[Objectives]The present study was conducted to investigate the change rule ofβ-fructofuranosidase gene expression and its enzyme activity in the midgut of 5 th instar silkworm(Bombyx mori),in order to provide a refer...[Objectives]The present study was conducted to investigate the change rule ofβ-fructofuranosidase gene expression and its enzyme activity in the midgut of 5 th instar silkworm(Bombyx mori),in order to provide a reference for illustrating the enzymatic mechanism of usingβ-fructofuranosidase to absorb sucrose nutrition from mulberry leaves.[Methods]Real-time fluorescent quantitative PCR was applied to analyze the expression of BmSuc1 and BmSuc2 in midgut of 5 th-instar silkworm larvae,meanwhile the activities ofβ-fructofuranosidase was determined.[Results]BmSuc1 was expressed in the midgut of 5 th-instar silkworm larvae at different developmental stages.Its expression was upregulated at the beginning of the 5 th instar and during the peak feeding period,whereas BmSuc2 expression remained very low throughout the entire 5 th instar.The activity ofβ-fructofuranosidase was relatively high during the peak feeding period of 5 th-instar larvae,showing a trend of increasing first and then decreasing.[Conclusions]The expression pattern of the BmSuc1 gene and the changes inβ-fructofuranosidase activity were generally consistent with the physiological process of sugar nutrient absorption and utilization from mulberry leaves in 5 th-instar silkworms.It suggests that BmSuc1,as a sucrose hydrolase gene,plays a major role in the digestion and absorption of sucrose nutrients from mulberry leaves in the midgut tissue.展开更多
Improved yield potential is the goal of barley domestication and cultivation.During this process,two-and six-rowed barley types emerged and have been utilised in breeding and production.The six-rowed type could produc...Improved yield potential is the goal of barley domestication and cultivation.During this process,two-and six-rowed barley types emerged and have been utilised in breeding and production.The six-rowed type could produce three times as many grains as its ancestral two-rowed forms,thus dominating barley cultivation for thousands of years.The deficiens form of the two-rowed type,characterised by extremely suppressed lateral spikelets,has gained dominance over the past few decades in barley-growing regions worldwide.We hypothesised that the absence of lateral spikelets in deficiens barley affects spike architecture and spike-related traits,contributing to its superior yield potential of deficiens barley cultivation.Currently,a deficiens barley variety,RGT Planet,is the most popular barley variety in the world.In this study,we used two F_(2) populations derived from crossing RGT Planet with two canonical two-rowed barley and identified the functional allele Vrs1.t1 associated with deficiens morphology.We observed that the Vrs1.t1 allele may contribute to high yield potential by optimising spike architecture through increased spikelet length,grain number,and grain size.Phylogenetic analysis suggests that the deficiens mutation was likely present from the early stages of barley cultivation in the Fertile Crescent and spread to Ethiopia and beyond with agricultural expansion.We conclude that the ancient deficiens allele Vrs1.t1 has been a critical driver for the recent success of modern barley improvement by optimising spike architecture.展开更多
Nurr1 defects could in part underlie Parkinson’s disease pathogenesis,and Nurr1 gene polymorphism has been found in Caucasian patients with Parkinson’s disease.In this study,heteroduplex technology was applied to co...Nurr1 defects could in part underlie Parkinson’s disease pathogenesis,and Nurr1 gene polymorphism has been found in Caucasian patients with Parkinson’s disease.In this study,heteroduplex technology was applied to compare the DNA sequences of eight exons of Nurr1 among 200 sporadic Parkinson’s disease patients and 200 healthy controls in the Han population in the Hubei province,China.One allele amplified from exon 3 of Nurr1 was polymorphic in five Parkinson’s disease patients（2.5%,5/200）,and two individuals had a polymorphic allele amplified from exon 2 （1%,2/200）.The anomalous electrophoresis fragment in exon 3 of Nurr1 gene contained a 709C/A missense mutation,and a polymorphic single nucleotide polymorphism at 388G/A was identified in exon 2.Compared with the control group,the Nurr1 gene expression level in the Parkinson’s disease group was decreased,and the Nurr1 gene expression levels in Parkinson’s disease patients carrying the polymorphisms at exons 2 and 3 were significantly decreased.Our data indicate that the single nucleotide polymorphism 388G/A in exon 2 and the 709C/A missense mutation in exon 3 of the Nurr1 gene in the Chinese population might affect the pathogenesis of Parkinson’s disease.展开更多
The relationship between genetics and infectious diseases is important in shaping our understanding of disease susceptibility,progression,and treatment.Recent research shows the impact of genetic variations,such as he...The relationship between genetics and infectious diseases is important in shaping our understanding of disease susceptibility,progression,and treatment.Recent research shows the impact of genetic variations,such as heme-oxygenase promoter length,on diseases like malaria and sepsis,revealing both protective and inconclusive effects.Studies on vaccine responses highlight genetic markers like human leukocyte antigens,emphasizing the potential for personalized immunization strategies.The ongoing battle against drug-resistant tuberculosis(TB)illustrates the complexity of genomic variants in predicting resistance,highlighting the need for integrated diagnostic tools.Additionally,genome-wide association studies reveal antibiotic resistance mechanisms in bacterial genomes,while host genetic polymorphisms,such as those in solute carrier family 11 member 1 and vitamin D receptor,demonstrate their role in TB susceptibility.Advanced techniques like metagenomic next-generation sequencing promise detailed pathogen detection but face challenges in cost and accessibility.A case report involving a highly virulent Mycobacterium TB strain with the pks1 gene further highlights the need for genetic insights in understanding disease severity and developing targeted interventions.This evolving landscape emphasizes the role of genetics in infectious diseases,while also addressing the need for standardized studies and accessible technologies.展开更多
BACKGROUND Dystrophic epidermolysis bullosa is characterized by fragile ulcerations of the skin caused by mutations in specific genes.However,genetic typing of this con-dition is rare.CASE SUMMARY An 11-year-old femal...BACKGROUND Dystrophic epidermolysis bullosa is characterized by fragile ulcerations of the skin caused by mutations in specific genes.However,genetic typing of this con-dition is rare.CASE SUMMARY An 11-year-old female suffered from recurrent fever,visible ulcerations of the entire skin,and severe malnutrition.Genetic testing revealed a frameshift mu-tation in the coding region 4047 of the 35th intron region of COL7A1,and she was diagnosed as malnutrition-type epidermolysis bullosa.Drug therapy(immu-noglobulin,fresh frozen plasma),topical therapy(silver ion dressing),fever redu-ction,cough relief,and promotion of gastrointestinal peristalsis are mainly used for respiratory and gastrointestinal complications.The patient’s condition impro-ved after treatment.CONCLUSION Dystrophic epidermolysis bullosa caused by a new framework shift mutation in COL7A1 should be taken seriously.展开更多
BACKGROUND:Adeno-associated virus(AAV)gene therapy has been proven to be reliable and safe for the treatment of osteoarthritis in recent years.However,given the complexity of osteoarthritis pathogenesis,single gene ma...BACKGROUND:Adeno-associated virus(AAV)gene therapy has been proven to be reliable and safe for the treatment of osteoarthritis in recent years.However,given the complexity of osteoarthritis pathogenesis,single gene manipulation for the treatment of osteoarthritis may not produce satisfactory results.Previous studies have shown that nuclear factorκB could promote the inflammatory pathway in osteoarthritic chondrocytes,and bone morphogenetic protein 4(BMP4)could promote cartilage regeneration.OBJECTIVE:To test whether combined application of AAV-p65shRNA and AAV-BMP4 will yield the synergistic effect on chondrocytes regeneration and osteoarthritis treatment.METHODS:Viral particles containing AAV-p65-shRNA and AAV-BMP4 were prepared.Their efficacy in inhibiting inflammation in chondrocytes and promoting chondrogenesis was assessed in vitro and in vivo by transfecting AAV-p65-shRNA or AAV-BMP4 into cells.The experiments were divided into five groups:PBS group;osteoarthritis group;AAV-BMP4 group;AAV-p65shRNA group;and BMP4-p65shRNA 1:1 group.Samples were collected at 4,12,and 24 weeks postoperatively.Tissue staining,including safranin O and Alcian blue,was applied after collecting articular tissue.Then,the optimal ratio between the two types of transfected viral particles was further investigated to improve the chondrogenic potential of mixed cells in vivo.RESULTS AND CONCLUSION:The combined application of AAV-p65shRNA and AAV-BMP4 together showed a synergistic effect on cartilage regeneration and osteoarthritis treatment.Mixed cells transfected with AAV-p65shRNA and AAV-BMP4 at a 1:1 ratio produced the most extracellular matrix synthesis(P<0.05).In vivo results also revealed that the combination of the two viruses had the highest regenerative potential for osteoarthritic cartilage(P<0.05).In the present study,we also discovered that the combined therapy had the maximum effect when the two viruses were administered in equal proportions.Decreasing either p65shRNA or BMP4 transfected cells resulted in less collagen II synthesis.This implies that inhibiting inflammation by p65shRNA and promoting regeneration by BMP4 are equally important for osteoarthritis treatment.These findings provide a new strategy for the treatment of early osteoarthritis by simultaneously inhibiting cartilage inflammation and promoting cartilage repair.展开更多
Background Verticillium dahliae,a soil-borne fungi,can cause Verticillium wilt,and seriously diminish the yield and quality of cotton.However,the pathogenic mechanism of V.dahliae is complex and not clearly understood...Background Verticillium dahliae,a soil-borne fungi,can cause Verticillium wilt,and seriously diminish the yield and quality of cotton.However,the pathogenic mechanism of V.dahliae is complex and not clearly understood at the moment.This study aimed to identify the high-affinity nicotinic acid transporter genes in V.dahliae.The gene expression profiles in V.dahliae following sensing of root exudates from susceptible and resistant cotton varieties were analyzed.The function of VdNAT1 in the pathogenic process of V.dahliae was studied using the tobacco rattle virus(TRV)-based host-induced gene silencing(HIGS)technique.Results Eight high-affinity nicotinic acid transporter genes were identified from V.dahliae through the bioinformatics method.Each protein contains a conserved major facilitator superfamily(MFS)domain,which belongs to the MFS superfamily.Evolutionary relationship analysis revealed that all 8 genes belong to the anion:cation symporter(ACS)subfamily.All proteins have transmembrane domains,ranging from 7 to 12.The expression levels of most VdNAT genes were significantly increased after induction by root exudates from susceptible cotton varieties.Silencing VdNAT1 gene by HIGS significantly inhibited the accumulation of fungal biomass in cotton plants,and alleviated the disease symptoms of cotton.Conclusions Eight VdNAT genes were identified from V.dahliae,and most VdNAT genes was up-regulated after induced by root exudates from susceptible cotton variety.In addition,VdNAT1 is required for the pathogenicity of V.dahliae.Overall,these findings will facilitate the pathogenic molecular mechanism of V.dahliae and provide candidate genes.展开更多
The canonical signaling of interferon gamma(IFN-γ)through the Janus kinase 1 and 2–signal transducer and activator of transcription 1(STAT1)axis leads to the expression of several interferon-stimulated genes(ISGs),w...The canonical signaling of interferon gamma(IFN-γ)through the Janus kinase 1 and 2–signal transducer and activator of transcription 1(STAT1)axis leads to the expression of several interferon-stimulated genes(ISGs),which have diverse effects depending on the cellular context.In glioblastoma,a highly aggressive primary brain tumor in adults,elements of IFN-γcanonical signaling are deregulated,resulting in the overexpression of STAT1-target ISGs associated with tumor progression.This mini-review highlights key ISGs,including STAT1,interferon regulatory factor 1,programmed death-ligand 1,indoleamine 2,3-dioxygenase 1,and interferon-stimulated gene 15,involved in the pathology of glioblastoma.These genes may serve as valuable biomarkers and have therapeutic potential for targeting IFN-γsignaling in this malignancy.展开更多
The present investigation aims at unveiling the main causes of the recorded disparate phylogeographic patterning among the two highly dispersive coastal crab species Carcinus aestuarii and Pachygrapsus marmoratus in t...The present investigation aims at unveiling the main causes of the recorded disparate phylogeographic patterning among the two highly dispersive coastal crab species Carcinus aestuarii and Pachygrapsus marmoratus in the Mediterranean Sea.For this purpose,available mitochondrial and nuclear data for both species were re-analyzed and investigated for genetic polymorphism and differentiation patterns across three defined geographic scales in their distribution ranges,but also across the same locations in the Mediterranean Sea.The temporal frame of genetic diversification was also determined for both species in order to check whether observed differences in phylogeographic patterns among these coastal decapods could be attributed to different evolutionary histories.The obtained results revealed a more variable and diversified gene pool in the green crab C.aestuarii than the one recorded in the marbled crab P.marmoratus.Lack of significant correlation between pairwise genetic dissimilarities observed among C.aestuarii populations and those detected for P.marmoratus was notably discerned across the same defined Mediterranean locations.This finding indicates that the pattern of pairwise genetic differentiation does not vary in the same way in both examined crab species.Significant outputs of population genetic differentiation,retrieved within both species,were shown to be differently associated with the potential effects of various kinds of isolation processes(related to geography,environment and biogeographic boundary).Evolutionary history reconstruction showed older genetic diversification event in C.aestuarii than the one recorded in P.marmoratus.These recorded temporal frames suggest different modes of genetic diversification in both crab species(glacial vicariance for C.aestuarii and interglacial dispersal for P.marmoratus).They may also provide an explanation for the recorded differences in variation of patterns of population genetic diversity and structure,when integrated with species ecological requirements and life-history traits.展开更多
BACKGROUND Dyschromatosis universalis hereditaria(DUH)is a rare type of autosomal dominant inheritance disease.It has varying gene mutation sites among different ethnicities.SASH1 and ABCB6 have been identified as the...BACKGROUND Dyschromatosis universalis hereditaria(DUH)is a rare type of autosomal dominant inheritance disease.It has varying gene mutation sites among different ethnicities.SASH1 and ABCB6 have been identified as the causative genes of this disorder.CASE SUMMARY A 30-year-old woman presented with irregular black pigmentation spots to our department.Upon examination,the pigmentations were found to be especially dense on the extremities and the face.She had no family history of inbreeding,nor any previous chemical exposure.Genetic testing confirmed that the disease occu-rred because the patient has a SASH1 gene mutation.Following the use of assisted reproductive technology and preimplantation genetic testing for monogenic disorders,the patient give birth to a health baby.CONCLUSION Using assisted reproductive technology/preimplantation genetic testing for monogenic disorders is an option for DUH patients to reduce the risk of trans-mitting the pathogenic variant to their offspring.展开更多
Polyembryony has posed a significant impediment to the advancement of citrus hybrid breeding.FhRWP is widely regarded as a pivotal factor governing asexual reproduction in citrus,and prior research has demonstrated th...Polyembryony has posed a significant impediment to the advancement of citrus hybrid breeding.FhRWP is widely regarded as a pivotal factor governing asexual reproduction in citrus,and prior research has demonstrated that FhARID1,acting as an upstream regulator,modulates FhRWP expression.In this study,we performed a genome-wide characterization of the ARID-HMG-related genes using the short juvenile minicitrus Fortunella hindsii.A total of 20 ARID-HMG-related genes were identified.Protein interaction network and enrichment analysis suggested that ARID-HMG-related proteins might might be involved in chromatin remodeling complexes.Knockout of FhARID1 in F.hindsii did not induce the conversion from polyembryony to monoembryony.However,fharid1 plants in T1 generation exhibited abnormal proliferation at axillary buds,which is similar to phenotype of fhrwp plants.Expression analysis of fharid1 ovary tissues revealed the downregulation of FhRWP.The results indicated that FhARID1,as an upstream regulator of FhRWP,has an effect on the development of citrus axillary buds.Expression analysis of overexpressed leaves of FhARID1 lines showed that no significant up-regulation of FhRWP,indicating that FhARID1 is not the sole upstream regulatory factor of FhRWP.Only FhARID2 showed a correlation in expression with FhARID1 among the ARID-related genes,further supporting the notion that this gene may be involved in complex formation rather than acting alone.Yeast two-hybrid and MS/MS spectra further indicated that FhARID1 function requires casein kinase II-mediated post-transcriptional phosphorylation.This study elucidated the function of FhARID1 in citrus apomixis and axillary bud development,providing a fundamental basis for understanding the role of ARID-HMG-related genes.展开更多
BACKGROUND Wolfram syndrome is a rare autosomal recessive genetic disorder characterized by early-onset diabetes and progressive neurodegeneration,most notably sensorineural hearing loss and optic atrophy.Because its ...BACKGROUND Wolfram syndrome is a rare autosomal recessive genetic disorder characterized by early-onset diabetes and progressive neurodegeneration,most notably sensorineural hearing loss and optic atrophy.Because its initial manifestations are usually similar to those of type 1 diabetes,the diagnosis may be delayed until other manifestations appear.Pathogenic variations of the WFS1 gene can disrupt endoplasmic reticulum function and cellular homeostasis,but the complete mutation spectrum of WFS1 has not been fully determined.Early identification of monogenic diabetes caused by Wolfram syndrome is of vital importance,as it enables the provision of targeted multidisciplinary care and genetic counseling for affected families.CASE SUMMARY A 2-year-old Han Chinese girl was admitted with a 1-month history of polydipsia,polyuria,and polyphagia,and was diagnosed with diabetic ketoacidosis and impaired insulin secretion.Sensorineural hearing loss was also detected.Wholeexome sequencing identified a previously unreported heterozygous mutation,WFS1 c.986T>C(p.Phe329Ser),in the patient and her father,confirming the diagnosis of Wolfram syndrome.Bioinformatic analysis supported the likely pathogenicity of this mutation.In silico pathogenicity predictors(REVEL,SIFT,Poly-Phen-2,MutationTaster,and GERP+)supported a deleterious effect on wolframin structure and function.The patient was initially treated with intravenous insulin and fluid resuscitation,then transitioned to a basal–bolus insulin regimen.Glycemic control was subsequently maintained with continuous subcutaneous insulin infusion and intermittent subcutaneous injections.At the 1-and 6-month follow-ups,blood glucose remained well controlled(hemoglobin A1c:5.89%and 6.58%,respectively),with no evidence of organ dysfunction or further complications.CONCLUSION This case identifies WFS1 c.986T>C(p.Phe329Ser)as a novel pathogenic variant causing Wolfram syndrome.It highlights the importance of early genetic testing in pediatric patients with atypical diabetes presentations to enable timely diagnosis,individualized therapy,and comprehensive family support.展开更多
Retinitis pigmentosa is a group of inherited diseases that lead to retinal degeneration and photoreceptor cell death.However,there is no effective treatment for retinitis pigmentosa caused by PDE6B mutation.Adeno-asso...Retinitis pigmentosa is a group of inherited diseases that lead to retinal degeneration and photoreceptor cell death.However,there is no effective treatment for retinitis pigmentosa caused by PDE6B mutation.Adeno-associated virus(AAV)-mediated gene therapy is a promising strategy for treating retinitis pigmentosa.The aim of this study was to explore the molecular mechanisms by which AAV2-PDE6B rescues retinal function.To do this,we injected retinal degeneration 10(rd10)mice subretinally with AAV2-PDE6B and assessed the therapeutic effects on retinal function and structure using dark-and light-adapted electroretinogram,optical coherence tomography,and immunofluorescence.Data-independent acquisition-mass spectrometry-based proteomic analysis was conducted to investigate protein expression levels and pathway enrichment,and the results from this analysis were verified by real-time polymerase chain reaction and western blotting.AAV2-PDE6B injection significantly upregulated PDE6βexpression,preserved electroretinogram responses,and preserved outer nuclear layer thickness in rd10 mice.Differentially expressed proteins between wild-type and rd10 mice were closely related to visual perception,and treating rd10 mice with AAV2-PDE6B restored differentially expressed protein expression to levels similar to those seen in wild-type mice.Kyoto Encyclopedia of Genes and Genome analysis showed that the differentially expressed proteins whose expression was most significantly altered by AAV2-PDE6B injection were enriched in phototransduction pathways.Furthermore,the phototransductionrelated proteins Pde6α,Rom1,Rho,Aldh1a1,and Rbp1 exhibited opposite expression patterns in rd10 mice with or without AAV2-PDE6B treatment.Finally,Bax/Bcl-2,p-ERK/ERK,and p-c-Fos/c-Fos expression levels decreased in rd10 mice following AAV2-PDE6B treatment.Our data suggest that AAV2-PDE6B-mediated gene therapy promotes phototransduction and inhibits apoptosis by inhibiting the ERK signaling pathway and upregulating Bcl-2/Bax expression in retinitis pigmentosa.展开更多
Objective To investigate the structural changes of rat thoracic aorta and changes in expression levels of Bmal1 and cyclins in thoracic aorta endothelial cells following heat stress.Methods Twenty male SD rats were ra...Objective To investigate the structural changes of rat thoracic aorta and changes in expression levels of Bmal1 and cyclins in thoracic aorta endothelial cells following heat stress.Methods Twenty male SD rats were randomized equally into control group and heat stress group.After exposure to 32℃for 2 weeks in the latter group,the rats were examined for histopathological changes and Bmal1 expression in the thoracic aorta using HE staining and immunohistochemistry.In the cell experiments,cultured rat thoracic aortic endothelial cells(RTAECs)were incubated at 40℃for 12 h with or without prior transfection with a Bmal1-specific small interfering RNA(si-Bmal1)or a negative sequence.In both rat thoracic aorta and RTAECs,the expressions of Bmal1,the cell cycle proteins CDK1,CDK4,CDK6,and cyclin B1,and apoptosis-related proteins Bax and Bcl-2 were detected using Western blotting.TUNEL staining was used to detect cell apoptosis in rat thoracic aorta,and the changes in cell cycle distribution and apoptosis in RTAECs were analyzed with flow cytometry.Results Compared with the control rats,the rats exposed to heat stress showed significantly increased blood pressures and lowered heart rate with elastic fiber disruption and increased expressions of Bmal1,cyclin B1 and CDK1 in the thoracic aorta(P<0.05).In cultured RTAECs,heat stress caused significant increase of Bmal1,cyclin B1 and CDK1 protein expression levels,which were obviously lowered in cells with prior si-Bmal1 transfection.Bmal1 knockdown also inhibited heat stress-induced increase of apoptosis in RTAECs as evidenced by decreased expression of Bax and increased expression of Bcl-2.Conclusion Heat stress upregulates Bmal1 expression and causes alterations in expressions of cyclins to trigger apoptosis of rat thoracic aorta endothelial cells,which can be partly alleviated by suppressing Bmal1 expression.展开更多
A chimeric gene, Bt29K, composed of coding sequences of activated Cry1Ac insecticidal protein and an endoplasm reticulum-retarding signal peptide, was synthesized. A plant expression vector containing two expression c...A chimeric gene, Bt29K, composed of coding sequences of activated Cry1Ac insecticidal protein and an endoplasm reticulum-retarding signal peptide, was synthesized. A plant expression vector containing two expression cassettes for the Bt29K and API-B genes was constructed. These two insect-resistant genes were transferred into two cotton ( Gossypium hirsutum L.) varieties ( or lines) via Agrobacterium-mediated transformation and nine homozygous transgenic cotton lines showing a mortality of 90.0% - 99.7% to cotton ballworm (Heliothis armigera) larvae and good agronomic traits were selected through six generations. Molecular biology analysis revealed that one or two copies of the insecticidal protein genes were integrated into the transgenic cotton genome and activated Cry1Ac and API-B protein expression was at a level of 0.17% and 0.09% of the total soluble protein in the transgenic cotton leaves, respectively. Comparison of the insect-resistance of the homozygous lines expressing the activated chimeric Cry1Ac and API-B with that expressing Cry1Ac only revealed that the insect-resistance of the former is apparently higher than the latter. These results also indicate that the strategy to construct a plant expression vector expressing two different insect-resistant genes reported here is reasonable.展开更多
Objective:Metabolic dysfunction-associated steatohepatitis(MASH),a progressive subtype of metabolic dysfunction-associated steatotic liver disease(MASLD),is characterized by hepatic steatosis,lobular inflammation,and ...Objective:Metabolic dysfunction-associated steatohepatitis(MASH),a progressive subtype of metabolic dysfunction-associated steatotic liver disease(MASLD),is characterized by hepatic steatosis,lobular inflammation,and hepatocyte ballooning,and may further progress to liver fibrosis and cirrhosis.Lectin-like oxidized low-density lipoprotein receptor-1(LOX-1),a member of the scavenger receptor family,recognizes and binds oxidized low-density lipoprotein.This study aims to investigate the role of LOX-1 in MASH progression.Methods:LOX-1 expression in MASLD mouse liver was analyzed using Gene Expression Omnibus(GEO)datasets.Immunofluorescence staining was performed to detect LOX-1 and alpha-smooth muscle actin(α-SMA)levels and co-localization in fibrotic liver tissues and LX-2 cells.LOX-1 knockout(Lox-1^(−/−))mice were generated using CRISPR/caspase-9(Cas9)and genotyped by PCR and Sanger sequencing.Wild-type(WT)and Lox-1^(−/−)mice were randomized into control and Western diet model groups.Serum and liver samples were collected for alanine aminotransferase(ALT)and aspartate aminotransferase(AST)measurement by biochemical kits,liver structure evaluation by hematoxylin and eosin(HE)staining,collagen deposition by Masson staining,lipid accumulation by Oil Red O staining,and fibrotic marker gene expression by real-time quantitative PCR(RT-qPCR).Network pharmacology and search tool for the retrieval of interacting genes/proteins(STRING)-based protein-protein interaction(PPI)with Gene Ontology(GO)enrichment were used to predict downstream targets and pathways.Results:The results from the GEO datasets GSE30552 and GSE40041 indicated LOX-1 mRNA was upregulated in high fat diet(HFD)and bile duct ligation(BDL)mouse models(both P<0.001).LOX-1 and α-SMA levels were elevated in fibrotic liver tissues.Lox-1^(−/−)mice were successfully established.Biochemical tests showed that serum AST and ALT levels were significantly elevated in WT mice fed a Western diet(both P<0.001),and these levels decreased after LOX-1 knockout(both P<0.05).HE staining revealed that WT mice on the Western diet exhibited marked hepatocellular ballooning degeneration,steatosis,inflammatory cell infiltration,and periportal fibroplasia,which were significantly ameliorated by LOX-1 knockout.Masson staining demonstrated increased blue-stained collagen fibers in the liver tissues of WT mice fed the Western diet compared with controldiet mice,and LOX-1 knockout inhibited collagen fiber deposition(all P<0.05).RT‑qPCR results showed that hepatic mRNA levels of Acta2,Col1a1,and Timp1 were significantly increased in Western diet-fed mice,and LOX-1 knockout reduced the expression of these fibrogenic marker genes.Oil Red O staining indicated that hepatocytes in WT mice fed the Western diet were notably enlarged,displayed macrovesicular steatosis,and exhibited diffusely distributed red lipid droplets,whereas LOX-1 knockout alleviated hepatic lipid accumulation(both P<0.001).RT‑qPCR results further demonstrated that knockdown of LOX-1 reduced Acta2,Col1a1,and Timp1 mRNA levels in LX‑2 cells(all P<0.05).Immunofluorescence analysis revealed co‑localization of LOX-1 and α‑SMA in LX‑2 cells,and LOX-1 silencing suppressed α‑SMA expression.Network pharmacology suggested LOX-1 may promote MASH via lipid and cholesterol metabolism networks.Conclusion:LOX-1 gene knockout ameliorates Western diet-induced MASH in mice and may serve as a potential therapeutic target.展开更多
The forkhead box(FOX)family represents a class of transcription factors characterized by a distinctive winged helical structure.Forkhead box A1(FOXA1),a member of the forkhead box A(FOXA)subfamily within the FOX gene ...The forkhead box(FOX)family represents a class of transcription factors characterized by a distinctive winged helical structure.Forkhead box A1(FOXA1),a member of the forkhead box A(FOXA)subfamily within the FOX gene family,was the first forkhead protein identified in mammals.It serves as a pivotal transcription factor in tissue-specific differentiation and functions.Upon activation,owing to its unique structural domains,FOXA1 can interact with nucleosomes to open chromatin,thereby facilitating the recruitment of other transcription factors.These factorsmay act independently or synergistically with recruited transcription factors to regulate gene expression.Consequently,FOXA1 and other FOXA subfamily members with similar functions are referred to as“pioneer factors.”In recent years,studies on FOXA1 have advanced our understanding of its crucial role in gene regulation and involvement in disease processes.However,owing to their tissue-specific effects and varying biological behaviors in different environmental contexts,the underlying mechanisms remain elusive.Weused the PubMed database to better understand the complexmechanisms of FOXA1.By using keywords such as“FOXA1”and“transcription factor,”an extensive literature was retrieved,and many of the most relevant publications were screened.The selected studies were then thoroughly synthesized and summarized.This review synthesizes recent findings on FOXA1,encompassing its structural characteristics,domain functions,roles in embryonic development and the maintenance of adult organ morphology and function,interactions with histone posttranslational modifications in gene regulation,and the influence of its posttranslational modifications on gene expression.We also explore the involvement of FOXA1 in various diseases.By elucidating the biological mechanisms and disease-related roles of FOXA1,this review aims to provide insights for future research on its complex mechanisms and potential therapeutic targets.展开更多
BACKGROUND Coronary heart disease(CHD)is a prominent cause of mortality and disability worldwide.Like most complex diseases,the risk of CHD in individuals is regulated by the interaction between genetic factors and li...BACKGROUND Coronary heart disease(CHD)is a prominent cause of mortality and disability worldwide.Like most complex diseases,the risk of CHD in individuals is regulated by the interaction between genetic factors and lifestyle.APOE and SLCO1B1 genetic polymorphisms and LPA KIV-2 copy number variation may influence the development and progression of CHD.Clarifying gene polymor-phisms can guide clinical precision and prevention,thereby improving treatment outcomes.AIM To investigate the influence of APOE and SLCO1B1 gene polymorphisms,as well as LPA KIV-2 copy number variation on CHD in the Teochew population.METHODS A total of 324 patients with CHD and 143 control participants were involved in this study.Single nucleotide polymorphisms rs429358 and rs7412 in the APOE gene,and rs2306283 and rs4149056 in the SLCO1B1 gene were analyzed via high-resolution melting curve analysis.Additionally,PCR was performed to detect KIV-2 copy number variations.Clinical risk factors and potential effects on CHD patients were subsequently assessed.RESULTS In the CHD group,the frequencies of APOE alleleε2,ε3,ε4 were 8.02%,82.97%,and 9.10%,respectively.Compared to the control groups(13.29%,79.37%,and 7.34%,respectively),theε2 allele frequency showed a significant difference(8.02%vs 13.29%,P=0.012).SLCO1B1 allele frequencies in the CHD group were not significantly different from those in the control group(*1a:26.69%vs 25.52%,*1b:61.17%vs 65.38%,*5:0.15%vs 0.35%,*15:11.83%vs 8.74%).The number of copies of the KIV-2 gene was significantly lower in the CHD group when compared to controls(23.35±8.78 vs 27.21±9.48;P<0.01).Logistic regression analysis revealed that sex,age,hypertension,diabetes,smoking,theε2 allele and KIV-2 copy number were factors influencing the presence of CHD.CONCLUSION In the Teochew population,the APOEε2 allele and a higher KIV-2 copy number were associated with a reduced risk of CHD.In contrast,the APOEε4 allele and SLCO1B1 gene were not associated with CHD.展开更多
Maize(Zea mays L.)is a globally significant crop essential for food,feed,and bioenergy production.The maize kernel,serving as a primary sink for starch,proteins,lipids,and essential micronutrients,is crucial for enhan...Maize(Zea mays L.)is a globally significant crop essential for food,feed,and bioenergy production.The maize kernel,serving as a primary sink for starch,proteins,lipids,and essential micronutrients,is crucial for enhancing maize yield and quality.Previous studies have established the critical role of Polycomb Repressive Complex 2(PRC2)in regulating kernel development.In this study,we applied a reverse genetics approach to investigate the role of ZmFIE1,the homolog of the PRC2 complex component Extra sex combs(Esc),in maize development.The functional loss of ZmFIE1 significantly reduces embryo size in the early stage but has a relatively small impact on mature kernels.Integrating transcriptional and metabolomic profiling suggests that ZmFIE1 is involved in regulating nutrient balance between the endosperm and embryo.In addition,we demonstrate that ZmFIE1 is maternally expressed,and that the maternal inheritance of the fie1 allele significantly affects the imprinting status of paternally imprinted genes.Overall,our results suggest that ZmFIE1 is a key gene involved in the modulation of embryo development via regulating genomic imprinting and nutrient balance between embryo and endosperm,which provides new insights into the regulation mechanism underlying kernel development.展开更多
Liver diseases are progressive conditions driven by multiple factors,including molecular regulators such as nonprotein-coding RNAs,which orchestrate genetic and epigenetic processes across various biological levels.Lo...Liver diseases are progressive conditions driven by multiple factors,including molecular regulators such as nonprotein-coding RNAs,which orchestrate genetic and epigenetic processes across various biological levels.Long noncoding RNAs(lncRNAs),RNA molecules longer than 200 nucleotides,have been identified as key modulators in both cancerous and noncancerous liver diseases.Among them,taurine-upregulated gene 1(TUG1),one of the earliest discovered lncRNAs,has emerged as a tumor promoter in hepatocellular carcinoma.Functionally,TUG1 exerts its regulatory effects primarily through microRNA sponging as a competing endogenous RNA while also exhibiting protein-binding capabilities that suggest additional roles in both transcriptional and posttranscriptional regulation.Furthermore,evidence suggests that dysregulation of TUG1 is closely linked to the development and progression of liver diseases.This review explores the key characteristics,mechanisms,and signaling pathways through which TUG1 affects liver disease,offering fresh insights into potential therapeutic directions and new avenues for future TUG1-related research.展开更多
基金Supported by General Project of Yunnan Provincial Agricultural Basic Research Joint Special Project(202301BD070001-229)Yunnan Provincial Key R&D Program(202403AK140075)+1 种基金Modern Sericulture Industry Technology System of Yunan Province(KJTX-07)Honghe Comprehensive Test Station of National Sericulture Industry Technology System(CARS-18).
文摘[Objectives]The present study was conducted to investigate the change rule ofβ-fructofuranosidase gene expression and its enzyme activity in the midgut of 5 th instar silkworm(Bombyx mori),in order to provide a reference for illustrating the enzymatic mechanism of usingβ-fructofuranosidase to absorb sucrose nutrition from mulberry leaves.[Methods]Real-time fluorescent quantitative PCR was applied to analyze the expression of BmSuc1 and BmSuc2 in midgut of 5 th-instar silkworm larvae,meanwhile the activities ofβ-fructofuranosidase was determined.[Results]BmSuc1 was expressed in the midgut of 5 th-instar silkworm larvae at different developmental stages.Its expression was upregulated at the beginning of the 5 th instar and during the peak feeding period,whereas BmSuc2 expression remained very low throughout the entire 5 th instar.The activity ofβ-fructofuranosidase was relatively high during the peak feeding period of 5 th-instar larvae,showing a trend of increasing first and then decreasing.[Conclusions]The expression pattern of the BmSuc1 gene and the changes inβ-fructofuranosidase activity were generally consistent with the physiological process of sugar nutrient absorption and utilization from mulberry leaves in 5 th-instar silkworms.It suggests that BmSuc1,as a sucrose hydrolase gene,plays a major role in the digestion and absorption of sucrose nutrients from mulberry leaves in the midgut tissue.
基金Funding for this research was provided by the Australia Grain Research and Development Corporation(9176507)the Western Crop Genetics Alliance.Jingye Cheng thanks The University of Tasmania,Australia for the scholarship(495802)。
文摘Improved yield potential is the goal of barley domestication and cultivation.During this process,two-and six-rowed barley types emerged and have been utilised in breeding and production.The six-rowed type could produce three times as many grains as its ancestral two-rowed forms,thus dominating barley cultivation for thousands of years.The deficiens form of the two-rowed type,characterised by extremely suppressed lateral spikelets,has gained dominance over the past few decades in barley-growing regions worldwide.We hypothesised that the absence of lateral spikelets in deficiens barley affects spike architecture and spike-related traits,contributing to its superior yield potential of deficiens barley cultivation.Currently,a deficiens barley variety,RGT Planet,is the most popular barley variety in the world.In this study,we used two F_(2) populations derived from crossing RGT Planet with two canonical two-rowed barley and identified the functional allele Vrs1.t1 associated with deficiens morphology.We observed that the Vrs1.t1 allele may contribute to high yield potential by optimising spike architecture through increased spikelet length,grain number,and grain size.Phylogenetic analysis suggests that the deficiens mutation was likely present from the early stages of barley cultivation in the Fertile Crescent and spread to Ethiopia and beyond with agricultural expansion.We conclude that the ancient deficiens allele Vrs1.t1 has been a critical driver for the recent success of modern barley improvement by optimising spike architecture.
基金supported by the Science and Technology Department of Jiangxi Province,No.20114BAB205076a Grant from the Jiangxi Provincial Health Department,No.20094008
文摘Nurr1 defects could in part underlie Parkinson’s disease pathogenesis,and Nurr1 gene polymorphism has been found in Caucasian patients with Parkinson’s disease.In this study,heteroduplex technology was applied to compare the DNA sequences of eight exons of Nurr1 among 200 sporadic Parkinson’s disease patients and 200 healthy controls in the Han population in the Hubei province,China.One allele amplified from exon 3 of Nurr1 was polymorphic in five Parkinson’s disease patients（2.5%,5/200）,and two individuals had a polymorphic allele amplified from exon 2 （1%,2/200）.The anomalous electrophoresis fragment in exon 3 of Nurr1 gene contained a 709C/A missense mutation,and a polymorphic single nucleotide polymorphism at 388G/A was identified in exon 2.Compared with the control group,the Nurr1 gene expression level in the Parkinson’s disease group was decreased,and the Nurr1 gene expression levels in Parkinson’s disease patients carrying the polymorphisms at exons 2 and 3 were significantly decreased.Our data indicate that the single nucleotide polymorphism 388G/A in exon 2 and the 709C/A missense mutation in exon 3 of the Nurr1 gene in the Chinese population might affect the pathogenesis of Parkinson’s disease.
文摘The relationship between genetics and infectious diseases is important in shaping our understanding of disease susceptibility,progression,and treatment.Recent research shows the impact of genetic variations,such as heme-oxygenase promoter length,on diseases like malaria and sepsis,revealing both protective and inconclusive effects.Studies on vaccine responses highlight genetic markers like human leukocyte antigens,emphasizing the potential for personalized immunization strategies.The ongoing battle against drug-resistant tuberculosis(TB)illustrates the complexity of genomic variants in predicting resistance,highlighting the need for integrated diagnostic tools.Additionally,genome-wide association studies reveal antibiotic resistance mechanisms in bacterial genomes,while host genetic polymorphisms,such as those in solute carrier family 11 member 1 and vitamin D receptor,demonstrate their role in TB susceptibility.Advanced techniques like metagenomic next-generation sequencing promise detailed pathogen detection but face challenges in cost and accessibility.A case report involving a highly virulent Mycobacterium TB strain with the pks1 gene further highlights the need for genetic insights in understanding disease severity and developing targeted interventions.This evolving landscape emphasizes the role of genetics in infectious diseases,while also addressing the need for standardized studies and accessible technologies.
文摘BACKGROUND Dystrophic epidermolysis bullosa is characterized by fragile ulcerations of the skin caused by mutations in specific genes.However,genetic typing of this con-dition is rare.CASE SUMMARY An 11-year-old female suffered from recurrent fever,visible ulcerations of the entire skin,and severe malnutrition.Genetic testing revealed a frameshift mu-tation in the coding region 4047 of the 35th intron region of COL7A1,and she was diagnosed as malnutrition-type epidermolysis bullosa.Drug therapy(immu-noglobulin,fresh frozen plasma),topical therapy(silver ion dressing),fever redu-ction,cough relief,and promotion of gastrointestinal peristalsis are mainly used for respiratory and gastrointestinal complications.The patient’s condition impro-ved after treatment.CONCLUSION Dystrophic epidermolysis bullosa caused by a new framework shift mutation in COL7A1 should be taken seriously.
文摘BACKGROUND:Adeno-associated virus(AAV)gene therapy has been proven to be reliable and safe for the treatment of osteoarthritis in recent years.However,given the complexity of osteoarthritis pathogenesis,single gene manipulation for the treatment of osteoarthritis may not produce satisfactory results.Previous studies have shown that nuclear factorκB could promote the inflammatory pathway in osteoarthritic chondrocytes,and bone morphogenetic protein 4(BMP4)could promote cartilage regeneration.OBJECTIVE:To test whether combined application of AAV-p65shRNA and AAV-BMP4 will yield the synergistic effect on chondrocytes regeneration and osteoarthritis treatment.METHODS:Viral particles containing AAV-p65-shRNA and AAV-BMP4 were prepared.Their efficacy in inhibiting inflammation in chondrocytes and promoting chondrogenesis was assessed in vitro and in vivo by transfecting AAV-p65-shRNA or AAV-BMP4 into cells.The experiments were divided into five groups:PBS group;osteoarthritis group;AAV-BMP4 group;AAV-p65shRNA group;and BMP4-p65shRNA 1:1 group.Samples were collected at 4,12,and 24 weeks postoperatively.Tissue staining,including safranin O and Alcian blue,was applied after collecting articular tissue.Then,the optimal ratio between the two types of transfected viral particles was further investigated to improve the chondrogenic potential of mixed cells in vivo.RESULTS AND CONCLUSION:The combined application of AAV-p65shRNA and AAV-BMP4 together showed a synergistic effect on cartilage regeneration and osteoarthritis treatment.Mixed cells transfected with AAV-p65shRNA and AAV-BMP4 at a 1:1 ratio produced the most extracellular matrix synthesis(P<0.05).In vivo results also revealed that the combination of the two viruses had the highest regenerative potential for osteoarthritic cartilage(P<0.05).In the present study,we also discovered that the combined therapy had the maximum effect when the two viruses were administered in equal proportions.Decreasing either p65shRNA or BMP4 transfected cells resulted in less collagen II synthesis.This implies that inhibiting inflammation by p65shRNA and promoting regeneration by BMP4 are equally important for osteoarthritis treatment.These findings provide a new strategy for the treatment of early osteoarthritis by simultaneously inhibiting cartilage inflammation and promoting cartilage repair.
基金supported by National Natural Science Foundation of China(No.32160615).
文摘Background Verticillium dahliae,a soil-borne fungi,can cause Verticillium wilt,and seriously diminish the yield and quality of cotton.However,the pathogenic mechanism of V.dahliae is complex and not clearly understood at the moment.This study aimed to identify the high-affinity nicotinic acid transporter genes in V.dahliae.The gene expression profiles in V.dahliae following sensing of root exudates from susceptible and resistant cotton varieties were analyzed.The function of VdNAT1 in the pathogenic process of V.dahliae was studied using the tobacco rattle virus(TRV)-based host-induced gene silencing(HIGS)technique.Results Eight high-affinity nicotinic acid transporter genes were identified from V.dahliae through the bioinformatics method.Each protein contains a conserved major facilitator superfamily(MFS)domain,which belongs to the MFS superfamily.Evolutionary relationship analysis revealed that all 8 genes belong to the anion:cation symporter(ACS)subfamily.All proteins have transmembrane domains,ranging from 7 to 12.The expression levels of most VdNAT genes were significantly increased after induction by root exudates from susceptible cotton varieties.Silencing VdNAT1 gene by HIGS significantly inhibited the accumulation of fungal biomass in cotton plants,and alleviated the disease symptoms of cotton.Conclusions Eight VdNAT genes were identified from V.dahliae,and most VdNAT genes was up-regulated after induced by root exudates from susceptible cotton variety.In addition,VdNAT1 is required for the pathogenicity of V.dahliae.Overall,these findings will facilitate the pathogenic molecular mechanism of V.dahliae and provide candidate genes.
基金Supported by Colegio de Ciencia y Tecnología de la Universidad Autónoma de la Ciudad de México,No.CCYT-2025-CON-11.
文摘The canonical signaling of interferon gamma(IFN-γ)through the Janus kinase 1 and 2–signal transducer and activator of transcription 1(STAT1)axis leads to the expression of several interferon-stimulated genes(ISGs),which have diverse effects depending on the cellular context.In glioblastoma,a highly aggressive primary brain tumor in adults,elements of IFN-γcanonical signaling are deregulated,resulting in the overexpression of STAT1-target ISGs associated with tumor progression.This mini-review highlights key ISGs,including STAT1,interferon regulatory factor 1,programmed death-ligand 1,indoleamine 2,3-dioxygenase 1,and interferon-stimulated gene 15,involved in the pathology of glioblastoma.These genes may serve as valuable biomarkers and have therapeutic potential for targeting IFN-γsignaling in this malignancy.
文摘The present investigation aims at unveiling the main causes of the recorded disparate phylogeographic patterning among the two highly dispersive coastal crab species Carcinus aestuarii and Pachygrapsus marmoratus in the Mediterranean Sea.For this purpose,available mitochondrial and nuclear data for both species were re-analyzed and investigated for genetic polymorphism and differentiation patterns across three defined geographic scales in their distribution ranges,but also across the same locations in the Mediterranean Sea.The temporal frame of genetic diversification was also determined for both species in order to check whether observed differences in phylogeographic patterns among these coastal decapods could be attributed to different evolutionary histories.The obtained results revealed a more variable and diversified gene pool in the green crab C.aestuarii than the one recorded in the marbled crab P.marmoratus.Lack of significant correlation between pairwise genetic dissimilarities observed among C.aestuarii populations and those detected for P.marmoratus was notably discerned across the same defined Mediterranean locations.This finding indicates that the pattern of pairwise genetic differentiation does not vary in the same way in both examined crab species.Significant outputs of population genetic differentiation,retrieved within both species,were shown to be differently associated with the potential effects of various kinds of isolation processes(related to geography,environment and biogeographic boundary).Evolutionary history reconstruction showed older genetic diversification event in C.aestuarii than the one recorded in P.marmoratus.These recorded temporal frames suggest different modes of genetic diversification in both crab species(glacial vicariance for C.aestuarii and interglacial dispersal for P.marmoratus).They may also provide an explanation for the recorded differences in variation of patterns of population genetic diversity and structure,when integrated with species ecological requirements and life-history traits.
文摘BACKGROUND Dyschromatosis universalis hereditaria(DUH)is a rare type of autosomal dominant inheritance disease.It has varying gene mutation sites among different ethnicities.SASH1 and ABCB6 have been identified as the causative genes of this disorder.CASE SUMMARY A 30-year-old woman presented with irregular black pigmentation spots to our department.Upon examination,the pigmentations were found to be especially dense on the extremities and the face.She had no family history of inbreeding,nor any previous chemical exposure.Genetic testing confirmed that the disease occu-rred because the patient has a SASH1 gene mutation.Following the use of assisted reproductive technology and preimplantation genetic testing for monogenic disorders,the patient give birth to a health baby.CONCLUSION Using assisted reproductive technology/preimplantation genetic testing for monogenic disorders is an option for DUH patients to reduce the risk of trans-mitting the pathogenic variant to their offspring.
基金funded by the National Key Research and Development Program of China(Grant No.2022YFF1003100)Modern Citrus Industry Technology System of China(Grant No.CARS-26).
文摘Polyembryony has posed a significant impediment to the advancement of citrus hybrid breeding.FhRWP is widely regarded as a pivotal factor governing asexual reproduction in citrus,and prior research has demonstrated that FhARID1,acting as an upstream regulator,modulates FhRWP expression.In this study,we performed a genome-wide characterization of the ARID-HMG-related genes using the short juvenile minicitrus Fortunella hindsii.A total of 20 ARID-HMG-related genes were identified.Protein interaction network and enrichment analysis suggested that ARID-HMG-related proteins might might be involved in chromatin remodeling complexes.Knockout of FhARID1 in F.hindsii did not induce the conversion from polyembryony to monoembryony.However,fharid1 plants in T1 generation exhibited abnormal proliferation at axillary buds,which is similar to phenotype of fhrwp plants.Expression analysis of fharid1 ovary tissues revealed the downregulation of FhRWP.The results indicated that FhARID1,as an upstream regulator of FhRWP,has an effect on the development of citrus axillary buds.Expression analysis of overexpressed leaves of FhARID1 lines showed that no significant up-regulation of FhRWP,indicating that FhARID1 is not the sole upstream regulatory factor of FhRWP.Only FhARID2 showed a correlation in expression with FhARID1 among the ARID-related genes,further supporting the notion that this gene may be involved in complex formation rather than acting alone.Yeast two-hybrid and MS/MS spectra further indicated that FhARID1 function requires casein kinase II-mediated post-transcriptional phosphorylation.This study elucidated the function of FhARID1 in citrus apomixis and axillary bud development,providing a fundamental basis for understanding the role of ARID-HMG-related genes.
基金Supported by Beijing Holistic Integrative Medicine Association Clinical Research Funding Program,No.ZHKY-2024-2209.
文摘BACKGROUND Wolfram syndrome is a rare autosomal recessive genetic disorder characterized by early-onset diabetes and progressive neurodegeneration,most notably sensorineural hearing loss and optic atrophy.Because its initial manifestations are usually similar to those of type 1 diabetes,the diagnosis may be delayed until other manifestations appear.Pathogenic variations of the WFS1 gene can disrupt endoplasmic reticulum function and cellular homeostasis,but the complete mutation spectrum of WFS1 has not been fully determined.Early identification of monogenic diabetes caused by Wolfram syndrome is of vital importance,as it enables the provision of targeted multidisciplinary care and genetic counseling for affected families.CASE SUMMARY A 2-year-old Han Chinese girl was admitted with a 1-month history of polydipsia,polyuria,and polyphagia,and was diagnosed with diabetic ketoacidosis and impaired insulin secretion.Sensorineural hearing loss was also detected.Wholeexome sequencing identified a previously unreported heterozygous mutation,WFS1 c.986T>C(p.Phe329Ser),in the patient and her father,confirming the diagnosis of Wolfram syndrome.Bioinformatic analysis supported the likely pathogenicity of this mutation.In silico pathogenicity predictors(REVEL,SIFT,Poly-Phen-2,MutationTaster,and GERP+)supported a deleterious effect on wolframin structure and function.The patient was initially treated with intravenous insulin and fluid resuscitation,then transitioned to a basal–bolus insulin regimen.Glycemic control was subsequently maintained with continuous subcutaneous insulin infusion and intermittent subcutaneous injections.At the 1-and 6-month follow-ups,blood glucose remained well controlled(hemoglobin A1c:5.89%and 6.58%,respectively),with no evidence of organ dysfunction or further complications.CONCLUSION This case identifies WFS1 c.986T>C(p.Phe329Ser)as a novel pathogenic variant causing Wolfram syndrome.It highlights the importance of early genetic testing in pediatric patients with atypical diabetes presentations to enable timely diagnosis,individualized therapy,and comprehensive family support.
基金supported by the National Natural Science Foundation of China,Nos.82071008(to BL)and 82004001(to XJ)Medical Science and Technology Program of Health Commission of Henan Province,No.LHGJ20210072(to RQ)Science and Technology Department of Henan Province,No.212102310307(to XJ)。
文摘Retinitis pigmentosa is a group of inherited diseases that lead to retinal degeneration and photoreceptor cell death.However,there is no effective treatment for retinitis pigmentosa caused by PDE6B mutation.Adeno-associated virus(AAV)-mediated gene therapy is a promising strategy for treating retinitis pigmentosa.The aim of this study was to explore the molecular mechanisms by which AAV2-PDE6B rescues retinal function.To do this,we injected retinal degeneration 10(rd10)mice subretinally with AAV2-PDE6B and assessed the therapeutic effects on retinal function and structure using dark-and light-adapted electroretinogram,optical coherence tomography,and immunofluorescence.Data-independent acquisition-mass spectrometry-based proteomic analysis was conducted to investigate protein expression levels and pathway enrichment,and the results from this analysis were verified by real-time polymerase chain reaction and western blotting.AAV2-PDE6B injection significantly upregulated PDE6βexpression,preserved electroretinogram responses,and preserved outer nuclear layer thickness in rd10 mice.Differentially expressed proteins between wild-type and rd10 mice were closely related to visual perception,and treating rd10 mice with AAV2-PDE6B restored differentially expressed protein expression to levels similar to those seen in wild-type mice.Kyoto Encyclopedia of Genes and Genome analysis showed that the differentially expressed proteins whose expression was most significantly altered by AAV2-PDE6B injection were enriched in phototransduction pathways.Furthermore,the phototransductionrelated proteins Pde6α,Rom1,Rho,Aldh1a1,and Rbp1 exhibited opposite expression patterns in rd10 mice with or without AAV2-PDE6B treatment.Finally,Bax/Bcl-2,p-ERK/ERK,and p-c-Fos/c-Fos expression levels decreased in rd10 mice following AAV2-PDE6B treatment.Our data suggest that AAV2-PDE6B-mediated gene therapy promotes phototransduction and inhibits apoptosis by inhibiting the ERK signaling pathway and upregulating Bcl-2/Bax expression in retinitis pigmentosa.
文摘Objective To investigate the structural changes of rat thoracic aorta and changes in expression levels of Bmal1 and cyclins in thoracic aorta endothelial cells following heat stress.Methods Twenty male SD rats were randomized equally into control group and heat stress group.After exposure to 32℃for 2 weeks in the latter group,the rats were examined for histopathological changes and Bmal1 expression in the thoracic aorta using HE staining and immunohistochemistry.In the cell experiments,cultured rat thoracic aortic endothelial cells(RTAECs)were incubated at 40℃for 12 h with or without prior transfection with a Bmal1-specific small interfering RNA(si-Bmal1)or a negative sequence.In both rat thoracic aorta and RTAECs,the expressions of Bmal1,the cell cycle proteins CDK1,CDK4,CDK6,and cyclin B1,and apoptosis-related proteins Bax and Bcl-2 were detected using Western blotting.TUNEL staining was used to detect cell apoptosis in rat thoracic aorta,and the changes in cell cycle distribution and apoptosis in RTAECs were analyzed with flow cytometry.Results Compared with the control rats,the rats exposed to heat stress showed significantly increased blood pressures and lowered heart rate with elastic fiber disruption and increased expressions of Bmal1,cyclin B1 and CDK1 in the thoracic aorta(P<0.05).In cultured RTAECs,heat stress caused significant increase of Bmal1,cyclin B1 and CDK1 protein expression levels,which were obviously lowered in cells with prior si-Bmal1 transfection.Bmal1 knockdown also inhibited heat stress-induced increase of apoptosis in RTAECs as evidenced by decreased expression of Bax and increased expression of Bcl-2.Conclusion Heat stress upregulates Bmal1 expression and causes alterations in expressions of cyclins to trigger apoptosis of rat thoracic aorta endothelial cells,which can be partly alleviated by suppressing Bmal1 expression.
文摘A chimeric gene, Bt29K, composed of coding sequences of activated Cry1Ac insecticidal protein and an endoplasm reticulum-retarding signal peptide, was synthesized. A plant expression vector containing two expression cassettes for the Bt29K and API-B genes was constructed. These two insect-resistant genes were transferred into two cotton ( Gossypium hirsutum L.) varieties ( or lines) via Agrobacterium-mediated transformation and nine homozygous transgenic cotton lines showing a mortality of 90.0% - 99.7% to cotton ballworm (Heliothis armigera) larvae and good agronomic traits were selected through six generations. Molecular biology analysis revealed that one or two copies of the insecticidal protein genes were integrated into the transgenic cotton genome and activated Cry1Ac and API-B protein expression was at a level of 0.17% and 0.09% of the total soluble protein in the transgenic cotton leaves, respectively. Comparison of the insect-resistance of the homozygous lines expressing the activated chimeric Cry1Ac and API-B with that expressing Cry1Ac only revealed that the insect-resistance of the former is apparently higher than the latter. These results also indicate that the strategy to construct a plant expression vector expressing two different insect-resistant genes reported here is reasonable.
基金supported by the Natural Science Foundation of Hunan Province,China(211142095031)。
文摘Objective:Metabolic dysfunction-associated steatohepatitis(MASH),a progressive subtype of metabolic dysfunction-associated steatotic liver disease(MASLD),is characterized by hepatic steatosis,lobular inflammation,and hepatocyte ballooning,and may further progress to liver fibrosis and cirrhosis.Lectin-like oxidized low-density lipoprotein receptor-1(LOX-1),a member of the scavenger receptor family,recognizes and binds oxidized low-density lipoprotein.This study aims to investigate the role of LOX-1 in MASH progression.Methods:LOX-1 expression in MASLD mouse liver was analyzed using Gene Expression Omnibus(GEO)datasets.Immunofluorescence staining was performed to detect LOX-1 and alpha-smooth muscle actin(α-SMA)levels and co-localization in fibrotic liver tissues and LX-2 cells.LOX-1 knockout(Lox-1^(−/−))mice were generated using CRISPR/caspase-9(Cas9)and genotyped by PCR and Sanger sequencing.Wild-type(WT)and Lox-1^(−/−)mice were randomized into control and Western diet model groups.Serum and liver samples were collected for alanine aminotransferase(ALT)and aspartate aminotransferase(AST)measurement by biochemical kits,liver structure evaluation by hematoxylin and eosin(HE)staining,collagen deposition by Masson staining,lipid accumulation by Oil Red O staining,and fibrotic marker gene expression by real-time quantitative PCR(RT-qPCR).Network pharmacology and search tool for the retrieval of interacting genes/proteins(STRING)-based protein-protein interaction(PPI)with Gene Ontology(GO)enrichment were used to predict downstream targets and pathways.Results:The results from the GEO datasets GSE30552 and GSE40041 indicated LOX-1 mRNA was upregulated in high fat diet(HFD)and bile duct ligation(BDL)mouse models(both P<0.001).LOX-1 and α-SMA levels were elevated in fibrotic liver tissues.Lox-1^(−/−)mice were successfully established.Biochemical tests showed that serum AST and ALT levels were significantly elevated in WT mice fed a Western diet(both P<0.001),and these levels decreased after LOX-1 knockout(both P<0.05).HE staining revealed that WT mice on the Western diet exhibited marked hepatocellular ballooning degeneration,steatosis,inflammatory cell infiltration,and periportal fibroplasia,which were significantly ameliorated by LOX-1 knockout.Masson staining demonstrated increased blue-stained collagen fibers in the liver tissues of WT mice fed the Western diet compared with controldiet mice,and LOX-1 knockout inhibited collagen fiber deposition(all P<0.05).RT‑qPCR results showed that hepatic mRNA levels of Acta2,Col1a1,and Timp1 were significantly increased in Western diet-fed mice,and LOX-1 knockout reduced the expression of these fibrogenic marker genes.Oil Red O staining indicated that hepatocytes in WT mice fed the Western diet were notably enlarged,displayed macrovesicular steatosis,and exhibited diffusely distributed red lipid droplets,whereas LOX-1 knockout alleviated hepatic lipid accumulation(both P<0.001).RT‑qPCR results further demonstrated that knockdown of LOX-1 reduced Acta2,Col1a1,and Timp1 mRNA levels in LX‑2 cells(all P<0.05).Immunofluorescence analysis revealed co‑localization of LOX-1 and α‑SMA in LX‑2 cells,and LOX-1 silencing suppressed α‑SMA expression.Network pharmacology suggested LOX-1 may promote MASH via lipid and cholesterol metabolism networks.Conclusion:LOX-1 gene knockout ameliorates Western diet-induced MASH in mice and may serve as a potential therapeutic target.
基金supported by grants from the National Natural Science Foundation of China (No.82470042)Liaoning Provincial Joint Science and Technology Plan (No.2023JH2/101800021)+1 种基金Basic Scientific Research Project of Liaoning Provincial Department of Education (No.LJKMZ20221186)Shenyang Municipal Public Health Research and Development Special Project (No.LJKMZ20221186)
文摘The forkhead box(FOX)family represents a class of transcription factors characterized by a distinctive winged helical structure.Forkhead box A1(FOXA1),a member of the forkhead box A(FOXA)subfamily within the FOX gene family,was the first forkhead protein identified in mammals.It serves as a pivotal transcription factor in tissue-specific differentiation and functions.Upon activation,owing to its unique structural domains,FOXA1 can interact with nucleosomes to open chromatin,thereby facilitating the recruitment of other transcription factors.These factorsmay act independently or synergistically with recruited transcription factors to regulate gene expression.Consequently,FOXA1 and other FOXA subfamily members with similar functions are referred to as“pioneer factors.”In recent years,studies on FOXA1 have advanced our understanding of its crucial role in gene regulation and involvement in disease processes.However,owing to their tissue-specific effects and varying biological behaviors in different environmental contexts,the underlying mechanisms remain elusive.Weused the PubMed database to better understand the complexmechanisms of FOXA1.By using keywords such as“FOXA1”and“transcription factor,”an extensive literature was retrieved,and many of the most relevant publications were screened.The selected studies were then thoroughly synthesized and summarized.This review synthesizes recent findings on FOXA1,encompassing its structural characteristics,domain functions,roles in embryonic development and the maintenance of adult organ morphology and function,interactions with histone posttranslational modifications in gene regulation,and the influence of its posttranslational modifications on gene expression.We also explore the involvement of FOXA1 in various diseases.By elucidating the biological mechanisms and disease-related roles of FOXA1,this review aims to provide insights for future research on its complex mechanisms and potential therapeutic targets.
基金Supported by Special Research Plan 2023 of Chaozhou,No.202303GY05。
文摘BACKGROUND Coronary heart disease(CHD)is a prominent cause of mortality and disability worldwide.Like most complex diseases,the risk of CHD in individuals is regulated by the interaction between genetic factors and lifestyle.APOE and SLCO1B1 genetic polymorphisms and LPA KIV-2 copy number variation may influence the development and progression of CHD.Clarifying gene polymor-phisms can guide clinical precision and prevention,thereby improving treatment outcomes.AIM To investigate the influence of APOE and SLCO1B1 gene polymorphisms,as well as LPA KIV-2 copy number variation on CHD in the Teochew population.METHODS A total of 324 patients with CHD and 143 control participants were involved in this study.Single nucleotide polymorphisms rs429358 and rs7412 in the APOE gene,and rs2306283 and rs4149056 in the SLCO1B1 gene were analyzed via high-resolution melting curve analysis.Additionally,PCR was performed to detect KIV-2 copy number variations.Clinical risk factors and potential effects on CHD patients were subsequently assessed.RESULTS In the CHD group,the frequencies of APOE alleleε2,ε3,ε4 were 8.02%,82.97%,and 9.10%,respectively.Compared to the control groups(13.29%,79.37%,and 7.34%,respectively),theε2 allele frequency showed a significant difference(8.02%vs 13.29%,P=0.012).SLCO1B1 allele frequencies in the CHD group were not significantly different from those in the control group(*1a:26.69%vs 25.52%,*1b:61.17%vs 65.38%,*5:0.15%vs 0.35%,*15:11.83%vs 8.74%).The number of copies of the KIV-2 gene was significantly lower in the CHD group when compared to controls(23.35±8.78 vs 27.21±9.48;P<0.01).Logistic regression analysis revealed that sex,age,hypertension,diabetes,smoking,theε2 allele and KIV-2 copy number were factors influencing the presence of CHD.CONCLUSION In the Teochew population,the APOEε2 allele and a higher KIV-2 copy number were associated with a reduced risk of CHD.In contrast,the APOEε4 allele and SLCO1B1 gene were not associated with CHD.
基金supported by STI2030-Major Projects(2023ZD04069,Z231100003723004)the National Science Fund for Distinguished Young Scholars(32425041)the Chinese Universities Scientific Fund(2024TC165).
文摘Maize(Zea mays L.)is a globally significant crop essential for food,feed,and bioenergy production.The maize kernel,serving as a primary sink for starch,proteins,lipids,and essential micronutrients,is crucial for enhancing maize yield and quality.Previous studies have established the critical role of Polycomb Repressive Complex 2(PRC2)in regulating kernel development.In this study,we applied a reverse genetics approach to investigate the role of ZmFIE1,the homolog of the PRC2 complex component Extra sex combs(Esc),in maize development.The functional loss of ZmFIE1 significantly reduces embryo size in the early stage but has a relatively small impact on mature kernels.Integrating transcriptional and metabolomic profiling suggests that ZmFIE1 is involved in regulating nutrient balance between the endosperm and embryo.In addition,we demonstrate that ZmFIE1 is maternally expressed,and that the maternal inheritance of the fie1 allele significantly affects the imprinting status of paternally imprinted genes.Overall,our results suggest that ZmFIE1 is a key gene involved in the modulation of embryo development via regulating genomic imprinting and nutrient balance between embryo and endosperm,which provides new insights into the regulation mechanism underlying kernel development.
文摘Liver diseases are progressive conditions driven by multiple factors,including molecular regulators such as nonprotein-coding RNAs,which orchestrate genetic and epigenetic processes across various biological levels.Long noncoding RNAs(lncRNAs),RNA molecules longer than 200 nucleotides,have been identified as key modulators in both cancerous and noncancerous liver diseases.Among them,taurine-upregulated gene 1(TUG1),one of the earliest discovered lncRNAs,has emerged as a tumor promoter in hepatocellular carcinoma.Functionally,TUG1 exerts its regulatory effects primarily through microRNA sponging as a competing endogenous RNA while also exhibiting protein-binding capabilities that suggest additional roles in both transcriptional and posttranscriptional regulation.Furthermore,evidence suggests that dysregulation of TUG1 is closely linked to the development and progression of liver diseases.This review explores the key characteristics,mechanisms,and signaling pathways through which TUG1 affects liver disease,offering fresh insights into potential therapeutic directions and new avenues for future TUG1-related research.
