Colorectal cancer(CRC)is a major contributor to global cancer-related mortality with increasing incidence rates in both developed and developing regions.Therefore,CRC presents a significant challenge to global health....Colorectal cancer(CRC)is a major contributor to global cancer-related mortality with increasing incidence rates in both developed and developing regions.Therefore,CRC presents a significant challenge to global health.The development of innovative tools for enhancing early CRC screening and diagnosis,along with novel treatments and therapies for improved management,remains an urgent necessity.CRC is intricately associated with the gut microbiota,which is integral to food digestion,nutrient generation,drug metabolism,metabolite production,immune enhancement,endocrine regulation,neurogenesis modulation,and the maintenance of physiologic and psychological equilibrium.Dysbiosis or imbalances in the gut microbiome have been implicated in various disorders,including CRC.Emerging evidence highlights the critical role of the gut microbiome in CRC pathogenesis and treatment,which presents potential opportunities for early detection and diagnosis.Despite substantial advances in understanding the relationship between the gut microbiota and CRC,significant challenges persist.Gaining a deeper and more detailed understanding of the interactions between the human microbiota and cancer is essential to fully realize the potential of the microbiota in cancer management.Unlike genetic factors,the gut microbiome is subject to modification,offering a promising avenue for the development of CRC treatments and drug discovery.This review provides an overview of the interactions between the human gut microbiome and CRC,while examining prospects for precision management of CRC.展开更多
Objective:Plasma cell-free DNA(cfDNA)methylation has shown potential in the detection and prognostic testing of multiple cancers.Here,we comprehensively investigate the performance of cfDNA methylation for gastric can...Objective:Plasma cell-free DNA(cfDNA)methylation has shown potential in the detection and prognostic testing of multiple cancers.Here,we comprehensively investigate the performance of cfDNA methylation for gastric cancer(GC)detection and prognosis.Methods:GC-specific differentially methylated regions(DMRs)were identified by sequencing 56 GC tissues and 59 normal adjacent tissues(NATs).We then performed targeted bisulfite sequencing of cfDNA from 294 GC and 446 non-gastric cancer(NGC)plasma samples,identifying 179 DMRs that overlapped with those in tissue samples.The efficacy of plasma cfDNA methylation markers for GC detection and prognosis was evaluated.Results:Based on the 179 DMRs overlapping with those in tissue samples,the random forest(RF)model using28 DMRs achieved an area under the curve(AUC)of 0.998 in the training cohort,whereas further refinement to the top 6 DMRs resulted in an AUC of 0.985.Consistent results were obtained in the validation cohort(28 DMR AUC:0.985;6 DMR AUC:0.988).Support vector machine(SVM)and logistic regression(LR)models also demonstrated robust performance.Additionally,an 11-DMR signature was developed for prognostic prediction,successfully identifying high-risk GC patients with significantly shorter overall survival.Conclusions:Our study highlights the potential utility of cfDNA methylation markers for both the detection and prognostication of GC.展开更多
Bitter gourd(Momordica charantia)is a popular cultivated vegetable in Asian and African countries.To reveal the characteristics of the genomic structure,evolutionary trajectory,and genetic basis underlying the domesti...Bitter gourd(Momordica charantia)is a popular cultivated vegetable in Asian and African countries.To reveal the characteristics of the genomic structure,evolutionary trajectory,and genetic basis underlying the domestication of bitter gourd,we performed whole-genome sequencing of the cultivar Dali-11 and the wild small-fruited line TR and resequencing of 187 bitter gourd germplasms from 16 countries.The major gene clusters(Bi clusters)for the biosynthesis of cucurbitane triterpenoids,which confer a bitter taste,are highly conserved in cucumber,melon,and watermelon.Comparative analysis among cucurbit genomes revealed that the Bi cluster involved in cucurbitane triterpenoid biosynthesis is absent in bitter gourd.Phylogenetic analysis revealed that the TR group,including 21 bitter gourd germplasms,may belong to a new species or subspecies independent from M.charantia.Furthermore,we found that the remaining 166 M.charantia germplasms are geographically differentiated,and we identified 710,412,and 290 candidate domestication genes in the South Asia,Southeast Asia,and China populations,respectively.This study provides new insights into bitter gourd genetic diversity and domestication and will facilitate the future genomics-enabled improvement of bitter gourd.展开更多
Some patients with chronic hepatitis B virus(HBV)infection failed to clear HBV,even persistently continue to produce antibodies to HBV.Here we performed a two stage genome wide association study in a cohort of Chinese...Some patients with chronic hepatitis B virus(HBV)infection failed to clear HBV,even persistently continue to produce antibodies to HBV.Here we performed a two stage genome wide association study in a cohort of Chinese patients designed to discover single nucleotide variants that associate with HBV infection and clearance of HBV.The first stage involved genome wide exome sequencing of 101 cases(HBsAg plus anti-HBs positive)compared with 102 control patients(antiHBs positive,HBsAg negative).Over 80%of individual sequences displayed 209 sequence coverage.Adapters,uncertain bases[10%or low-quality base calls([50%)were filtered and compared to the human reference genome hg19.In the second stage,579 chronic HBV infected cases and 439 HBV clearance controls were sequenced with selected genes from the first stage.Although there were no significant associated gene variants in the first stage,two significant gene associations were discovered when the two stages were assessed in a combined analysis.One association showed rs506121-“T”allele[within the dedicator of cytokinesis 8(DOCK8)gene]was higher in chronic HBV infection group than that in clearance group(P=0.002,OR=0.77,95%CI[0.65,0.91]).The second association involved rs2071676—A allele within the Carbonic anhydrase(CA9)gene that was significantly elevated in chronic HBV infection group compared to the clearance group(P=0.0003,OR=1.35,95%CI[1.15,1.58]).Upon replication these gene associations would suggest the influence of DOCK8 and CA9 as potential risk genetic factors in the persistence of HBV infection.展开更多
Ginger(Zingiber officinale),the type species of Zingiberaceae,is one of the most widespread medicinal plants and spices.Here,we report a high-quality,chromosome-scale reference genome of ginger‘Zhugen’,a traditional...Ginger(Zingiber officinale),the type species of Zingiberaceae,is one of the most widespread medicinal plants and spices.Here,we report a high-quality,chromosome-scale reference genome of ginger‘Zhugen’,a traditionally cultivated ginger in Southwest China used as a fresh vegetable,assembled from PacBio long reads,Illumina short reads,and high-throughput chromosome conformation capture(Hi-C)reads.The ginger genome was phased into two haplotypes,haplotype 1(1.53 Gb with a contig N50 of 4.68 M)and haplotype 0(1.51 Gb with a contig N50 of 5.28 M).Homologous ginger chromosomes maintained excellent gene pair collinearity.In 17,226 pairs of allelic genes,11.9%exhibited differential expression between alleles.Based on the results of ginger genome sequencing,transcriptome analysis,and metabolomic analysis,we proposed a backbone biosynthetic pathway of gingerol analogs,which consists of 12 enzymatic gene families,PAL,C4H,4CL,CST,C3’H,C3OMT,CCOMT,CSE,PKS,AOR,DHN,and DHT.These analyses also identified the likely transcription factor networks that regulate the synthesis of gingerol analogs.Overall,this study serves as an excellent resource for further research on ginger biology and breeding,lays a foundation for a better understanding of ginger evolution,and presents an intact biosynthetic pathway for species-specific gingerol biosynthesis.展开更多
Objective This study was aimed at investigating the carrier rate of,and molecular variation in,α-andβ-globin gene mutations in Hunan Province.Methods We recruited 25,946 individuals attending premarital screening fr...Objective This study was aimed at investigating the carrier rate of,and molecular variation in,α-andβ-globin gene mutations in Hunan Province.Methods We recruited 25,946 individuals attending premarital screening from 42 districts and counties in all 14 cities of Hunan Province.Hematological screening was performed,and molecular parameters were assessed.Results The overall carrier rate of thalassemia was 7.1%,including 4.83%forα-thalassemia,2.15%forβ-thalassemia,and 0.12%for bothα-andβ-thalassemia.The highest carrier rate of thalassemia was in Yongzhou(14.57%).The most abundant genotype ofα-thalassemia andβ-thalassemia was-α^(3.7)/αα(50.23%)andβ^(IVS-Ⅱ-654)/β^(N)(28.23%),respectively.Fourα-globin mutations[CD108(ACC>AAC),CAP+29(G>C),Hb Agrinio and Hb Cervantes]and sixβ-globin mutations[CAP+8(C>T),IVS-Ⅱ-848(C>T),-56(G>C),beta nt-77(G>C),codon 20/21(-TGGA)and Hb Knossos]had not previously been identified in China.Furthermore,this study provides the first report of the carrier rates of abnormal hemoglobin variants andα-globin triplication in Hunan Province,which were 0.49%and 1.99%,respectively.Conclusion Our study demonstrates the high complexity and diversity of thalassemia gene mutations in the Hunan population.The results should facilitate genetic counselling and the prevention of severe thalassemia in this region.展开更多
BACKGROUND The poly(ADP-ribose)polymerase(PARP)inhibitor olaparib has displayed superior clinical effect in metastatic castration-resistant prostate cancer(mCRPC)patients with the homologous recombination repair(HRR)g...BACKGROUND The poly(ADP-ribose)polymerase(PARP)inhibitor olaparib has displayed superior clinical effect in metastatic castration-resistant prostate cancer(mCRPC)patients with the homologous recombination repair(HRR)genes mutations.However,when a patient’s tumor tissue volume is insufficient for genomic profiling of HRR gene mutations,circulating tumor DNA(ctDNA)may be useful in helping to determine and monitor the efficacy of olaparib,as well as in abiraterone-combination treatment,and for understanding any resistance mechanism related to such mutations.CASE SUMMARY A 61-year-old man who was diagnosed with metastatic prostate adenocarcinoma was initially hormone sensitivity,showing high Gleason score(5+5=10)and absolute positive rate(14/14 biopsied specimens).Following failure of several standard therapies,the patient progressed to mCRPC.Surprisingly,the patient showed good response to olaparib-abiraterone-prednisone combination treatment(an androgen-deprivation therapy,provided as the‘final choice’in China).Serum total prostate-specific antigen(TPSA)level reduced and symptoms remitted for 4 months.However,thereafter,serum TPSA levels began slowly increasing,indicating development of olaparib resistance.Subsequent comprehensive genomic profiling of ctDNA, screening 508 cancer-related genes by next-generation sequencing,identified 10 somatic variants as well as 3 copy number alterations. Two identified reversemissense mutations in partner and localizer of BRCA2 (PALB2) may have recovered the readingframe, restoring function of the primary germline PALB2 mutation and causing resistance to thePARP inhibitor olaparib.CONCLUSIONReverse mutations in PALB2, discovered via genomic profiling of ctDNA, may represent apotential resistance mechanism against olaparib in mCRPC.展开更多
Nicotine is widely recognized as the primary contributor to tobacco dependence.Previous studies have indicated that molecular and behavioral responses to nicotine are primarily mediated by ventral tegmental area(VTA)n...Nicotine is widely recognized as the primary contributor to tobacco dependence.Previous studies have indicated that molecular and behavioral responses to nicotine are primarily mediated by ventral tegmental area(VTA)neurons,and accumulating evidence suggests that glia play prominent roles in nicotine addiction.However,VTA neurons and glia have yet to be characterized at the transcriptional level during the progression of nicotine self-administration.Here,a male mouse model of nicotine self-administration is established and the timing of three critical phases(pre-addiction,addicting,and post-addiction phase)is characterized.Single-nucleus RNA sequencing in the VTA at each phase is performed to comprehensively classify specific cell subtypes.Adaptive changes occurred during the addicting and post-addiction phases,with the addicting phase displaying highly dynamic neuroplasticity that profoundly impacts the transcription in each cell subtype.Furthermore,significant transcriptional changes in energy metabolism-related genes are observed,accompanied by notable structural alterations in neuronal mitochondria during the progression of nicotine self-administration.The results provide insights into mechanisms underlying the progression of nicotine addiction,serving as an important resource for identifying potential molecular targets for nicotine cessation.展开更多
This study aimed to identify possible pathogenic genes in a 90-member family with a rare combination of multiple neurodegenerative disease phenotypes,which has not been depicted by the known neurodegenerative disease....This study aimed to identify possible pathogenic genes in a 90-member family with a rare combination of multiple neurodegenerative disease phenotypes,which has not been depicted by the known neurodegenerative disease.We performed physical and neurological examinations with International Rating Scales to assess signs of ataxia,Parkinsonism,and cognitive function,as well as brain magnetic resonance imaging scans with seven sequences.We searched for co-segregations of abnormal repeat-expansion loci,pathogenic variants in known spinocerebellar ataxiarelated genes,and novel rare mutations via whole-genome sequencing and linkage analysis.A rare co-segregating missense mutation in the CARS gene was validated by Sanger sequencing and the aminoacylation activity of mutant CARS was measured by spectrophotometric assay.This pedigree presented novel late-onset core characteristics including cerebellar ataxia,Parkinsonism,and pyramidal signs in all nine affected members.Brain magnetic resonance imaging showed cerebellar/pons atrophy,pontine-midline linear hyperintensity,decreased rCBF in the bilateral basal ganglia and cerebellar dentate nucleus,and hypo-intensities of the cerebellar dentate nuclei,basal ganglia,mesencephalic red nuclei,and substantia nigra,all of which suggested neurodegeneration.Whole-genome sequencing identified a novel pathogenic heterozygous mutation(E795V)in the CARS gene,meanwhile,exhibited none of the known repeat-expansions or point mutations in pathogenic genes.Remarkably,this CARS mutation causes a 20%decrease in aminoacylation activity to charge tRNA^(Cys) with L-cysteine in protein synthesis compared with that of the wild type.All family members carrying a heterozygous mutation CARS(E795V)had the same clinical manifestations and neuropathological changes of Parkinsonism and spinocerebellar-ataxia.These findings identify novel pathogenesis of Parkinsonismspinocerebellar ataxia and provide insights into its genetic architecture.展开更多
During the early systemic infection of plant pathogens,individual cells can harbor pathogens at various stages of infection,ranging from absent to abundant.Consequently,gene expression levels within these cells in res...During the early systemic infection of plant pathogens,individual cells can harbor pathogens at various stages of infection,ranging from absent to abundant.Consequently,gene expression levels within these cells in response to the pathogens exhibit significant variability.These variations are pivotal in determining pathogenicity or susceptibility,yet they remain largely unexplored and poorly understood.Sugarcane mosaic virus(SCMV)is a representative member of the monocot-infecting potyviruses with a polyadeny-lated RNA genome,which can be captured by single-cell RNA sequencing(scRNA-seq).Here,we per-formed scRNA-seq on SCMV-infected maize leaves during early systemic infection(prior to symptom mani-festation)to investigate the co-variation patterns between viral accumulation and intracellular gene expression alterations.We identifiedfive cell types and found that mesophyll-4(MS4)cells exhibited the highest levels of viral accumulation in most cells.Early systemic infection of SCMV resulted in a greater up-regulation of differentially expressed genes,which were mainly enriched in biological processes related to translation,peptide biosynthesis,and metabolism.Co-variation analysis of the altered maize gene expres-sion and viral accumulation levels in MS1,2,and 4 revealed several patterns,and the co-expression rela-tionships between them were mainly positive.Furthermore,functional studies identified several potential anti-or pro-viral factors that may play crucial roles during the early stage of SCMV systemic infection.These results not only provide new insights into plant gene regulation during viral infection but also offer a foundation for future investigations of host–virus interactions across molecular,cellular,and physiolog-ical scales.展开更多
Homologous recombination deficiency(HRD)has emerged as a critical prognostic and predictive biomarker in oncology.However,current test-ing methods,especially those reliant on targeted panels,are plagued by inconsisten...Homologous recombination deficiency(HRD)has emerged as a critical prognostic and predictive biomarker in oncology.However,current test-ing methods,especially those reliant on targeted panels,are plagued by inconsistent results from the same samples.This highlights the urgent need for standardized benchmarks to evaluate HRD assay performance.In phases lla and Ilb of the Chinese HRD Harmonization Project,we de-veloped ten pairs of well-characterized DNA reference materials derived from lung,breast,and melanoma cancer cell lines and their matched normal cell lines,keeping each paired with seven cancer-to-normal mass ratios.Reference datasets for allele-specific copy number variations(AsCNVs)and HRD scores were established and validated using three sequencing methods and nine analytical pipelines.The genomic instabil-ity scores(GISs)of the reference materials ranged from 11 to 96,enabling validation across various thresholds.The AsCNV reference datasets covered a genomic span of 2340 to 2749 Mb,equivalent to 81.2%to 95.4%of the autosomes in the 37d5 reference genome.These bench-marks were subsequently utilized to assess the accuracy and reproducibility of four HRD panel assays,revealing significant variability in both ASCNV detection and HRD scores.The concordance between panel-detected GISs and reference GISs ranged from 0.81 to 0.94,with only two assays exhibiting high overall agreement with Myriad MyChoice CDx for HRD classification.This study also identified specific challenges in ASCNV detection in HRD-related regions and the profound impact of high ploidy on consistency.The established HRD reference materials and datasets providea robust toolkit forobjective evaluation of HRD testing.展开更多
Background:Bladder cancer is a common malignancy of the genitourinary system.Recent studies have confirmed the existence of microorganisms in urine.This study aimed to characterize changes in the urinary microbiota of...Background:Bladder cancer is a common malignancy of the genitourinary system.Recent studies have confirmed the existence of microorganisms in urine.This study aimed to characterize changes in the urinary microbiota of Chinese bladder cancer patients and determine differences between patients with muscle-invasive bladder cancer(MIBC)and those with non-muscle-invasive bladder cancer(NMIBC).Methods:Urine samples were collected from 64 patients with bladder cancer and 94 disease-free controls using the clean catch method and sequenced by 16S rRNA gene sequencing.Sequencing reads were filtered by VSEARCH and clustered by UPARSE.Results:Significant associations were found between urinary microbiota and factors such as sex,age,and disease status.After age adjustment,differences in beta diversity were observed between healthy men and women,cancer patients and healthy controls,and NMIBC and MIBC patients.The cancer patients had an increased abundance of 14 bacterial genera,including Stenotrophomonas,Propionibacterium,and Acinetobacter.Notably,Peptoniphilus spp.were enriched in high-risk MIBC patients,indicating their potential as a risk marker.Functional prediction via PICRUSt analysis suggested enriched metabolic pathways in specific disease groups.Furthermore,molecular ecological network analysis revealed differences based on sex and disease type.Conclusions:This significant microbial diversity indicates a potential correlation between urinary microbiota dysbiosis and bladder cancer,with implications for risk stratification and disease management.The identified urinary microbiota may serve as noninvasive markers for bladder cancer,warranting further validation in larger cohorts.This study provides a foundation for further research on the mechanisms of bladder cancer progression.展开更多
In China,an estimated 48.42-82.11 million individuals are affected by rare diseases.This estimate is derived from the Orphanet database,based on the global population of 7.55 billion and China's population of 1.39...In China,an estimated 48.42-82.11 million individuals are affected by rare diseases.This estimate is derived from the Orphanet database,based on the global population of 7.55 billion and China's population of 1.39 billion in 2017(source:National Bureau of Statistics of China)[1,2].展开更多
The entorhinal cortex(EC)-hippocampal(HPC)circuit is particularly vulnerable to Alzheimer's disease(AD)pathol-ogy,yet the underlying molecular mechanisms remain unclear.By employing the high-depth sequencing strat...The entorhinal cortex(EC)-hippocampal(HPC)circuit is particularly vulnerable to Alzheimer's disease(AD)pathol-ogy,yet the underlying molecular mechanisms remain unclear.By employing the high-depth sequencing strategy Smart-seq2,we tracked gene expression changes across various neuron types within this circuit at different stages of AD pathology.We observed a decrease in the extent of gene expression changes in AD versus wild-type(WT)mice as the disease advanced.Functionally,we demonstrate that both mitochondrial and ribosomal pathways were increasingly activated,while neuronal pathways were inhibited with AD progression.Our findings indicate that the reduction of EC-stellate cells disrupts Meg3-mediated energy metabolism,contributing to energy dysfunction in AD.Additionally,we identified GFAP-positive neurons as a distinct population of disease-associated neurons,exhibiting a loss of neuronal-like characteristics,alongside the emergence of glia-and stem-like features.The num-ber of GFAP-positive neurons increased with AD progression,a trend consistently observed in both AD model mice and AD patients.In summary,this study identifies and characterizes GFAP-positive neurons as a novel subtype of disease-associated neurons in AD pathology,providing insights into their potential role in disease progression.展开更多
Hair loss and graying,the earliest visible signs of skin aging,are driven by the functional decline of hair follicle stem cells and their niches.To elucidate the transcriptional mechanisms involved in scalp aging,we c...Hair loss and graying,the earliest visible signs of skin aging,are driven by the functional decline of hair follicle stem cells and their niches.To elucidate the transcriptional mechanisms involved in scalp aging,we conducted a comprehensive analysis of human scalp samples using single-cell RNA sequencing and spatial transcriptomic technologies.Our study profiled the transcriptomes of 57,181 cells from scalp samples obtained from four young,six middle-aged,and one elderly individual.The integrated bioinformatic pipeline included cell clustering,spatial deconvolution,pseudotime trajectory,as well as cell-type specific gene expression,and intercellular communication analysis.An additional 92 volunteers were included,comprising 90(37 young,27 middle-aged,and 26 elderly)for trichoscopic examination,one young individual for senescence-associated β-galactosidase(SA-β-gal)staining,and one elderly individual for both MKI67 immunofluorescence and SA-β-gal staining.This approach led to several key findings:we identified three subtypes of mitotic keratinocytes that localized in the interfollicular epidermis(IFE),outer root sheath(ORS),and hair matrix,with pseudotime trajectory further confirming their transitional stage.Furthermore,in middleaged scalps,we observed activated activator protein 1(AP-1)transcription factor complex in keratinocytes,upregulated DCT gene in melanocytes,and decreased bone morphogenetic protein(BMP)and noncanonical wingless/integrated(ncWNT)signaling in dermal papilla(DP)-keratinocytes cross-talk.Due to the insufficient sample size and under-representation of elderly samples,transcriptional features associated with late aging,sex,and scalp regions were not completely captured.Nevertheless,our study provides valuable cell-resolved transcriptional insights into hair follicle aging and may support the development of future regenerative therapies.展开更多
Advances in multi-omics datasets and analytical methods have revolutionized cancer research,offering a comprehensive,pan-cancer perspective.Pancancer studies identify shared mechanisms and unique traits across differe...Advances in multi-omics datasets and analytical methods have revolutionized cancer research,offering a comprehensive,pan-cancer perspective.Pancancer studies identify shared mechanisms and unique traits across different cancer types,which are reshaping diagnostic and treatment strategies.However,continued innovation is required to refine these approaches and deepen our understanding of cancer biology and medicine.This review summarized key findings from pan-cancer research and explored their potential to drive future advancements in oncology。展开更多
There are two main types of root systems in flowering plants,namely taproot systems of dicots and fibrous root systems found in monocots.Despite this fundamental split,our current knowledge of cellular and molecular m...There are two main types of root systems in flowering plants,namely taproot systems of dicots and fibrous root systems found in monocots.Despite this fundamental split,our current knowledge of cellular and molecular mechanism driving root development is mainly based on studies of the dicot model Arabidopsis.However,the world major crops are monocots and little is known about the transcriptional programs underlying cell-type specification in this clade.Here,we report the transcriptomes of more than 20000 single cells derived from root tips of two agronomically important rice cultivars.Using combined computational and experimental analyses we were able to robustly identify most of the major cell types and define novel cell-type-specific marker genes for both cultivars.Importantly,we found divergent cell types associated with specific regulatory programs,including phytohormone biosynthesis,signaling,and response,which were well conserved between the two rice cultivars.In addition,we detected substantial differences between the cell-type transcript profiles of Arabidopsis and rice.These species-specific features emphasize the importance of analyzing tissues across diverse model species,including rice.Taken together,our study provides insight into the transcriptomic landscape of major cell types of rice root tip at single-cell resolution and opens new avenues to study cell-type specification,function,and evolution in plants.展开更多
Although seed weight has increased following domestication from wild soybean(Glycine soja) to cultivated soybean(Glycine max), the genetic basis underlying this change is unclear. Using mapping populations derived fro...Although seed weight has increased following domestication from wild soybean(Glycine soja) to cultivated soybean(Glycine max), the genetic basis underlying this change is unclear. Using mapping populations derived from chromosome segment substitution lines of wild soybean, we identified SW16.1 as the causative gene underlying a major quantitative trait locus controlling seed weight.SW16.1 encodes a nucleus-localized LIM domaincontaining protein. Importantly, the GsSW16.1 allele from wild soybean accession N24852 had a negative effect on seed weight, whereas the GmSW16.1 allele from cultivar NN1138-2 had a positive effect. Gene expression network analysis,reverse-transcription quantitative polymerase chain reaction, and promoter-luciferase reporter transient expression assays suggested that SW16.1 regulates the transcription of MT4, a positive regulator of seed weight. The natural variations in SW16.1 and other known seed weight genes were analyzed in soybean germplasm. The SW16.1 polymorphism was associated with seed weight in 247 soybean accessions, showing much higher frequency of positive-effect alleles in cultivated soybean than in wild soybean. Interestingly,gene allele matrix analysis of the known seed weight genes revealed that G. max has lost 38.5%of the G. soja alleles and that most of the lost alleles had negative effects on seed weight. Our results suggest that eliminating negative alleles from G. soja led to a higher frequency of positive alleles and changed genetic backgrounds in G. max,which contributed to larger seeds in cultivated soybean after domestication from wild soybean.Our findings provide new insights regarding soybean domestication and should assist current soybean breeding programs.展开更多
The order Acipenseriformes,which includes sturgeons and paddlefishes,represents“living fossils”with complex genomes that are good models for understanding whole-genome duplication(WGD)and ploidy evolution in fishes....The order Acipenseriformes,which includes sturgeons and paddlefishes,represents“living fossils”with complex genomes that are good models for understanding whole-genome duplication(WGD)and ploidy evolution in fishes.Here,we sequenced and assembled the first high-quality chromosome-level genome for the complex octoploid Acipenser sinensis(Chinese sturgeon),a critically endangered species that also represents a poorly understood ploidy group in Acipenseriformes.Our results show that A.sinensis is a complex autooctoploid species containing four kinds of octovalents(8n),a hexavalent(6n),two tetravalents(4n),and a divalent(2n).An analysis taking into account delayed rediploidization reveals that the octoploid genome composition of Chinese sturgeon results from two rounds of homologous WGDs,and further provides insights into the timing of its ploidy evolution.This study provides the first octoploid genome resource of Acipenseriformes for understanding ploidy compositions and evolutionary trajectories of polyploid fishes.展开更多
Alport syndrome(AS) is a hereditary progressive nephropathy characterized by hematuria, ultrastructural lesions of the glomerular basement membrane, ocular lesions and sensorineural hearing loss. Germline mutations of...Alport syndrome(AS) is a hereditary progressive nephropathy characterized by hematuria, ultrastructural lesions of the glomerular basement membrane, ocular lesions and sensorineural hearing loss. Germline mutations of COL4 A5 are associated with X-linked AS with an extreme phenotypic heterogeneity. Here, we investigated a Chinese family with Alport syndrome. The proband was a 9-year-old boy with hematuria and proteinuria. Based on the test results of renal biopsy and immunofluorescence,the proband was initially diagnosed as Ig A nephropathy and the treatment was recommended accordingly. Meanwhile, we found that the treatment outcome was poor. Therefore, for proper clinical diagnosis and appropriate treatment, targeted exome-based next-generation sequencing has been undertaken. We identified a novel hemizygous single nucleotide deletion c.1902 del A in COL4 A5 gene. Segregation analysis identified that this novel mutation is co-segregated among the affected family members but absent in unaffected family members. The clinical diagnosis of the proband was revised as AS accompanied by Ig A nephropathy,which has been rarely reported. Our findings demonstrated the significance of the application of Genetic screening, expanded the mutation spectrum of COL4 A5 associated AS patients with atypical renal phenotypes and provided a good lesson to be learned from our detour during the diagnosis.展开更多
基金the Hangzhou Institute of Medicine(HIM)and Chinese Academy of Sciences for supporting work of this article。
文摘Colorectal cancer(CRC)is a major contributor to global cancer-related mortality with increasing incidence rates in both developed and developing regions.Therefore,CRC presents a significant challenge to global health.The development of innovative tools for enhancing early CRC screening and diagnosis,along with novel treatments and therapies for improved management,remains an urgent necessity.CRC is intricately associated with the gut microbiota,which is integral to food digestion,nutrient generation,drug metabolism,metabolite production,immune enhancement,endocrine regulation,neurogenesis modulation,and the maintenance of physiologic and psychological equilibrium.Dysbiosis or imbalances in the gut microbiome have been implicated in various disorders,including CRC.Emerging evidence highlights the critical role of the gut microbiome in CRC pathogenesis and treatment,which presents potential opportunities for early detection and diagnosis.Despite substantial advances in understanding the relationship between the gut microbiota and CRC,significant challenges persist.Gaining a deeper and more detailed understanding of the interactions between the human microbiota and cancer is essential to fully realize the potential of the microbiota in cancer management.Unlike genetic factors,the gut microbiome is subject to modification,offering a promising avenue for the development of CRC treatments and drug discovery.This review provides an overview of the interactions between the human gut microbiome and CRC,while examining prospects for precision management of CRC.
基金supported by National Key R&D Program of China(No.2021YFA0910100)National Natural Science Foundation of China(No.82374544,82204828,82422078)+2 种基金Healthy Zhejiang One Million People Cohort(No.K-20230085)Program of Zhejiang Provincial TCM Sci-tech Plan(No.GZY-ZJ-KJ-230003,No.GZY-ZJ-KJ23048)Natural Science Foundation of Zhejiang Province(No.LHDMY22H160008)。
文摘Objective:Plasma cell-free DNA(cfDNA)methylation has shown potential in the detection and prognostic testing of multiple cancers.Here,we comprehensively investigate the performance of cfDNA methylation for gastric cancer(GC)detection and prognosis.Methods:GC-specific differentially methylated regions(DMRs)were identified by sequencing 56 GC tissues and 59 normal adjacent tissues(NATs).We then performed targeted bisulfite sequencing of cfDNA from 294 GC and 446 non-gastric cancer(NGC)plasma samples,identifying 179 DMRs that overlapped with those in tissue samples.The efficacy of plasma cfDNA methylation markers for GC detection and prognosis was evaluated.Results:Based on the 179 DMRs overlapping with those in tissue samples,the random forest(RF)model using28 DMRs achieved an area under the curve(AUC)of 0.998 in the training cohort,whereas further refinement to the top 6 DMRs resulted in an AUC of 0.985.Consistent results were obtained in the validation cohort(28 DMR AUC:0.985;6 DMR AUC:0.988).Support vector machine(SVM)and logistic regression(LR)models also demonstrated robust performance.Additionally,an 11-DMR signature was developed for prognostic prediction,successfully identifying high-risk GC patients with significantly shorter overall survival.Conclusions:Our study highlights the potential utility of cfDNA methylation markers for both the detection and prognostication of GC.
文摘Bitter gourd(Momordica charantia)is a popular cultivated vegetable in Asian and African countries.To reveal the characteristics of the genomic structure,evolutionary trajectory,and genetic basis underlying the domestication of bitter gourd,we performed whole-genome sequencing of the cultivar Dali-11 and the wild small-fruited line TR and resequencing of 187 bitter gourd germplasms from 16 countries.The major gene clusters(Bi clusters)for the biosynthesis of cucurbitane triterpenoids,which confer a bitter taste,are highly conserved in cucumber,melon,and watermelon.Comparative analysis among cucurbit genomes revealed that the Bi cluster involved in cucurbitane triterpenoid biosynthesis is absent in bitter gourd.Phylogenetic analysis revealed that the TR group,including 21 bitter gourd germplasms,may belong to a new species or subspecies independent from M.charantia.Furthermore,we found that the remaining 166 M.charantia germplasms are geographically differentiated,and we identified 710,412,and 290 candidate domestication genes in the South Asia,Southeast Asia,and China populations,respectively.This study provides new insights into bitter gourd genetic diversity and domestication and will facilitate the future genomics-enabled improvement of bitter gourd.
基金supported by grant from the International Science&Technology Cooperation Program of China(No.2014DFR31200)the National Infrastructure of Chinese Genetic Resources(YCZYPT[2017]01-6)+1 种基金federal funds from the National Cancer Institute,National Institutes of Health,USA(No.N01-CO12400)the National Natural Science Foundation of China(No.30671855)。
文摘Some patients with chronic hepatitis B virus(HBV)infection failed to clear HBV,even persistently continue to produce antibodies to HBV.Here we performed a two stage genome wide association study in a cohort of Chinese patients designed to discover single nucleotide variants that associate with HBV infection and clearance of HBV.The first stage involved genome wide exome sequencing of 101 cases(HBsAg plus anti-HBs positive)compared with 102 control patients(antiHBs positive,HBsAg negative).Over 80%of individual sequences displayed 209 sequence coverage.Adapters,uncertain bases[10%or low-quality base calls([50%)were filtered and compared to the human reference genome hg19.In the second stage,579 chronic HBV infected cases and 439 HBV clearance controls were sequenced with selected genes from the first stage.Although there were no significant associated gene variants in the first stage,two significant gene associations were discovered when the two stages were assessed in a combined analysis.One association showed rs506121-“T”allele[within the dedicator of cytokinesis 8(DOCK8)gene]was higher in chronic HBV infection group than that in clearance group(P=0.002,OR=0.77,95%CI[0.65,0.91]).The second association involved rs2071676—A allele within the Carbonic anhydrase(CA9)gene that was significantly elevated in chronic HBV infection group compared to the clearance group(P=0.0003,OR=1.35,95%CI[1.15,1.58]).Upon replication these gene associations would suggest the influence of DOCK8 and CA9 as potential risk genetic factors in the persistence of HBV infection.
基金This work was supported by funding from the Ginger Genome Project of Chongqing University of Arts and Sciences(2018)the Natural Science Foundation of Chongqing(cstc2019jcyj-msxmX0300,cstc2019jcyj-msxmX0697,CQYC201903201,cstc2019jscx-dxwtBX0028)+4 种基金the Foundation for High-level Talents of Chongqing University of Arts and Science(2017RTZ21,P2018TZ05)the Scientific and Technological Research Program of Chongqing Municipal Education Commission(KJZD-K202001304,KJQN201801339,KJQN201801330,KJQN201801335)the Foundation of Hubei Rural Science and Technology(2020BBA037)the State Key Research and Development Program of Hubei(2020BBA037)the Foundation of Laiwu Experimental Station of the National Characteristic Vegetable Industry System.
文摘Ginger(Zingiber officinale),the type species of Zingiberaceae,is one of the most widespread medicinal plants and spices.Here,we report a high-quality,chromosome-scale reference genome of ginger‘Zhugen’,a traditionally cultivated ginger in Southwest China used as a fresh vegetable,assembled from PacBio long reads,Illumina short reads,and high-throughput chromosome conformation capture(Hi-C)reads.The ginger genome was phased into two haplotypes,haplotype 1(1.53 Gb with a contig N50 of 4.68 M)and haplotype 0(1.51 Gb with a contig N50 of 5.28 M).Homologous ginger chromosomes maintained excellent gene pair collinearity.In 17,226 pairs of allelic genes,11.9%exhibited differential expression between alleles.Based on the results of ginger genome sequencing,transcriptome analysis,and metabolomic analysis,we proposed a backbone biosynthetic pathway of gingerol analogs,which consists of 12 enzymatic gene families,PAL,C4H,4CL,CST,C3’H,C3OMT,CCOMT,CSE,PKS,AOR,DHN,and DHT.These analyses also identified the likely transcription factor networks that regulate the synthesis of gingerol analogs.Overall,this study serves as an excellent resource for further research on ginger biology and breeding,lays a foundation for a better understanding of ginger evolution,and presents an intact biosynthetic pathway for species-specific gingerol biosynthesis.
基金supported by the National Key Research and Development Program of China[2021YFC1005300]the science and technology innovation Program of Hunan Province—Major Scientific and Technological Projects for Collaborative Prevention and Control of Birth Defects in Hunan Province[2019SK1010 and 2019SK1011]Hunan Province Clinical Medical Technology Innovation Guidance Project"Screening,prevention and control of single gene disease carriers and panel research in childbearing age people in Hunan Province"[2021SK50602].
文摘Objective This study was aimed at investigating the carrier rate of,and molecular variation in,α-andβ-globin gene mutations in Hunan Province.Methods We recruited 25,946 individuals attending premarital screening from 42 districts and counties in all 14 cities of Hunan Province.Hematological screening was performed,and molecular parameters were assessed.Results The overall carrier rate of thalassemia was 7.1%,including 4.83%forα-thalassemia,2.15%forβ-thalassemia,and 0.12%for bothα-andβ-thalassemia.The highest carrier rate of thalassemia was in Yongzhou(14.57%).The most abundant genotype ofα-thalassemia andβ-thalassemia was-α^(3.7)/αα(50.23%)andβ^(IVS-Ⅱ-654)/β^(N)(28.23%),respectively.Fourα-globin mutations[CD108(ACC>AAC),CAP+29(G>C),Hb Agrinio and Hb Cervantes]and sixβ-globin mutations[CAP+8(C>T),IVS-Ⅱ-848(C>T),-56(G>C),beta nt-77(G>C),codon 20/21(-TGGA)and Hb Knossos]had not previously been identified in China.Furthermore,this study provides the first report of the carrier rates of abnormal hemoglobin variants andα-globin triplication in Hunan Province,which were 0.49%and 1.99%,respectively.Conclusion Our study demonstrates the high complexity and diversity of thalassemia gene mutations in the Hunan population.The results should facilitate genetic counselling and the prevention of severe thalassemia in this region.
基金Supported by the Natural Science Foundation of Chongqing,No. cstc2018jcyj AX0781the Major Project of Chongqing Health Committee,No. cstc2016 shmszx130033031+1 种基金the National Natural Science Foundation of China,No. 81302316the Chongqing technological innovation and application development-Major theme projects,No. cstc2019jscxfxydx0008
文摘BACKGROUND The poly(ADP-ribose)polymerase(PARP)inhibitor olaparib has displayed superior clinical effect in metastatic castration-resistant prostate cancer(mCRPC)patients with the homologous recombination repair(HRR)genes mutations.However,when a patient’s tumor tissue volume is insufficient for genomic profiling of HRR gene mutations,circulating tumor DNA(ctDNA)may be useful in helping to determine and monitor the efficacy of olaparib,as well as in abiraterone-combination treatment,and for understanding any resistance mechanism related to such mutations.CASE SUMMARY A 61-year-old man who was diagnosed with metastatic prostate adenocarcinoma was initially hormone sensitivity,showing high Gleason score(5+5=10)and absolute positive rate(14/14 biopsied specimens).Following failure of several standard therapies,the patient progressed to mCRPC.Surprisingly,the patient showed good response to olaparib-abiraterone-prednisone combination treatment(an androgen-deprivation therapy,provided as the‘final choice’in China).Serum total prostate-specific antigen(TPSA)level reduced and symptoms remitted for 4 months.However,thereafter,serum TPSA levels began slowly increasing,indicating development of olaparib resistance.Subsequent comprehensive genomic profiling of ctDNA, screening 508 cancer-related genes by next-generation sequencing,identified 10 somatic variants as well as 3 copy number alterations. Two identified reversemissense mutations in partner and localizer of BRCA2 (PALB2) may have recovered the readingframe, restoring function of the primary germline PALB2 mutation and causing resistance to thePARP inhibitor olaparib.CONCLUSIONReverse mutations in PALB2, discovered via genomic profiling of ctDNA, may represent apotential resistance mechanism against olaparib in mCRPC.
基金supported by the Major Project of Tobacco Biological Effects(552022AK0070,110202102014)。
文摘Nicotine is widely recognized as the primary contributor to tobacco dependence.Previous studies have indicated that molecular and behavioral responses to nicotine are primarily mediated by ventral tegmental area(VTA)neurons,and accumulating evidence suggests that glia play prominent roles in nicotine addiction.However,VTA neurons and glia have yet to be characterized at the transcriptional level during the progression of nicotine self-administration.Here,a male mouse model of nicotine self-administration is established and the timing of three critical phases(pre-addiction,addicting,and post-addiction phase)is characterized.Single-nucleus RNA sequencing in the VTA at each phase is performed to comprehensively classify specific cell subtypes.Adaptive changes occurred during the addicting and post-addiction phases,with the addicting phase displaying highly dynamic neuroplasticity that profoundly impacts the transcription in each cell subtype.Furthermore,significant transcriptional changes in energy metabolism-related genes are observed,accompanied by notable structural alterations in neuronal mitochondria during the progression of nicotine self-administration.The results provide insights into mechanisms underlying the progression of nicotine addiction,serving as an important resource for identifying potential molecular targets for nicotine cessation.
基金supported by the NIH-NIA Research Project (R21AG036454)the National Key R&D Program of China (2016YFC0901500)+4 种基金CAMS Innovation Fund for Medical Sciences (2016-12M-1-004)the National Key R&D Program of China (2016YFC1305900)the National Natural Science Foundation of China (3203004)the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB02030001)Shenzhen Municipal of Government of China (JCYJ20170412153248372 and JCYJ20180507183615145).
文摘This study aimed to identify possible pathogenic genes in a 90-member family with a rare combination of multiple neurodegenerative disease phenotypes,which has not been depicted by the known neurodegenerative disease.We performed physical and neurological examinations with International Rating Scales to assess signs of ataxia,Parkinsonism,and cognitive function,as well as brain magnetic resonance imaging scans with seven sequences.We searched for co-segregations of abnormal repeat-expansion loci,pathogenic variants in known spinocerebellar ataxiarelated genes,and novel rare mutations via whole-genome sequencing and linkage analysis.A rare co-segregating missense mutation in the CARS gene was validated by Sanger sequencing and the aminoacylation activity of mutant CARS was measured by spectrophotometric assay.This pedigree presented novel late-onset core characteristics including cerebellar ataxia,Parkinsonism,and pyramidal signs in all nine affected members.Brain magnetic resonance imaging showed cerebellar/pons atrophy,pontine-midline linear hyperintensity,decreased rCBF in the bilateral basal ganglia and cerebellar dentate nucleus,and hypo-intensities of the cerebellar dentate nuclei,basal ganglia,mesencephalic red nuclei,and substantia nigra,all of which suggested neurodegeneration.Whole-genome sequencing identified a novel pathogenic heterozygous mutation(E795V)in the CARS gene,meanwhile,exhibited none of the known repeat-expansions or point mutations in pathogenic genes.Remarkably,this CARS mutation causes a 20%decrease in aminoacylation activity to charge tRNA^(Cys) with L-cysteine in protein synthesis compared with that of the wild type.All family members carrying a heterozygous mutation CARS(E795V)had the same clinical manifestations and neuropathological changes of Parkinsonism and spinocerebellar-ataxia.These findings identify novel pathogenesis of Parkinsonismspinocerebellar ataxia and provide insights into its genetic architecture.
基金supported by grants from the National Natural Science Foundation of China(grant 32072384,W2412104)the China Agriculture Research System of MOF and MARA(CARS-02)+2 种基金This study was also supported by the Ministry of Agriculture and Rural Affairs of China(NK2023070202)S.C.G.is supported by startup funds from the University of California,Riversideby a grant from the National Institute of General Medical Sciences of the National Institutes of Health(award no.R35GM151194).
文摘During the early systemic infection of plant pathogens,individual cells can harbor pathogens at various stages of infection,ranging from absent to abundant.Consequently,gene expression levels within these cells in response to the pathogens exhibit significant variability.These variations are pivotal in determining pathogenicity or susceptibility,yet they remain largely unexplored and poorly understood.Sugarcane mosaic virus(SCMV)is a representative member of the monocot-infecting potyviruses with a polyadeny-lated RNA genome,which can be captured by single-cell RNA sequencing(scRNA-seq).Here,we per-formed scRNA-seq on SCMV-infected maize leaves during early systemic infection(prior to symptom mani-festation)to investigate the co-variation patterns between viral accumulation and intracellular gene expression alterations.We identifiedfive cell types and found that mesophyll-4(MS4)cells exhibited the highest levels of viral accumulation in most cells.Early systemic infection of SCMV resulted in a greater up-regulation of differentially expressed genes,which were mainly enriched in biological processes related to translation,peptide biosynthesis,and metabolism.Co-variation analysis of the altered maize gene expres-sion and viral accumulation levels in MS1,2,and 4 revealed several patterns,and the co-expression rela-tionships between them were mainly positive.Furthermore,functional studies identified several potential anti-or pro-viral factors that may play crucial roles during the early stage of SCMV systemic infection.These results not only provide new insights into plant gene regulation during viral infection but also offer a foundation for future investigations of host–virus interactions across molecular,cellular,and physiolog-ical scales.
基金supported by the National Key R&D Program of China(Grant No.2022YFF1202203)the NIFDC Fund for Key Technology Research,China(Grant No.GJJS-2022-2-1).
文摘Homologous recombination deficiency(HRD)has emerged as a critical prognostic and predictive biomarker in oncology.However,current test-ing methods,especially those reliant on targeted panels,are plagued by inconsistent results from the same samples.This highlights the urgent need for standardized benchmarks to evaluate HRD assay performance.In phases lla and Ilb of the Chinese HRD Harmonization Project,we de-veloped ten pairs of well-characterized DNA reference materials derived from lung,breast,and melanoma cancer cell lines and their matched normal cell lines,keeping each paired with seven cancer-to-normal mass ratios.Reference datasets for allele-specific copy number variations(AsCNVs)and HRD scores were established and validated using three sequencing methods and nine analytical pipelines.The genomic instabil-ity scores(GISs)of the reference materials ranged from 11 to 96,enabling validation across various thresholds.The AsCNV reference datasets covered a genomic span of 2340 to 2749 Mb,equivalent to 81.2%to 95.4%of the autosomes in the 37d5 reference genome.These bench-marks were subsequently utilized to assess the accuracy and reproducibility of four HRD panel assays,revealing significant variability in both ASCNV detection and HRD scores.The concordance between panel-detected GISs and reference GISs ranged from 0.81 to 0.94,with only two assays exhibiting high overall agreement with Myriad MyChoice CDx for HRD classification.This study also identified specific challenges in ASCNV detection in HRD-related regions and the profound impact of high ploidy on consistency.The established HRD reference materials and datasets providea robust toolkit forobjective evaluation of HRD testing.
基金supported by the Guangdong Provincial Key Laboratory of Human Disease Genomics(Grant 2020B1212070028).
文摘Background:Bladder cancer is a common malignancy of the genitourinary system.Recent studies have confirmed the existence of microorganisms in urine.This study aimed to characterize changes in the urinary microbiota of Chinese bladder cancer patients and determine differences between patients with muscle-invasive bladder cancer(MIBC)and those with non-muscle-invasive bladder cancer(NMIBC).Methods:Urine samples were collected from 64 patients with bladder cancer and 94 disease-free controls using the clean catch method and sequenced by 16S rRNA gene sequencing.Sequencing reads were filtered by VSEARCH and clustered by UPARSE.Results:Significant associations were found between urinary microbiota and factors such as sex,age,and disease status.After age adjustment,differences in beta diversity were observed between healthy men and women,cancer patients and healthy controls,and NMIBC and MIBC patients.The cancer patients had an increased abundance of 14 bacterial genera,including Stenotrophomonas,Propionibacterium,and Acinetobacter.Notably,Peptoniphilus spp.were enriched in high-risk MIBC patients,indicating their potential as a risk marker.Functional prediction via PICRUSt analysis suggested enriched metabolic pathways in specific disease groups.Furthermore,molecular ecological network analysis revealed differences based on sex and disease type.Conclusions:This significant microbial diversity indicates a potential correlation between urinary microbiota dysbiosis and bladder cancer,with implications for risk stratification and disease management.The identified urinary microbiota may serve as noninvasive markers for bladder cancer,warranting further validation in larger cohorts.This study provides a foundation for further research on the mechanisms of bladder cancer progression.
基金supported by the National Key Research and Development Program of China(2022YFC2703100)The Ministry of Finance of the People's Republic of China funded the UPWARDS projectthe National Health Commission of the People's Republic of China(NHC)for supporting this study。
文摘In China,an estimated 48.42-82.11 million individuals are affected by rare diseases.This estimate is derived from the Orphanet database,based on the global population of 7.55 billion and China's population of 1.39 billion in 2017(source:National Bureau of Statistics of China)[1,2].
基金supported by the National Natural Science Foundation of China(Grant Nos.82125009,82330045,32121002,82071185,82172061,and 92149303)the National Key R&D Program of China(Grant Nos.2020YFA0509300,2021YFA0804900,and 2022YFC2703102)+4 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39000000)CAS Project for Young Scientists in Basic Research(YSBR-013),Plans for Major Provincial Science&Technology Projects(202303a07020004)Hefei Comprehensive National Science Center Hefei Brain Project,Research Funds of Center for Advanced Interdisciplinary Science and Biomedicine of IHM(QYZD20220003)the Major Frontier Research Project of the University of Science and Technology of China(LS9100000002)S&T Program of Shijiazhuang(235790429H).
文摘The entorhinal cortex(EC)-hippocampal(HPC)circuit is particularly vulnerable to Alzheimer's disease(AD)pathol-ogy,yet the underlying molecular mechanisms remain unclear.By employing the high-depth sequencing strategy Smart-seq2,we tracked gene expression changes across various neuron types within this circuit at different stages of AD pathology.We observed a decrease in the extent of gene expression changes in AD versus wild-type(WT)mice as the disease advanced.Functionally,we demonstrate that both mitochondrial and ribosomal pathways were increasingly activated,while neuronal pathways were inhibited with AD progression.Our findings indicate that the reduction of EC-stellate cells disrupts Meg3-mediated energy metabolism,contributing to energy dysfunction in AD.Additionally,we identified GFAP-positive neurons as a distinct population of disease-associated neurons,exhibiting a loss of neuronal-like characteristics,alongside the emergence of glia-and stem-like features.The num-ber of GFAP-positive neurons increased with AD progression,a trend consistently observed in both AD model mice and AD patients.In summary,this study identifies and characterizes GFAP-positive neurons as a novel subtype of disease-associated neurons in AD pathology,providing insights into their potential role in disease progression.
基金supported by the Science,Technology,and Innovation Commission of Shenzhen Municipality(grant number JCYJ20220818102809021 to F.X.).
文摘Hair loss and graying,the earliest visible signs of skin aging,are driven by the functional decline of hair follicle stem cells and their niches.To elucidate the transcriptional mechanisms involved in scalp aging,we conducted a comprehensive analysis of human scalp samples using single-cell RNA sequencing and spatial transcriptomic technologies.Our study profiled the transcriptomes of 57,181 cells from scalp samples obtained from four young,six middle-aged,and one elderly individual.The integrated bioinformatic pipeline included cell clustering,spatial deconvolution,pseudotime trajectory,as well as cell-type specific gene expression,and intercellular communication analysis.An additional 92 volunteers were included,comprising 90(37 young,27 middle-aged,and 26 elderly)for trichoscopic examination,one young individual for senescence-associated β-galactosidase(SA-β-gal)staining,and one elderly individual for both MKI67 immunofluorescence and SA-β-gal staining.This approach led to several key findings:we identified three subtypes of mitotic keratinocytes that localized in the interfollicular epidermis(IFE),outer root sheath(ORS),and hair matrix,with pseudotime trajectory further confirming their transitional stage.Furthermore,in middleaged scalps,we observed activated activator protein 1(AP-1)transcription factor complex in keratinocytes,upregulated DCT gene in melanocytes,and decreased bone morphogenetic protein(BMP)and noncanonical wingless/integrated(ncWNT)signaling in dermal papilla(DP)-keratinocytes cross-talk.Due to the insufficient sample size and under-representation of elderly samples,transcriptional features associated with late aging,sex,and scalp regions were not completely captured.Nevertheless,our study provides valuable cell-resolved transcriptional insights into hair follicle aging and may support the development of future regenerative therapies.
基金supported by the Self-supporting Program of Guangzhou Laboratory(SRPG22007)the CAS Research Fund(XDB38050200)+1 种基金the National Key Research and Development Program of China(2021YFA0910100)Healthy Zhejiang One Million People Cohort(K-20230085).
文摘Advances in multi-omics datasets and analytical methods have revolutionized cancer research,offering a comprehensive,pan-cancer perspective.Pancancer studies identify shared mechanisms and unique traits across different cancer types,which are reshaping diagnostic and treatment strategies.However,continued innovation is required to refine these approaches and deepen our understanding of cancer biology and medicine.This review summarized key findings from pan-cancer research and explored their potential to drive future advancements in oncology。
基金This work was supported by National Transgenic Major Program(2019ZX08010-002)(to X.G.)Central Public-interest Scientific Institution Basal Research Fund(no.Y2020PT06 to X.G.)+1 种基金the DECODE ERC Synergy grant(to J.U.L.)the intramural research support from Chinese Academy of Agricultural Sciences,Centre for Organismal Studies,Heidelberg University.
文摘There are two main types of root systems in flowering plants,namely taproot systems of dicots and fibrous root systems found in monocots.Despite this fundamental split,our current knowledge of cellular and molecular mechanism driving root development is mainly based on studies of the dicot model Arabidopsis.However,the world major crops are monocots and little is known about the transcriptional programs underlying cell-type specification in this clade.Here,we report the transcriptomes of more than 20000 single cells derived from root tips of two agronomically important rice cultivars.Using combined computational and experimental analyses we were able to robustly identify most of the major cell types and define novel cell-type-specific marker genes for both cultivars.Importantly,we found divergent cell types associated with specific regulatory programs,including phytohormone biosynthesis,signaling,and response,which were well conserved between the two rice cultivars.In addition,we detected substantial differences between the cell-type transcript profiles of Arabidopsis and rice.These species-specific features emphasize the importance of analyzing tissues across diverse model species,including rice.Taken together,our study provides insight into the transcriptomic landscape of major cell types of rice root tip at single-cell resolution and opens new avenues to study cell-type specification,function,and evolution in plants.
基金support from the Bioinformatics Center of Nanjing Agricultural Universitysupported by funding from the National Key Research and Development Program of China (2021YFF1001204)+5 种基金the Core Technology Development for Breeding Program of Jiangsu Province (JBGS-2021-014)the Program for Changjiang Scholars and Innovative Research Team in University (IRT_17R55)the Guidance Foundation, the Sanya Institute of Nanjing Agricultural University (NAUSY-ZZ02, NAUSY-MS05)the Natural Science Foundation of China (31601325)the BGI non profit fund, the USDA National Institute of Food and Agriculture Hatch project 02685the Jiangsu Funding Program for Excellent Postdoctoral Talent (2022ZB334)。
文摘Although seed weight has increased following domestication from wild soybean(Glycine soja) to cultivated soybean(Glycine max), the genetic basis underlying this change is unclear. Using mapping populations derived from chromosome segment substitution lines of wild soybean, we identified SW16.1 as the causative gene underlying a major quantitative trait locus controlling seed weight.SW16.1 encodes a nucleus-localized LIM domaincontaining protein. Importantly, the GsSW16.1 allele from wild soybean accession N24852 had a negative effect on seed weight, whereas the GmSW16.1 allele from cultivar NN1138-2 had a positive effect. Gene expression network analysis,reverse-transcription quantitative polymerase chain reaction, and promoter-luciferase reporter transient expression assays suggested that SW16.1 regulates the transcription of MT4, a positive regulator of seed weight. The natural variations in SW16.1 and other known seed weight genes were analyzed in soybean germplasm. The SW16.1 polymorphism was associated with seed weight in 247 soybean accessions, showing much higher frequency of positive-effect alleles in cultivated soybean than in wild soybean. Interestingly,gene allele matrix analysis of the known seed weight genes revealed that G. max has lost 38.5%of the G. soja alleles and that most of the lost alleles had negative effects on seed weight. Our results suggest that eliminating negative alleles from G. soja led to a higher frequency of positive alleles and changed genetic backgrounds in G. max,which contributed to larger seeds in cultivated soybean after domestication from wild soybean.Our findings provide new insights regarding soybean domestication and should assist current soybean breeding programs.
基金supported by the Three Gorges Environmental Funds of China Three Gorges Corporation(Grant No.XN270)。
文摘The order Acipenseriformes,which includes sturgeons and paddlefishes,represents“living fossils”with complex genomes that are good models for understanding whole-genome duplication(WGD)and ploidy evolution in fishes.Here,we sequenced and assembled the first high-quality chromosome-level genome for the complex octoploid Acipenser sinensis(Chinese sturgeon),a critically endangered species that also represents a poorly understood ploidy group in Acipenseriformes.Our results show that A.sinensis is a complex autooctoploid species containing four kinds of octovalents(8n),a hexavalent(6n),two tetravalents(4n),and a divalent(2n).An analysis taking into account delayed rediploidization reveals that the octoploid genome composition of Chinese sturgeon results from two rounds of homologous WGDs,and further provides insights into the timing of its ploidy evolution.This study provides the first octoploid genome resource of Acipenseriformes for understanding ploidy compositions and evolutionary trajectories of polyploid fishes.
基金supported by the Key Research and Development Program of Hunan Province in China (2018SK2139)
文摘Alport syndrome(AS) is a hereditary progressive nephropathy characterized by hematuria, ultrastructural lesions of the glomerular basement membrane, ocular lesions and sensorineural hearing loss. Germline mutations of COL4 A5 are associated with X-linked AS with an extreme phenotypic heterogeneity. Here, we investigated a Chinese family with Alport syndrome. The proband was a 9-year-old boy with hematuria and proteinuria. Based on the test results of renal biopsy and immunofluorescence,the proband was initially diagnosed as Ig A nephropathy and the treatment was recommended accordingly. Meanwhile, we found that the treatment outcome was poor. Therefore, for proper clinical diagnosis and appropriate treatment, targeted exome-based next-generation sequencing has been undertaken. We identified a novel hemizygous single nucleotide deletion c.1902 del A in COL4 A5 gene. Segregation analysis identified that this novel mutation is co-segregated among the affected family members but absent in unaffected family members. The clinical diagnosis of the proband was revised as AS accompanied by Ig A nephropathy,which has been rarely reported. Our findings demonstrated the significance of the application of Genetic screening, expanded the mutation spectrum of COL4 A5 associated AS patients with atypical renal phenotypes and provided a good lesson to be learned from our detour during the diagnosis.
