynthesis.Precision modification strategies employ genome editing tools to reprogram endogenous metabolic networks,while de novo design reconstructs metabolic pathways through the introduction of exogenous biological elements—thereby both approaches enable the targeted enhancement of desired traits.These strategies have been effectively implemented in major food crops.However,simultaneously enhancing nutritional quality and stress resilience remains challenging due to inherent trade-offs and resource competition in distinct metabolic pathways within plants.Future research should integrate AI-driven predictive models with multi-omics datasets to decipher dynamic metabolic homeostasis and engineer climate-smart crops that maximize yield while preserving quality and environmental adaptability.展开更多
Prostate-associated gene 4 （PAGE4） is a remarkably prostate-specific Cancer/Testis Antigen that is highly upregulated in the human fetal prostate and its diseased states but not in the adult normal gland. PAGE4 is a...Prostate-associated gene 4 （PAGE4） is a remarkably prostate-specific Cancer/Testis Antigen that is highly upregulated in the human fetal prostate and its diseased states but not in the adult normal gland. PAGE4 is an intrinsically disordered protein （IDP） that functions as a stress-response protein to suppress reactive oxygen species as well as prevent DNA damage. In addition, PAGE4 is also a transcriptional regulator that potentiates transactivation by the oncogene c-Jun, c-Jun forms the AP-1 complex by heterodimerizing with members of the Fos family and plays an important role in the development and pathology of the prostate gland, underscoring the importance of the PAGE4/c-Jun interaction. HIPK1, also a component of the stress-response pathway, phosphorylates PAGE4 at T51 which is critical for its transcriptional activity. Phosphorylation induces conformational and dynamic switching in the PAGE4 ensemble leading to a new cellular function. Finally, bioinformatics evidence suggests that the PAGE4 mRNA could be alternatively spliced resulting in four potential isoforms of the polypeptide alluding to the possibility of a range of conformational ensembles with latent functions. Considered together, the data suggest that PAGE4 may represent the first molecular link between stress and prostate cancer （PCa）. Thus, pharmacologically targeting PAGE4 may be a novel opportunity for treating and managing patients with PCa, especially patients with low-risk disease.展开更多
The analysis of bacterial diversity in aquatic systems particularly in rivers, lakes, and streams can provide useful data on the effect of anthropogenic activities on such water bodies to humans and fishes. Idah River...The analysis of bacterial diversity in aquatic systems particularly in rivers, lakes, and streams can provide useful data on the effect of anthropogenic activities on such water bodies to humans and fishes. Idah River, the focal point of this study, is an offshoot of the two major Nigerian rivers characterized by observed human activities and pollution sources. Water samples were collected from four designated sites and assessed for their bacterial assemblages and structure, using PacBio Single-Molecule Real-Time (SMRT) sequencing technology. The full length of the 16S rRNA gene was sequenced, and Amplicon Sequence Variants were generated using the DADA2 workflow optimised for PacBio long-read amplicons in Rstudio. A total of 8751 high-quality reads obtained were taxonomically classified as 24 phyla, 42 classes, 84 orders, 125 families, 156 genera, and 106 species. Taxonomical composition revealed Proteobacteria as the most abundant phyla across all sample sites. At the genera level, Azospira (57.03%) was the most dominant ASV in Docking Point A, while Acinetobacter (66.67%) was the most abundant ASV in Docking Point B. In Idah Axis Confluence, hgcl clade (65.66%) was the most prevalent ASV, whereas Holophaga (42.86%) was the most common ASV in Idah Axis Midstream. Genera analysis also revealed that 12.9% of the total ASVs were discovered across all sample sites. Among these were pathogenic bacteria, reducers, and degraders of domestic and animal wastes. Observed results provide evidence that sampled sites of Idah River are contaminated, most likely through constant human activities and thus, could have an impact on resident fishes as well. This study, therefore, agrees with a previous report from the river, which used standard microbial procedures. However, next-generation sequencing techniques employed revealed more bacterial community than the former, including unresolved taxonomic sequences that may be novel.展开更多
Only in recent years, the draft sequences for several agricultural animals have been assembled. Assembling an individual animal＇s entire genome sequence or specific region（s） of interest is increasingly important f...Only in recent years, the draft sequences for several agricultural animals have been assembled. Assembling an individual animal＇s entire genome sequence or specific region（s） of interest is increasingly important for agricultura researchers to perform genetic comparisons between animals with different performance. We review the current status for several sequenced agricultural species and suggest that next generation sequencing （NGS） technology with decreased sequencing cost and increased speed of sequencing can benefit agricultural researchers. By taking advantage of advanced NGS technologies, genes and chromosomal regions that are more labile to the influence of environmental factors could be pinpointed. A more long term goal would be addressing the question of how animals respond at the molecular and cellular levels to different environmental models （e.g. nutrition）. Upon revealing important genes and gene-environment interactions, the rate of genetic improvement can also be accelerated. It is clear that NGS technologies will be able to assist animal scientists to efficiently raise animals and to better prevent infectious diseases so that overall costs of animal production can be decreased.展开更多
Haplotypes provide useful information for genomics-based approaches,genomic prediction,and genome-wide association study.As a small number of superior founders have contributed largely to the breeding history of fruit...Haplotypes provide useful information for genomics-based approaches,genomic prediction,and genome-wide association study.As a small number of superior founders have contributed largely to the breeding history of fruit trees,the information of founder haplotypes may be relevant for performing the genomics-based approaches in these plants.In this study,we proposed a method to estimate 14 haplotypes from 7 founders and automatically trace the haplotypes forward to apple parental(185 varieties)and breeding(659 F 1 individuals from 16 full-sib families)populations based on 11,786 single-nucleotide polymorphisms,by combining multiple algorithms.Overall,92%of the single-nucleotide polymorphisms information in the parental and breeding populations was characterized by the 14 founder haplotypes.The use of founder haplotype information improved the accuracy of genomic prediction in 7 traits and the resolution of genome-wide association study in 13 out of 27 fruit quality traits analyzed in this study.We also visualized the significant propagation of the founder haplotype with the largest genetic effect in genome-wide association study over the pedigree tree of the parental population.These results suggest that the information of founder haplotypes can be useful for not only genetic improvement of fruit quality traits in apples but also for understanding the selection history of founder haplotypes in the breeding program of Japanese apple varieties.展开更多
BACKGROUND Human epidermal growth factor receptor 2(HER2)amplification is a molecular driver for a subset of colorectal cancers(CRCs)and one of the major causes of anti-epidermal growth factor receptor(EGFR)treatment ...BACKGROUND Human epidermal growth factor receptor 2(HER2)amplification is a molecular driver for a subset of colorectal cancers(CRCs)and one of the major causes of anti-epidermal growth factor receptor(EGFR)treatment failure.Compared to dual anti-HER2 treatments,which have been shown to be effective in HER2-positive metastatic CRC patients,single-agent anti-HER2 therapy is rarely used to treat CRC.CASE SUMMARY Herein,we report a case of RAS/BRAF-wild-type metastatic CRC that was identified as HER2-positive through circulating tumor DNA(ctDNA)testing by next-generation sequencing following the failure of two lines of therapy.Subsequently,the patient was given lapatinib monotherapy that led to a partial response with a progression-free survival of 7.9 mo.Moreover,serial ctDNA detection was used to monitor the efficacy of lapatinib.The aberration of HER2 copy number disappeared when radiographic assessment revealed a partial response.However,a high level of HER2 amplification was detected again at the time of disease progression.Finally,a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha mutation was identified at the time of tumor progression,which may explain the acquired resistance to lapatinib.CONCLUSION This is the first case report of HER2-positive RAS/BRAF wild-type metastatic CRC patient responding to lapatinib monotherapy.It highlights that ctDNA testing is an effective and feasible approach to evaluate the efficacy of anti-HER2 therapy.展开更多
Polyploidy is common among agriculturally important crops. Popular genetic methods and their implementations cannot always be applied to polyploid genetic data. We give an overview about available tools and their limi...Polyploidy is common among agriculturally important crops. Popular genetic methods and their implementations cannot always be applied to polyploid genetic data. We give an overview about available tools and their limitations in terms of levels of ploidy, auto- and allo-ploidy. The main classes of tools are genotype calling, linkage mapping and haplotyping. The usability of the tools is discussed with a focus on their applicability to data sets produced by state of the art technologies. We show that many challenges remain until the toolset for polyploidy provides similar functionalities as those which are already available for diploids. Some tools have been developed over a decade ago and are now outdated. In addition, we discuss necessary steps to overcome this shortage in the future.展开更多
The prevalence of metabolic-dysfunction-associated steatotic liver disease(MASLD)is alarmingly high;it is estimated to affect up to a quarter of the global population,making it the most common liver disorder worldwide...The prevalence of metabolic-dysfunction-associated steatotic liver disease(MASLD)is alarmingly high;it is estimated to affect up to a quarter of the global population,making it the most common liver disorder worldwide.MASLD is characterized by excessive hepatic fat accumulation and is commonly associated with comorbidities such as obesity,dyslipidemia,and insulin resistance;however,it can also manifest in lean individuals.Therefore,it is crucial to develop effective therapies for this complex condition.Currently,there are no approved medications for MASLD treatment,so there is a pressing need to investigate alternative approaches.Extensive research has characterized MASLD as a multifaceted disease,frequently linked to metabolic disorders that stem from dietary habits.Evidence suggests that changes in the gut microbiome play a fundamental role in the development and progression of MASLD from simple steatosis to steatohepatitis and even hepatocellular carcinoma(HCC).In this review,we critically examine the literature on the emerging field of gut-microbiota-based therapies for MASLD and metabolicdysfunction-associated steatohepatitis(MASH),including interventions such as fecal microbiota transplantation(FMT),probiotics,prebiotics,short-chain fatty acids,antibiotics,metabolic pathway targeting,and immune checkpoint kinase blockade.展开更多
We consider the problem of fair rate control for wireless ad-hoc networks with time varying channel capacities. The interaction between links in wireless ad-hoc networks introduces additional constraints on the flow r...We consider the problem of fair rate control for wireless ad-hoc networks with time varying channel capacities. The interaction between links in wireless ad-hoc networks introduces additional constraints on the flow rate. A primal-dual algorithm that guarantees fair rate control is proved to be trajectory stable. Various fairness indexes are obtained by choosing the specified form of the utility functions, and the numerical results validate the effectiveness of the proposed algorithm.展开更多
Finding water resources for the desert plants is one of the important research areas since it enables saving water resources.Bromus inermis plant was noticed to keep 5%of moisture in its rhizosphere zone;therefore,thi...Finding water resources for the desert plants is one of the important research areas since it enables saving water resources.Bromus inermis plant was noticed to keep 5%of moisture in its rhizosphere zone;therefore,this study aimed to identify this source of water.Thirteen endophytic bacteria were isolated from the root of B.inermis and identified.Their specific respiration rate was determined.Alcaligenes faecalis showed the highest specific respiration rate.It is a facultative chemoautotrophic hydrogen-fixing bacterium that utilizes the hydrogen gas as energy source and the water is produced as an end product.The source of hydrogen gas for this bacterium is not only from air and soil gases but also from the hydrogen-producing bacteria such as Enterobacter spp.,which was among the isolated bacteria.The hydrogenases synthesizing genes(HoxC,HypA and HypB)were detected in most of the isolated bacteria and roots of four wild plants,out from 18 wild plant samples,epically the grains of the wild wheat plant.This result suggests that the hydrogen-fixing and hydrogen-producing bacteria transfer from the root through the plant to inhabit the grain/seeds.This can help the grain/seeds to germinate in drought environment.展开更多
Soybean is the primary source of plant protein for humans.Owing to the indigestibility of the raffinose family of oligosaccharides(RFO),raffinose and stachyose are considered anti-nutritive factors in soybean seeds.Lo...Soybean is the primary source of plant protein for humans.Owing to the indigestibility of the raffinose family of oligosaccharides(RFO),raffinose and stachyose are considered anti-nutritive factors in soybean seeds.Low-RFO soybean cultivars are generated by mutagenesis of RFO biosynthesis genes,but the carbohydrate profiles invite further modification to lower RFOs.This study employed a pooled multiplex genome editing approach to target four seed-specifically expressed genes mediating RFO biosynthesis,encoding three raffinose synthases(RS2,RS3,and RS4)and one stachyose synthase.In T1progeny,rs2/rs3 and rs4/sts homozygous double mutants and a rs2/rs3/rs4/sts quadruple mutant(rfo-4m)were characterized.The rs2/rs3 mutant showed reduced raffinose and stachyose contents,but the rs4/sts mutant showed only reduced stachyose in seeds.The RFO contents in the rfo-4m mutant were almost eliminated.Metabolomic analysis showed that the mutation of four RFO biosynthesis genes led to a shift of metabolic profile in the seeds,including the accumulation of several oligosaccharides-related metabolites.These mutants could contribute to precision breeding of soybean cultivars for soy food production.展开更多
Background:In many cancer types,aryl hydrocarbon receptor nuclear translocator 2(ARNT2)has been found to be associated with tumor cell proliferation and prognosis.However,the role of ARNT2 in clear cell renal cell car...Background:In many cancer types,aryl hydrocarbon receptor nuclear translocator 2(ARNT2)has been found to be associated with tumor cell proliferation and prognosis.However,the role of ARNT2 in clear cell renal cell carcinoma(ccRCC)has not been completely elucidated.In this study,the potential role of ARNT2 in ccRCC development was characterized.Methods:A pan-cancer dataset(TCGA-TARGET-GTEx)was accessed from UCSC Xena Data Browser.ARNT2 expression in normal and tumor samples was compared.Univariate Cox regression was performed to evaluate the prognostic value of ARNT2.Single sample gene set enrichment analysis(ssGSEA)was used to estimate the enrichment of functional pathways and gene signatures.CIBERSORT and ESTIMATE methods evaluated the immune infiltration.The ARNT2 expression was determined in ccRCC tissue and cell lines using RT-qPCR and Western blot.Results:ARNT2 expression was significantly dysregulated in 23 out of 30 cancer types.Pan-cancer data revealed a strong correlation between ARNT2 expression and immune modulators,immune cell infiltration,and genomic alternations.In ccRCC patients,the low-ARNT2 expression group had higher immune infiltration,CD8 T cells,and programmed cell death ligand 1 expression,as well as higher enrichment score of immunotherapeutic predictors than those in the high-ARNT2 expression group.Low-ARNT2 expression group was more responsive to immunotherapy.Moreover,low ARNT2 expression was observed in ccRCC tissue and cell lines.Conclusions:Dysregulated ARNT2 expression is involved in cancer development and the modulation of the immune microenvironment.ARNT2 can be potentially used as a prognostic indicator and an immunotherapeutic indicator for ccRCC.展开更多
Bovine tuberculosis (BTB) is a considerable threat to livestock keepers and public health in many developing and underdeveloped countries. We investigated associations between 20 microsatellite markers and three pheno...Bovine tuberculosis (BTB) is a considerable threat to livestock keepers and public health in many developing and underdeveloped countries. We investigated associations between 20 microsatellite markers and three phenotypes for BTB in a sample of the Chadian cattle population. The phenotypes measured were: 1) single intra-dermal comparative cervical tuberculin test (SICCT) performed on live animals, 2) presence of lesion post-slaughter, 3) a bacteriological tissue culture test for Mycobacterium bovis using the samples with observed lesions and 4) a predicted Bayesian model (BM) estimate of a true BTB disease status using all tested animals. All traits were recorded in binary form and as either 1 = presence or 0 = absence. A total of 224 animals for SICCT, lesion and BM traits and 96 animals with bacteriological culture test were genotyped. Generalised linear models were fitted to the binary BTB phenotypes that consisted of age (covariate), sex (2 levels), breed (2 levels) and markers (alleles: 5 - 14 levels) as explanatory variables and implemented in R using glm with a logit link function. The model was fitted for each marker, separately. Six out of 20 markers tested were significantly associated with at least one trait considered;these were ILSTS005, ILSTS006, TGLA227, BM2113 and CSRM66. Genomic regions around these markers may serve as a basis for further functional investigations. This is the first study to report association of microsatellite markers with bovine tuberculosis traits in African or Chadian cattle population.展开更多
Degenerate primers are particularly useful in amplifying homologous genes from different organisms. This paper describes a method for designing degenerate primers for a given multiple alignment of DNA sequences of hsp...Degenerate primers are particularly useful in amplifying homologous genes from different organisms. This paper describes a method for designing degenerate primers for a given multiple alignment of DNA sequences of hsp70 gene family using ClustalW algorithm and detect the consensus region in gene family of hsp70 in a plant species which have not any recorded information about hsp70 gene family in the Genbank of National Centre of Biotechnology Information （NCBI） like Arando donax .The sequenced consensus sequence ofArando donax is considered a gene marker in building the genome map sequence. The BLASTn program is used to find a homology between more than one accession numbers of DNA sequences, （X67711.2） was for Oryza sativa （hsp70）, （AY372071. l） was for Nicotiana tabacum （hsp70） and （L41253.2） was for Lycopersicon esculentum （Hsc70）. In silco PCR module was performed to detect the melting temperatures （Tm） and predicted the PCR product size （783 bp）.The result of designed degenerate primers showed that there was a homology founded among the designed primers and the DNA templates of the recorded sequences （AY372071.1, X67711.2 and L41253.2） with at least 80% identity. The designed degenerate primers were used to isolate a consensus region ofhsp70 gene family ofArando donax at the expected molecular weight （783 bp）. The isolated PCR product, （783 bp） ofArando donax was sequenced and submitted to the Database of Japan （DDBJ） with accession number AB819871. The ORF finder tool translated the accession number AB819871 and gave a selected frame which used to build 3D structure model. In conclusion, this study focused on the importance of designing the degenerate primers to isolate the gene family and predict the 3D structure of gene family depending on the ORF finder tool of Genebank.展开更多
Recently, NK1R （Neurokinin-1 receptors） take attention as new and promising target in anticancer drug development area. It has been proved that non-peptide NK1R antagonists L-733,060, aprepitant and L-732,138 inhibi...Recently, NK1R （Neurokinin-1 receptors） take attention as new and promising target in anticancer drug development area. It has been proved that non-peptide NK1R antagonists L-733,060, aprepitant and L-732,138 inhibited tumor growth in several cancer cell lines. For the development of novel NK1R antagonists as antitumor agents, heterocyclic compounds which were previously synthesized by our team, tested for their cytotoxic activities in several cancer cell lines in this study. Among the tested compounds, a benzothiazole derivative BSN-009 inhibited colon cancer cell lines growth by 57.53% by comparing the activity to the control drug aprepitant. Molecular modeling studies such as molecular docking and pharmacophore generation were performed with known NK1R antagonists and BSN-009 by using Discovery Studio 3.5 in order to explain their binding modes to NK1R. BSN-009 may be a good anticancer drug candidate as a possible NK1R antagonist and is worthy to carry on the anticancer studies.展开更多
Inflammatory bowel diseases (IBD) are complex multifactorial disorders that include Crohn’s disease (CD) and ulcerative colitis (UC). Considering that IBD is a genetic and multifactorial disease, we screened for the ...Inflammatory bowel diseases (IBD) are complex multifactorial disorders that include Crohn’s disease (CD) and ulcerative colitis (UC). Considering that IBD is a genetic and multifactorial disease, we screened for the distribution dynamism of IBD pathogenic genetic variants (single nucleotide polymorphisms;SNPs) and risk factors in four (4) IBD pediatric patients, by integrating both clinical exome sequencing and computational statistical approaches, aiming to categorize IBD patients in CD and UC phenotype. To this end, we first aligned genomic read sequences of these IBD patients to hg19 human genome by using bowtie 2 package. Next, we performed genetic variant calling analysis in terms of single nucleotide polymorphism (SNP) for genes covered by at least 20 read genomic sequences. Finally, we checked for biological and genomic functions of genes exhibiting statistically significant genetic variant (SNPs) by introducing Fitcon genomic parameter. Findings showed Fitcon parameter as normalizing IBD patient’s population variability, as well as inducing a relative good clustering between IBD patients in terms of CD and UC phenotypes. Genomic analysis revealed a random distribution of risk factors and as well pathogenic SNPs genetic variants in the four IBD patient’s genome, claiming to be involved in: i) Metabolic disorders, ii) Autoimmune deficiencies;iii) Crohn’s disease pathways. Integration of genomic and computational statistical analysis supported a relative genetic variability regarding IBD patient population by processing IBD pathogenic SNP genetic variants as opposite to IBD risk factor variants. Interestingly, findings clearly allowed categorizing IBD patients in CD and UC phenotypes by applying Fitcon parameter in selecting IBD pathogenic genetic variants. Considering as a whole, the study suggested the efficiency of integrating clinical exome sequencing and computational statistical tools as a right approach in discriminating IBD phenotypes as well as improving inflammatory bowel disease (IBD) molecular diagnostic process.展开更多
Objective:Clinical features of upper tract urothelial carcinoma(UTUC)vary widely across countries.We aimed to provide clinical observations and compare oncological outcomes among regions in East Asia and Europe.Method...Objective:Clinical features of upper tract urothelial carcinoma(UTUC)vary widely across countries.We aimed to provide clinical observations and compare oncological outcomes among regions in East Asia and Europe.Methods:This retrospective study(March 2000 to July 2020)included 664 UTUC patients undergoing radical nephroureterectomy in China,Japan,the Republic of Korea,and Germany.Cohorts from China comprised patients from the Hong Kong Special Administrative Region and the Taiwan region,respectively.Demographic and clinicopathological parameters were analyzed.Continuous variables were analyzed using the Student’s t-test,and categorical variables were assessed using the Pearson’s chi-square test.The Cox proportional hazards model was employed to evaluate overall survival(OS),cancer-specific survival(CSS),and bladder recurrence-free survival across regions and various parameters.Results:Females had a higher proportion of patients than males only in Taiwan,China.Few patients received preoperative ureteroscopic biopsy prior to radical surgery in Seoul,the Republic of Korea.In the multivariate analysis,patients’regional origin was not associated with worse OS and CSS.Older age,multifocal tumors,high pT stage(pT4),positive lymphovascular invasion,and distant metastasis were associated with worse OS.High pT stage(pT4)and distant metastasis were independent factors leading to worse CSS.Patients’regional origin(Seoul,the Republic of Korea;Schleswig-Holstein,Germany;and Chiba,Japan)was associated with worse bladder recurrence-free survival.The preoperative ureteroscopic biopsy did not increase the intravesical recurrence.Conclusion:This international observational study revealed variations in the epidemiological distributions and practice patterns among UTUC patients in China,Japan,the Republic of Korea,and Germany.Cohorts from China comprised patients from the Hong Kong Special Administrative Region and the Taiwan region,respectively.However,ethnic and regional differences did not affect OS and CSS after radical nephroureterectomy.展开更多
Cells are the fundamental units of biological systems and exhibit unique development trajectories and molecular features.Our exploration of how the genomes orchestrate the formation and maintenance of each cell,and co...Cells are the fundamental units of biological systems and exhibit unique development trajectories and molecular features.Our exploration of how the genomes orchestrate the formation and maintenance of each cell,and control the cellular phenotypes of various organismsis,is both captivating and intricate.Since the inception of the first single-cell RNA technology,technologies related to single-cell sequencing have experienced rapid advancements in recent years.These technologies have expanded horizontally to include single-cell genome,epigenome,proteome,and metabolome,while vertically,they have progressed to integrate multiple omics data and incorporate additional information such as spatial scRNA-seq and CRISPR screening.Single-cell omics represent a groundbreaking advancement in the biomedical field,offering profound insights into the understanding of complex diseases,including cancers.Here,we comprehensively summarize recent advances in single-cell omics technologies,with a specific focus on the methodology section.This overview aims to guide researchers in selecting appropriate methods for single-cell sequencing and related data analysis.展开更多
Background:Lymphocyte activation gene 3(LAG-3)is a promising immune checkpoint for combination im-munotherapy.This study aims to elucidate the exact synergistic anti-tumor mechanism of programmed death 1(PD-1)and LAG-...Background:Lymphocyte activation gene 3(LAG-3)is a promising immune checkpoint for combination im-munotherapy.This study aims to elucidate the exact synergistic anti-tumor mechanism of programmed death 1(PD-1)and LAG-3 dual inhibition in lung cancer.Methods:Multiple patient-derived xenograft(PDX)models of lung cancer were constructed and analyzed by single-cell RNA sequencing(scRNA-seq).Clustering of all human-derived cells,identification of biomarker genes of three cell types,trajectory analysis,and calculation of tumor heterogeneity scores were performed.Differen-tially expressed genes(DEGs)were identified and functional enrichment analyses of cancer-associated genes were conducted.The functional significance of DEGs in the immune system was evaluated using the Reactome online server.Major histocompatibility complex(MHC)pathways and angiogenesis-associated pathways were analyzed.The Cancer Genome Atlas(TCGA)was used for further verification.Results:PD-1 and LAG-3 dual inhibition achieved synergistic tumor inhibition in squamous cell carcinoma(SCC)PDX models,but not in adenocarcinoma and small cell lung cancer PDX models.A total of 8127 cells,including 2699 basal,4109 malignant,and 1319 epithelial cells,were identified by scRNA-seq.Malignant cells evolved from basal and epithelial cells in the trajectory analysis.The responders to the combination therapy of PD-1 and LAG-3 inhibitors had lower heterogeneity scores than non-responders.Compared with anti-PD-1 monotherapy,the combination group exhibited higher levels of neutrophil degranulation.The DEGs were correlated with disease,metabolism,and programmed cell death-associated pathways.The MHC classⅠ-associated pathways and pericyte pathways were upregulated,whereas the vascular endothelial growth factor pathway was downregulated in the combination group.Conclusion:We discovered the superior efficacy of PD-1 and LAG-3 dual inhibition in SCC PDX models,and showed that it may be associated with low tumor heterogeneity scores,upregulation of the MHC classⅠpathway,and normalization of tumor angiogenesis.展开更多
基金supported by the Project of Sanya Yazhou Bay Science and Technology City (SKJC-JYRC-2024-26)the National Natural Science Foundation of China (32460072)+4 种基金Hainan Provincial Natural Science Foundation of China (323RC421)the Hainan Province Science and Technology Special Fund (ZDYF2022XDNY144)the Hainan Provincial Academician Innovation Platform Project (HDYSZX-202004)the Collaborative Innovation Center of Nanfan and High-Efficiency Tropical Agriculture, Hainan University (XTCX2022NYB06)Hainan Postdoctoral Research Grant Project
文摘In light of the pressing global challenges of climate change,declining crop resilience,and hidden hunger,it is imperative to overcome the limitations of conventional crop breeding to enhance both the nutritional quality and stress tolerance of crops.Synthetic metabolic engineering presents innovative strategies for the precision modification and de novo design of metabolic pathways.This approach generally encompasses three essential steps:identifying key metabolites through metabolomics,integrating multi-omics technologies to investigate the synthesis and regulation of these metabolites,and utilizing gene editing or de novo design to modify crop metabolic pathways associated with desirable agronomic traits.This review underscores the vital role of plant metabolite diversity in enhancing crop nutritional quality and stress resilience.Integrated multi-omics analyses facilitate the metabolic engineering by identifying key genes,transporters,and transcription factors that regulate metabolite biosynthesis.Precision modification strategies employ genome editing tools to reprogram endogenous metabolic networks,while de novo design reconstructs metabolic pathways through the introduction of exogenous biological elements—thereby both approaches enable the targeted enhancement of desired traits.These strategies have been effectively implemented in major food crops.However,simultaneously enhancing nutritional quality and stress resilience remains challenging due to inherent trade-offs and resource competition in distinct metabolic pathways within plants.Future research should integrate AI-driven predictive models with multi-omics datasets to decipher dynamic metabolic homeostasis and engineer climate-smart crops that maximize yield while preserving quality and environmental adaptability.
文摘Prostate-associated gene 4 （PAGE4） is a remarkably prostate-specific Cancer/Testis Antigen that is highly upregulated in the human fetal prostate and its diseased states but not in the adult normal gland. PAGE4 is an intrinsically disordered protein （IDP） that functions as a stress-response protein to suppress reactive oxygen species as well as prevent DNA damage. In addition, PAGE4 is also a transcriptional regulator that potentiates transactivation by the oncogene c-Jun, c-Jun forms the AP-1 complex by heterodimerizing with members of the Fos family and plays an important role in the development and pathology of the prostate gland, underscoring the importance of the PAGE4/c-Jun interaction. HIPK1, also a component of the stress-response pathway, phosphorylates PAGE4 at T51 which is critical for its transcriptional activity. Phosphorylation induces conformational and dynamic switching in the PAGE4 ensemble leading to a new cellular function. Finally, bioinformatics evidence suggests that the PAGE4 mRNA could be alternatively spliced resulting in four potential isoforms of the polypeptide alluding to the possibility of a range of conformational ensembles with latent functions. Considered together, the data suggest that PAGE4 may represent the first molecular link between stress and prostate cancer （PCa）. Thus, pharmacologically targeting PAGE4 may be a novel opportunity for treating and managing patients with PCa, especially patients with low-risk disease.
文摘The analysis of bacterial diversity in aquatic systems particularly in rivers, lakes, and streams can provide useful data on the effect of anthropogenic activities on such water bodies to humans and fishes. Idah River, the focal point of this study, is an offshoot of the two major Nigerian rivers characterized by observed human activities and pollution sources. Water samples were collected from four designated sites and assessed for their bacterial assemblages and structure, using PacBio Single-Molecule Real-Time (SMRT) sequencing technology. The full length of the 16S rRNA gene was sequenced, and Amplicon Sequence Variants were generated using the DADA2 workflow optimised for PacBio long-read amplicons in Rstudio. A total of 8751 high-quality reads obtained were taxonomically classified as 24 phyla, 42 classes, 84 orders, 125 families, 156 genera, and 106 species. Taxonomical composition revealed Proteobacteria as the most abundant phyla across all sample sites. At the genera level, Azospira (57.03%) was the most dominant ASV in Docking Point A, while Acinetobacter (66.67%) was the most abundant ASV in Docking Point B. In Idah Axis Confluence, hgcl clade (65.66%) was the most prevalent ASV, whereas Holophaga (42.86%) was the most common ASV in Idah Axis Midstream. Genera analysis also revealed that 12.9% of the total ASVs were discovered across all sample sites. Among these were pathogenic bacteria, reducers, and degraders of domestic and animal wastes. Observed results provide evidence that sampled sites of Idah River are contaminated, most likely through constant human activities and thus, could have an impact on resident fishes as well. This study, therefore, agrees with a previous report from the river, which used standard microbial procedures. However, next-generation sequencing techniques employed revealed more bacterial community than the former, including unresolved taxonomic sequences that may be novel.
基金supported by the National Institutes of Health Grant #U54 DA021519
文摘Only in recent years, the draft sequences for several agricultural animals have been assembled. Assembling an individual animal＇s entire genome sequence or specific region（s） of interest is increasingly important for agricultura researchers to perform genetic comparisons between animals with different performance. We review the current status for several sequenced agricultural species and suggest that next generation sequencing （NGS） technology with decreased sequencing cost and increased speed of sequencing can benefit agricultural researchers. By taking advantage of advanced NGS technologies, genes and chromosomal regions that are more labile to the influence of environmental factors could be pinpointed. A more long term goal would be addressing the question of how animals respond at the molecular and cellular levels to different environmental models （e.g. nutrition）. Upon revealing important genes and gene-environment interactions, the rate of genetic improvement can also be accelerated. It is clear that NGS technologies will be able to assist animal scientists to efficiently raise animals and to better prevent infectious diseases so that overall costs of animal production can be decreased.
文摘Haplotypes provide useful information for genomics-based approaches,genomic prediction,and genome-wide association study.As a small number of superior founders have contributed largely to the breeding history of fruit trees,the information of founder haplotypes may be relevant for performing the genomics-based approaches in these plants.In this study,we proposed a method to estimate 14 haplotypes from 7 founders and automatically trace the haplotypes forward to apple parental(185 varieties)and breeding(659 F 1 individuals from 16 full-sib families)populations based on 11,786 single-nucleotide polymorphisms,by combining multiple algorithms.Overall,92%of the single-nucleotide polymorphisms information in the parental and breeding populations was characterized by the 14 founder haplotypes.The use of founder haplotype information improved the accuracy of genomic prediction in 7 traits and the resolution of genome-wide association study in 13 out of 27 fruit quality traits analyzed in this study.We also visualized the significant propagation of the founder haplotype with the largest genetic effect in genome-wide association study over the pedigree tree of the parental population.These results suggest that the information of founder haplotypes can be useful for not only genetic improvement of fruit quality traits in apples but also for understanding the selection history of founder haplotypes in the breeding program of Japanese apple varieties.
文摘BACKGROUND Human epidermal growth factor receptor 2(HER2)amplification is a molecular driver for a subset of colorectal cancers(CRCs)and one of the major causes of anti-epidermal growth factor receptor(EGFR)treatment failure.Compared to dual anti-HER2 treatments,which have been shown to be effective in HER2-positive metastatic CRC patients,single-agent anti-HER2 therapy is rarely used to treat CRC.CASE SUMMARY Herein,we report a case of RAS/BRAF-wild-type metastatic CRC that was identified as HER2-positive through circulating tumor DNA(ctDNA)testing by next-generation sequencing following the failure of two lines of therapy.Subsequently,the patient was given lapatinib monotherapy that led to a partial response with a progression-free survival of 7.9 mo.Moreover,serial ctDNA detection was used to monitor the efficacy of lapatinib.The aberration of HER2 copy number disappeared when radiographic assessment revealed a partial response.However,a high level of HER2 amplification was detected again at the time of disease progression.Finally,a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha mutation was identified at the time of tumor progression,which may explain the acquired resistance to lapatinib.CONCLUSION This is the first case report of HER2-positive RAS/BRAF wild-type metastatic CRC patient responding to lapatinib monotherapy.It highlights that ctDNA testing is an effective and feasible approach to evaluate the efficacy of anti-HER2 therapy.
文摘Polyploidy is common among agriculturally important crops. Popular genetic methods and their implementations cannot always be applied to polyploid genetic data. We give an overview about available tools and their limitations in terms of levels of ploidy, auto- and allo-ploidy. The main classes of tools are genotype calling, linkage mapping and haplotyping. The usability of the tools is discussed with a focus on their applicability to data sets produced by state of the art technologies. We show that many challenges remain until the toolset for polyploidy provides similar functionalities as those which are already available for diploids. Some tools have been developed over a decade ago and are now outdated. In addition, we discuss necessary steps to overcome this shortage in the future.
基金Federal Ministry of Education and Research(Q-HCC,01KD2214)the Sino-German Center for Research Promotion(GZ-1546 and C-0012)+5 种基金the State Ministry of Baden-Wuerttemberg for Sciences,Research and Arts supporting the Clinical Cooperation Unit Healthy Metabolism at the Center for Preventive Medicine and Digital Health(CCU Healthy Metabolism)the Baden-Wuerttemberg Center for Digital Early Disease Detection and Prevention(BW-ZDFP)the Foundation for Biomedical Alcohol Research,Schriesheim,Germanyfunded by the Federal Ministry of Education and Research(BMBF)the Ministry of Culture and Science of the German State of North Rhine-Westphalia(MKW)(NRW Rueckkehrprogramm)under the Excellence Strategy of the Federal Government and the Länderthe German Research Foundation(DFG,403224013-SFB1382,gut-liver axis).
文摘The prevalence of metabolic-dysfunction-associated steatotic liver disease(MASLD)is alarmingly high;it is estimated to affect up to a quarter of the global population,making it the most common liver disorder worldwide.MASLD is characterized by excessive hepatic fat accumulation and is commonly associated with comorbidities such as obesity,dyslipidemia,and insulin resistance;however,it can also manifest in lean individuals.Therefore,it is crucial to develop effective therapies for this complex condition.Currently,there are no approved medications for MASLD treatment,so there is a pressing need to investigate alternative approaches.Extensive research has characterized MASLD as a multifaceted disease,frequently linked to metabolic disorders that stem from dietary habits.Evidence suggests that changes in the gut microbiome play a fundamental role in the development and progression of MASLD from simple steatosis to steatohepatitis and even hepatocellular carcinoma(HCC).In this review,we critically examine the literature on the emerging field of gut-microbiota-based therapies for MASLD and metabolicdysfunction-associated steatohepatitis(MASH),including interventions such as fecal microbiota transplantation(FMT),probiotics,prebiotics,short-chain fatty acids,antibiotics,metabolic pathway targeting,and immune checkpoint kinase blockade.
基金supported by the National Natural Science Foundation of China for Distinguished Young Scholars(No.60525303)the National Natural Science Foundation of China(No.60904048,60404022,60604012)the Natural Science Foundation of Hebei Province(No.F2005000390,F2006000270)
文摘We consider the problem of fair rate control for wireless ad-hoc networks with time varying channel capacities. The interaction between links in wireless ad-hoc networks introduces additional constraints on the flow rate. A primal-dual algorithm that guarantees fair rate control is proved to be trajectory stable. Various fairness indexes are obtained by choosing the specified form of the utility functions, and the numerical results validate the effectiveness of the proposed algorithm.
文摘Finding water resources for the desert plants is one of the important research areas since it enables saving water resources.Bromus inermis plant was noticed to keep 5%of moisture in its rhizosphere zone;therefore,this study aimed to identify this source of water.Thirteen endophytic bacteria were isolated from the root of B.inermis and identified.Their specific respiration rate was determined.Alcaligenes faecalis showed the highest specific respiration rate.It is a facultative chemoautotrophic hydrogen-fixing bacterium that utilizes the hydrogen gas as energy source and the water is produced as an end product.The source of hydrogen gas for this bacterium is not only from air and soil gases but also from the hydrogen-producing bacteria such as Enterobacter spp.,which was among the isolated bacteria.The hydrogenases synthesizing genes(HoxC,HypA and HypB)were detected in most of the isolated bacteria and roots of four wild plants,out from 18 wild plant samples,epically the grains of the wild wheat plant.This result suggests that the hydrogen-fixing and hydrogen-producing bacteria transfer from the root through the plant to inhabit the grain/seeds.This can help the grain/seeds to germinate in drought environment.
基金supported by the Chuying Scholar Project in Fujian Province and the Innovative Research Project at Fujian Agriculture and Forestry University。
文摘Soybean is the primary source of plant protein for humans.Owing to the indigestibility of the raffinose family of oligosaccharides(RFO),raffinose and stachyose are considered anti-nutritive factors in soybean seeds.Low-RFO soybean cultivars are generated by mutagenesis of RFO biosynthesis genes,but the carbohydrate profiles invite further modification to lower RFOs.This study employed a pooled multiplex genome editing approach to target four seed-specifically expressed genes mediating RFO biosynthesis,encoding three raffinose synthases(RS2,RS3,and RS4)and one stachyose synthase.In T1progeny,rs2/rs3 and rs4/sts homozygous double mutants and a rs2/rs3/rs4/sts quadruple mutant(rfo-4m)were characterized.The rs2/rs3 mutant showed reduced raffinose and stachyose contents,but the rs4/sts mutant showed only reduced stachyose in seeds.The RFO contents in the rfo-4m mutant were almost eliminated.Metabolomic analysis showed that the mutation of four RFO biosynthesis genes led to a shift of metabolic profile in the seeds,including the accumulation of several oligosaccharides-related metabolites.These mutants could contribute to precision breeding of soybean cultivars for soy food production.
基金funded by the Shenzhen Longhua District Medical and Health Institutions Research Fund(Project No.2022102).
文摘Background:In many cancer types,aryl hydrocarbon receptor nuclear translocator 2(ARNT2)has been found to be associated with tumor cell proliferation and prognosis.However,the role of ARNT2 in clear cell renal cell carcinoma(ccRCC)has not been completely elucidated.In this study,the potential role of ARNT2 in ccRCC development was characterized.Methods:A pan-cancer dataset(TCGA-TARGET-GTEx)was accessed from UCSC Xena Data Browser.ARNT2 expression in normal and tumor samples was compared.Univariate Cox regression was performed to evaluate the prognostic value of ARNT2.Single sample gene set enrichment analysis(ssGSEA)was used to estimate the enrichment of functional pathways and gene signatures.CIBERSORT and ESTIMATE methods evaluated the immune infiltration.The ARNT2 expression was determined in ccRCC tissue and cell lines using RT-qPCR and Western blot.Results:ARNT2 expression was significantly dysregulated in 23 out of 30 cancer types.Pan-cancer data revealed a strong correlation between ARNT2 expression and immune modulators,immune cell infiltration,and genomic alternations.In ccRCC patients,the low-ARNT2 expression group had higher immune infiltration,CD8 T cells,and programmed cell death ligand 1 expression,as well as higher enrichment score of immunotherapeutic predictors than those in the high-ARNT2 expression group.Low-ARNT2 expression group was more responsive to immunotherapy.Moreover,low ARNT2 expression was observed in ccRCC tissue and cell lines.Conclusions:Dysregulated ARNT2 expression is involved in cancer development and the modulation of the immune microenvironment.ARNT2 can be potentially used as a prognostic indicator and an immunotherapeutic indicator for ccRCC.
文摘Bovine tuberculosis (BTB) is a considerable threat to livestock keepers and public health in many developing and underdeveloped countries. We investigated associations between 20 microsatellite markers and three phenotypes for BTB in a sample of the Chadian cattle population. The phenotypes measured were: 1) single intra-dermal comparative cervical tuberculin test (SICCT) performed on live animals, 2) presence of lesion post-slaughter, 3) a bacteriological tissue culture test for Mycobacterium bovis using the samples with observed lesions and 4) a predicted Bayesian model (BM) estimate of a true BTB disease status using all tested animals. All traits were recorded in binary form and as either 1 = presence or 0 = absence. A total of 224 animals for SICCT, lesion and BM traits and 96 animals with bacteriological culture test were genotyped. Generalised linear models were fitted to the binary BTB phenotypes that consisted of age (covariate), sex (2 levels), breed (2 levels) and markers (alleles: 5 - 14 levels) as explanatory variables and implemented in R using glm with a logit link function. The model was fitted for each marker, separately. Six out of 20 markers tested were significantly associated with at least one trait considered;these were ILSTS005, ILSTS006, TGLA227, BM2113 and CSRM66. Genomic regions around these markers may serve as a basis for further functional investigations. This is the first study to report association of microsatellite markers with bovine tuberculosis traits in African or Chadian cattle population.
文摘Degenerate primers are particularly useful in amplifying homologous genes from different organisms. This paper describes a method for designing degenerate primers for a given multiple alignment of DNA sequences of hsp70 gene family using ClustalW algorithm and detect the consensus region in gene family of hsp70 in a plant species which have not any recorded information about hsp70 gene family in the Genbank of National Centre of Biotechnology Information （NCBI） like Arando donax .The sequenced consensus sequence ofArando donax is considered a gene marker in building the genome map sequence. The BLASTn program is used to find a homology between more than one accession numbers of DNA sequences, （X67711.2） was for Oryza sativa （hsp70）, （AY372071. l） was for Nicotiana tabacum （hsp70） and （L41253.2） was for Lycopersicon esculentum （Hsc70）. In silco PCR module was performed to detect the melting temperatures （Tm） and predicted the PCR product size （783 bp）.The result of designed degenerate primers showed that there was a homology founded among the designed primers and the DNA templates of the recorded sequences （AY372071.1, X67711.2 and L41253.2） with at least 80% identity. The designed degenerate primers were used to isolate a consensus region ofhsp70 gene family ofArando donax at the expected molecular weight （783 bp）. The isolated PCR product, （783 bp） ofArando donax was sequenced and submitted to the Database of Japan （DDBJ） with accession number AB819871. The ORF finder tool translated the accession number AB819871 and gave a selected frame which used to build 3D structure model. In conclusion, this study focused on the importance of designing the degenerate primers to isolate the gene family and predict the 3D structure of gene family depending on the ORF finder tool of Genebank.
文摘Recently, NK1R （Neurokinin-1 receptors） take attention as new and promising target in anticancer drug development area. It has been proved that non-peptide NK1R antagonists L-733,060, aprepitant and L-732,138 inhibited tumor growth in several cancer cell lines. For the development of novel NK1R antagonists as antitumor agents, heterocyclic compounds which were previously synthesized by our team, tested for their cytotoxic activities in several cancer cell lines in this study. Among the tested compounds, a benzothiazole derivative BSN-009 inhibited colon cancer cell lines growth by 57.53% by comparing the activity to the control drug aprepitant. Molecular modeling studies such as molecular docking and pharmacophore generation were performed with known NK1R antagonists and BSN-009 by using Discovery Studio 3.5 in order to explain their binding modes to NK1R. BSN-009 may be a good anticancer drug candidate as a possible NK1R antagonist and is worthy to carry on the anticancer studies.
文摘Inflammatory bowel diseases (IBD) are complex multifactorial disorders that include Crohn’s disease (CD) and ulcerative colitis (UC). Considering that IBD is a genetic and multifactorial disease, we screened for the distribution dynamism of IBD pathogenic genetic variants (single nucleotide polymorphisms;SNPs) and risk factors in four (4) IBD pediatric patients, by integrating both clinical exome sequencing and computational statistical approaches, aiming to categorize IBD patients in CD and UC phenotype. To this end, we first aligned genomic read sequences of these IBD patients to hg19 human genome by using bowtie 2 package. Next, we performed genetic variant calling analysis in terms of single nucleotide polymorphism (SNP) for genes covered by at least 20 read genomic sequences. Finally, we checked for biological and genomic functions of genes exhibiting statistically significant genetic variant (SNPs) by introducing Fitcon genomic parameter. Findings showed Fitcon parameter as normalizing IBD patient’s population variability, as well as inducing a relative good clustering between IBD patients in terms of CD and UC phenotypes. Genomic analysis revealed a random distribution of risk factors and as well pathogenic SNPs genetic variants in the four IBD patient’s genome, claiming to be involved in: i) Metabolic disorders, ii) Autoimmune deficiencies;iii) Crohn’s disease pathways. Integration of genomic and computational statistical analysis supported a relative genetic variability regarding IBD patient population by processing IBD pathogenic SNP genetic variants as opposite to IBD risk factor variants. Interestingly, findings clearly allowed categorizing IBD patients in CD and UC phenotypes by applying Fitcon parameter in selecting IBD pathogenic genetic variants. Considering as a whole, the study suggested the efficiency of integrating clinical exome sequencing and computational statistical tools as a right approach in discriminating IBD phenotypes as well as improving inflammatory bowel disease (IBD) molecular diagnostic process.
文摘Objective:Clinical features of upper tract urothelial carcinoma(UTUC)vary widely across countries.We aimed to provide clinical observations and compare oncological outcomes among regions in East Asia and Europe.Methods:This retrospective study(March 2000 to July 2020)included 664 UTUC patients undergoing radical nephroureterectomy in China,Japan,the Republic of Korea,and Germany.Cohorts from China comprised patients from the Hong Kong Special Administrative Region and the Taiwan region,respectively.Demographic and clinicopathological parameters were analyzed.Continuous variables were analyzed using the Student’s t-test,and categorical variables were assessed using the Pearson’s chi-square test.The Cox proportional hazards model was employed to evaluate overall survival(OS),cancer-specific survival(CSS),and bladder recurrence-free survival across regions and various parameters.Results:Females had a higher proportion of patients than males only in Taiwan,China.Few patients received preoperative ureteroscopic biopsy prior to radical surgery in Seoul,the Republic of Korea.In the multivariate analysis,patients’regional origin was not associated with worse OS and CSS.Older age,multifocal tumors,high pT stage(pT4),positive lymphovascular invasion,and distant metastasis were associated with worse OS.High pT stage(pT4)and distant metastasis were independent factors leading to worse CSS.Patients’regional origin(Seoul,the Republic of Korea;Schleswig-Holstein,Germany;and Chiba,Japan)was associated with worse bladder recurrence-free survival.The preoperative ureteroscopic biopsy did not increase the intravesical recurrence.Conclusion:This international observational study revealed variations in the epidemiological distributions and practice patterns among UTUC patients in China,Japan,the Republic of Korea,and Germany.Cohorts from China comprised patients from the Hong Kong Special Administrative Region and the Taiwan region,respectively.However,ethnic and regional differences did not affect OS and CSS after radical nephroureterectomy.
基金supported by the National Natural Science Foundation of China(32130020,32025009,82030099,30700397,31970638,61572361,81973701,U23A20513,32222026,82373446)the National Key Research and Development Program of China(2021YFF1201200,2021YFF1200900,2022YFA1106000)+10 种基金the Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)the Fundamental Research Funds for the Central Universities(20002150110,22120230292)Beihang University&Capital Medical University Plan(BHME-201904)the Special Fund of the Pediatric Medical Coordinated Development Center of Beijing Hospitals Authority(XTCX201809)the Cooperative Research Fund of the Affiliated Wuhu Hospital of East China Normal University(40500-20104-222400)the Fundamental Research Funds for the Central Universities(226-2024-00001)the Shanghai Municipal Science and Technology Commission“Science and Technology Innovation Action Plan”technical standard project(21DZ2201700)the Shanghai Municipal Science and Technology Commission“Science and Technology Innovation Action Plan”natural science foundation project(23ZR1435800)the Shanghai Natural Science Foundation Program(17ZR1449400)the Shanghai Artificial Intelligence Technology Standard Project(19DZ2200900)the Open Research Fund of Key Laboratory of Advanced Theory and Application in Statistics and Data Science-MOE,ECNU,Key Laboratory of MEA,Ministry of Education,ECNU.
文摘Cells are the fundamental units of biological systems and exhibit unique development trajectories and molecular features.Our exploration of how the genomes orchestrate the formation and maintenance of each cell,and control the cellular phenotypes of various organismsis,is both captivating and intricate.Since the inception of the first single-cell RNA technology,technologies related to single-cell sequencing have experienced rapid advancements in recent years.These technologies have expanded horizontally to include single-cell genome,epigenome,proteome,and metabolome,while vertically,they have progressed to integrate multiple omics data and incorporate additional information such as spatial scRNA-seq and CRISPR screening.Single-cell omics represent a groundbreaking advancement in the biomedical field,offering profound insights into the understanding of complex diseases,including cancers.Here,we comprehensively summarize recent advances in single-cell omics technologies,with a specific focus on the methodology section.This overview aims to guide researchers in selecting appropriate methods for single-cell sequencing and related data analysis.
基金supported in part by a grant from the National Key Research and Development Program of China(No.2022YFF0705300)the National Natural Science Foundation of China(No.52272281)+3 种基金the Shanghai Municipal Science and Technology Major Project(No.2021SHZDZX0100)the Fundamental Research Funds for the Central Universities,Shanghai Municipal Health Commission Health Industry Clinical Research Project,Clinical Research Project of Shanghai Pul-monary Hospital(No.FKLY20010)Young Talents in Shanghai(No.2019 QNBJ),Shanghai Shuguang Scholar,2021 Science and Technology Think Tank Youth Talent Plan of China Association for Science and Technology,“Dream Tutor”Outstanding Young Talents Program(No.fkyq1901)the National Key Research and Development Program of China(Nos.2021YFF1201200 and 2021YFF1200900).
文摘Background:Lymphocyte activation gene 3(LAG-3)is a promising immune checkpoint for combination im-munotherapy.This study aims to elucidate the exact synergistic anti-tumor mechanism of programmed death 1(PD-1)and LAG-3 dual inhibition in lung cancer.Methods:Multiple patient-derived xenograft(PDX)models of lung cancer were constructed and analyzed by single-cell RNA sequencing(scRNA-seq).Clustering of all human-derived cells,identification of biomarker genes of three cell types,trajectory analysis,and calculation of tumor heterogeneity scores were performed.Differen-tially expressed genes(DEGs)were identified and functional enrichment analyses of cancer-associated genes were conducted.The functional significance of DEGs in the immune system was evaluated using the Reactome online server.Major histocompatibility complex(MHC)pathways and angiogenesis-associated pathways were analyzed.The Cancer Genome Atlas(TCGA)was used for further verification.Results:PD-1 and LAG-3 dual inhibition achieved synergistic tumor inhibition in squamous cell carcinoma(SCC)PDX models,but not in adenocarcinoma and small cell lung cancer PDX models.A total of 8127 cells,including 2699 basal,4109 malignant,and 1319 epithelial cells,were identified by scRNA-seq.Malignant cells evolved from basal and epithelial cells in the trajectory analysis.The responders to the combination therapy of PD-1 and LAG-3 inhibitors had lower heterogeneity scores than non-responders.Compared with anti-PD-1 monotherapy,the combination group exhibited higher levels of neutrophil degranulation.The DEGs were correlated with disease,metabolism,and programmed cell death-associated pathways.The MHC classⅠ-associated pathways and pericyte pathways were upregulated,whereas the vascular endothelial growth factor pathway was downregulated in the combination group.Conclusion:We discovered the superior efficacy of PD-1 and LAG-3 dual inhibition in SCC PDX models,and showed that it may be associated with low tumor heterogeneity scores,upregulation of the MHC classⅠpathway,and normalization of tumor angiogenesis.
