Objective:Keratoconus(KC)is a progressive corneal ectasia disorder,arising from a myriad of causes including genetic predispositions,environmental factors,biomechanical influences,and inflammatory reactions.This study...Objective:Keratoconus(KC)is a progressive corneal ectasia disorder,arising from a myriad of causes including genetic predispositions,environmental factors,biomechanical influences,and inflammatory reactions.This study aims to identify potential pathogenetic gene mutations in patients with sporadic KC in the Han Chinese population.Methods:Twenty-five patients with primary KC as well as 50 unrelated population matched healthy controls,were included in this study to identify potential pathogenic gene mutations among sporadic KC patients in the Han Chinese population.Sanger sequencing and whole-exome sequencing(WES)were used to analyze mutations in the zinc finger protein 469(ZNF469)gene.Bioinformatics analysis was conducted to explore the potential role of ZNF469 in KC pathogenesis.Results:Five novel heterozygous missense variants were identified in KC patients.Among them,2 compound heterozygous variants,c.8986G>C(p.E2996Q)with c.11765A>C(p.D3922A),and c.4423C>G(p.L1475V)with c.10633G>A(p.G3545R),were determined to be possible pathogenic factors for KC.Conclusion:Mutations in the ZNF469 gene may contribute to the development of KC in the Han Chinese population.These mutation sites may provide valuable information for future genetic screening of KC patients and their families.展开更多
Multiple morphological abnormalities of the sperm flagella(MMAF)are characterized by bent,irregular,short,coiled,and absent flagella.MMAF is caused by a variety of genes,some of which have been identified.However,the ...Multiple morphological abnormalities of the sperm flagella(MMAF)are characterized by bent,irregular,short,coiled,and absent flagella.MMAF is caused by a variety of genes,some of which have been identified.However,the underlying genetic factors responsible for the majority of MMAF cases are still largely unknown.The glutamine-rich 2(QRICH2)gene plays an essential role in the development of sperm flagella by regulating the expression of essential sperm flagellar biogenesis-associated proteins,and genetic variants of QRICH2 have been identified as the primary cause of MMAF in humans and mice.Here,we recruited a Pakistani consanguineous family to identify the genetic variant causing infertility in patients with MMAF.Whole-exome sequencing and Sanger sequencing were conducted to identify potentially pathogenic variants causing MMAF in infertile patients.Hematoxylin and eosin(HE)staining was performed to analyze sperm morphology.Quantitative polymerase chain reaction,western blot,and immunofluorescence staining analyses were conducted to observe the expression of QRICH2 in spermatozoa.A novel homozygous missense variant(c.4618C>T)in QRICH2 was identified in the affected patients.Morphological analysis of spermatozoa revealed the MMAF phenotype in infertile patients.qPCR revealed a significant reduction in the level of sperm QRICH2 mRNA,and immunofluorescence staining revealed a lack of sperm QRICH2 expression.Additionally,patients harboring a homozygous QRICH2 mutation presented reduced expression of outer dense fiber 2(ODF2)in sperm,whereas sperm expression of A-kinase anchor protein 4(AKAP4)was normal.These findings expand our understanding of the genetic causes of MMAF-associated male infertility and emphasize the importance of genetic counseling.展开更多
Methylenetetrahydrofolate reductase(MTHFR)deficiency is a rare autosomal recessive genetic disorder caused by mutations in the MTHFR gene,leading to a variety of clinical manifestations.In October 2022,the Second Xian...Methylenetetrahydrofolate reductase(MTHFR)deficiency is a rare autosomal recessive genetic disorder caused by mutations in the MTHFR gene,leading to a variety of clinical manifestations.In October 2022,the Second Xiangya Hospital of Central South University admitted a 21-year-old male patient with neuropsychiatric disorders,presenting primarily with cognitive decline,limb tremors,abnormal mental and behavioral symptoms,seizures,and gait disturbances.These symptoms had gradually developed over 5 years,worsening significantly in the past year.The patient’s plasma homocysteine levels were 10 times higher than normal,and brain MRI revealed brain atrophy and significant abnormal signals in the bilateral paraventricular nuclei and heads of the bilateral caudate nuclei.Further genetic testing identified a paternal mutation c.1604G>A(p.R535Q)and a maternal mutation c.227T>G(p.L76R)of the MTHFR gene.After betaine supplementation,the plasma homocysteine levels decreased within a week,and the symptoms improved.The patient was ultimately diagnosed with severe hyperhomocysteinemia due to MTHFR deficiency.The c.227T>G(p.L76R)mutation represents a novel missense mutation in the MTHFR gene associated with MTHFR deficiency,but further research is needed to confirm its potential pathogenicity.Early treatment with betaine can fully reverse the symptoms.展开更多
Background and objective EGFR-tyrosine kinase inhibitors(EGFR-TKIs) were used to treat non-small cell lung cancer(NSCLC) patients with EGFR mutation positive. This study aims to compare the effectiveness of first line...Background and objective EGFR-tyrosine kinase inhibitors(EGFR-TKIs) were used to treat non-small cell lung cancer(NSCLC) patients with EGFR mutation positive. This study aims to compare the effectiveness of first line TKIs;gefitinib, erlotinib, and afatinib in the treatment of advanced stage NSCLC patients with EGFR mutation positive in the Indonesian population.Methods A retrospective cohort study of 88 NSCLC patients with EGFR mutation positive treated with gefitinib(n=59), erlotinib(n=22), and afatinib(n=7) was performed in national cancer hospital in Indonesia.Inclusion criteria were stage IIIb or IV NSCLC with adenocarcinoma subtype. Subjects less than 18 years or with a history of other malignancy were excluded. Outcomes were treatment response, progression-free survival(PFS), and mortality rate. Results Complete response, partial response, and stable disease were shown in 1.1%, 35.2%, and 31.8% of subjects, respectively. There were 31.8% of subjects developed progressive disease during treatment. Regarding EGFR mutation positive profile, a total of 56.8% subjects had deletion in exon 19, 42% subjects had mutation in exon 21, and rare mutation in exon 18 was found in 3.4% of total subjects. Demography and clinical characteristics had no significant association with the risk of progressive disease. The median PFS of subjects was 11 months(95%CI: 6.8-15.2 months). There was no statistical difference of PFS between treatment groups.Conclusion Gefitinib, erlotinib, and afatinib have similar effectiveness in advanced stage NSCLC with EGFR mutation positive. Afatinib tends to be associated with longer PFS but further investigation is required.展开更多
Nine strains resistant to five fluoroquinolones （Ciprofloxacin, Ofloxacin, Enrofloxacin, Danofloxacin, Sarafloxacin） were isolated from clinical samples and extracted the chromosomal DNA of these strains. Designed p...Nine strains resistant to five fluoroquinolones （Ciprofloxacin, Ofloxacin, Enrofloxacin, Danofloxacin, Sarafloxacin） were isolated from clinical samples and extracted the chromosomal DNA of these strains. Designed primers to amplify the Quinolone-resistance-determining region （QRDR） of gyrA and par（？,, then the PCR products were sequenced and analyzed. In comparision with NCTC5776, a single mutation was found at base 371 in gyrA of strain 38 which changed from C to T, and a single mutation was found at base 350 in gyrA of strain 60 which changed from A to C. No mutation was found in gyrA of the rest The mutation of strain 38 led to an amino acid substitution of Arg99Cys and the mutation of 60 led to an amino acid substitution of Met 92 Leu. No mutation was found in parC QRDR of all the isolates. These results indicats that the DNA gyrase will be the primary target to salmonella of fluoroquinolone.展开更多
An adaptive genetic algorithm with diversity-guided mutation, which combines adaptive probabilities of crossover and mutation was proposed. By means of homogeneous finite Markov chains, it is proved that adaptive gene...An adaptive genetic algorithm with diversity-guided mutation, which combines adaptive probabilities of crossover and mutation was proposed. By means of homogeneous finite Markov chains, it is proved that adaptive genetic algorithm with diversity-guided mutation and genetic algorithm with diversity-guided mutation converge to the global optimum if they maintain the best solutions, and the convergence of adaptive genetic algorithms with adaptive probabilities of crossover and mutation was studied. The performances of the above algorithms in optimizing several unimodal and multimodal functions were compared. The results show that for multimodal functions the average convergence generation of the adaptive genetic algorithm with diversity-guided mutation is about 900 less than that of (adaptive) genetic algorithm with adaptive probabilities and genetic algorithm with diversity-guided mutation, and the adaptive genetic algorithm with diversity-guided mutation does not lead to premature convergence. It is also shown that the better balance between overcoming premature convergence and quickening convergence speed can be gotten.展开更多
In order to screen a high-yield spergualin-production strain and an optimal fermentation medium, large numbers of isolates were selected after ultraviolet （UV） mutation and self-tolerant mutation of Bacillus lateros...In order to screen a high-yield spergualin-production strain and an optimal fermentation medium, large numbers of isolates were selected after ultraviolet （UV） mutation and self-tolerant mutation of Bacillus laterosporus A7. A high-yield strain A-94-7 was obtained and the spergualin productivity was 4. 1-fold of the parent strain. The genetic stability of the high-yield strain Bacillus laterosporus A-94-7 was very good. Aider fermentation medium optimization, Bacillus laterosporus A-94-7 was able to produce 380 mg· L^-1 The spergualin productivity in Bacillus laterosporus A7 was increased 4.75-fold by mutation and medium optimization.展开更多
Mixed microorganisms with elevated activity of chalcocite-leaching were screened by mutation methods. The original microorganisms collected from acid mine drainage of different sites were mixed and then treated with m...Mixed microorganisms with elevated activity of chalcocite-leaching were screened by mutation methods. The original microorganisms collected from acid mine drainage of different sites were mixed and then treated with mutagens NO2^- , diethyl sulfate （DES）, UV and their combinations, respectively. Five groups of mixed microorganisms with much stronger ore-leaching ability were obtained by screening on the leaching media. Among them, group E of mixed microorganisms （treated with 1% DES for 60 min） with the best perfonnance on chalcocite-leaching, increases the content of Cu^2＋ by 101.4% in 20 d of leaching compared with the control culture. In addition, group E is more tolerant to Cu^2＋ in media than the control without mutation treatment. Analysis for the diversity of microbial clones indicates that half of operational taxonomic units （OTUs） in group E are Acidithiobacillus ferrooxidans. These observations suggest that group E might have potentials for industrial application.展开更多
By means of mathematical modeling methods, we analyzed the relationship between the resistance to fluoroquinolones and GyrA mutation of Salmonella from animal isolates. We found that considering the influence of the r...By means of mathematical modeling methods, we analyzed the relationship between the resistance to fluoroquinolones and GyrA mutation of Salmonella from animal isolates. We found that considering the influence of the resistance to ciprofloxacin hydrochloride, enrofloxacin, ofloxacin, pefloacin mesylate and norfloxacin nicotinate of the five types of fluoroquinolones to GyrA mutation of animal Salmonella, the resistance of pefloacin mesylate had the most significant effect, while the resistance of ciprofloxacin hydrochloride and enrofloxacin were the least significant factors. Nearly half of the Salmonella supports such a rule that the MIC of norfloxacin nicotinate reaching 64 or 128 might lead to the mutation Ser83→Phe, MIC exceeding 512 might lead to the mutation Ser83→Gly; 60% of the sample supported that the MIC of enrofloxacin reaching 32 or 64 might lead to the mutation Asp87 →Asn. 80% of them agreed to the fact that the MIC of neither ciprofloxacin hydrochloride under 64 nor pefloacin mesylate below 512 might result in the gene mutation in 119 site. All Salmonella isolates supported the conclusion that the mutation Alal19→Val took place, if and only if the MIC of norfloxacin nicotinate exceeded 512.展开更多
Background and objective:Epidermal growth factor receptor(EGFR)mutations are often associated with non-EGFR genetic alterations,which maybe a reason for the poor efficacy of EGFR tyrosine kinase inhibitors(TKIs).Here ...Background and objective:Epidermal growth factor receptor(EGFR)mutations are often associated with non-EGFR genetic alterations,which maybe a reason for the poor efficacy of EGFR tyrosine kinase inhibitors(TKIs).Here we conducted this study to explore whether EGFR-TKIs combined with chemotherapy would benefit advanced lung adenocarcinoma patients with both sensitive EGFR mutation and concomitant non-EGFR genetic alterations.Materials and methods:Cases of advanced lung adenocarcinoma with EGFR mutation combined with concomitant nonEGFR genetic alterations were retrospectively collected.And the patients were required to receive first-line EGFR-TKIs and chemotherapy combination or EGFR-TKIs monotherapy.Demographic,clinical and pathological data were collected,and the electronic imaging data were retrieved to evaluate the efficacy and time of disease progression.Survival data were obtained through face-to-face or telephone follow-up.The differences between the two groups in objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS)and overall survival(OS)were investigated.Results:107 patients were included,including 63 cases in the combination group and 44 cases in the monotherapy group.The ORR were 78%and 50%(P=0.003),and DCR were 97%and 77%(P=0.002),respectively.At a median follow-up of 13.7 mon,a PFS event occurred in 38.1%and 81.8%of patients in the two groups,with median PFS of18.8 mon and 5.3 mon,respectively(P<0.000,1).Median OS was unreached in the combination group,and 27.8 mon in the monotherapy group(P=0.31).According to the Cox multivariate regression analysis,combination therapy was an independent prognostic factor of PFS.Conclusion:In patients with EGFR-mutant advanced lung adenocarcinoma with concomitant non-EGFR genetic alterations,combination of TKIs and chemotherapy was significantly superior to EGFR-TKIs monotherapy,which should be the preferred treatment option.展开更多
PCR-SSCP was used to detect mutations of bone morphogenetic protein 15(BMP15) gene in both high prolificacy(Small Tail Han sheep,Hu sheep,Jining Grey goat and Boer goat) and low prolificacy breeds(Dorset sheep,Texel s...PCR-SSCP was used to detect mutations of bone morphogenetic protein 15(BMP15) gene in both high prolificacy(Small Tail Han sheep,Hu sheep,Jining Grey goat and Boer goat) and low prolificacy breeds(Dorset sheep,Texel sheep,Inner Mongolia Cashmere goat and Angora goat).Both the nucleotide sequences and the amino acid sequences were compared in amplification fragments of both Small Tail Han sheep and Jining Grey goat.The results indicated that none of the four sheep and the four goat breeds carried the same FecX<sup>R</sup> mutation of the BMP15 gene as do Rasa Aragonesa sheep.The nucleotide sequence of Small Tail Han sheep was completely identical with that of the sheep BMP15 sequence(GenBank AF236079,NM<sub>0</sub>01114767).Three base substitutions(T529G,C530G and T576C) and two amino acid changes(V155G and S171P) were found in Jining Grey goat compared with Small Tail Han sheep.The FecX<sup>R</sup> mutation of the BMP15 gene had no significant effect on high prolificacy of Small Tail Han sheep, Hu sheep,Jining Grey goat and Boer goat.展开更多
The aim of this work was to develop a mutation and selection procedure to select the high-yield strain, and this strain could alleviate the inhibition in the biosynthesis of ramoplanin caused by L-leucine. In this exp...The aim of this work was to develop a mutation and selection procedure to select the high-yield strain, and this strain could alleviate the inhibition in the biosynthesis of ramoplanin caused by L-leucine. In this experiment, the strain Actinoplanes sp. C6-78-14 that produced 384.8 mg of total productivity per liter was isolated. Its ramoplanin productivity was 4.13-fold higher than that of the parent strain A ctinoplanes sp. C2-9-45. The subculture experiments showed that the hereditary character of C6-78-14 was stable. Subsequent media studies with strain Actinoplanes sp. C6-78-14 showed that adding 0.001% FeSO4· 7H2O, 0.001% CoCl2· 6H2O and 0.001% CuSO4· 5H2O to fermentation medium respectively could enhance the ramoplanin production, and the production of each group was increased by 10%, 15% and 20% compared with the control group.展开更多
A novel multi-chip module(MCM) interconnect test generation scheme based on ant algorithm(AA) with mutation operator was presented.By combing the characteristics of MCM interconnect test generation,the pheromone updat...A novel multi-chip module(MCM) interconnect test generation scheme based on ant algorithm(AA) with mutation operator was presented.By combing the characteristics of MCM interconnect test generation,the pheromone updating rule and state transition rule of AA is designed.Using mutation operator,this scheme overcomes ordinary AA’s defects of slow convergence speed,easy to get stagnate,and low ability of full search.The international standard MCM benchmark circuit provided by the MCNC group was used to verify the approach.The results of simulation experiments,which compare to the results of standard ant algorithm,genetic algorithm(GA) and other deterministic interconnecting algorithms,show that the proposed scheme can achieve high fault coverage,compact test set and short CPU time,that it is a newer optimized method deserving research.展开更多
Objective To characterize a novel frameshift mutation of the epithelial sodium channel(ENaC)βsubunit in a Chinese family with clinical suspicion of Liddle syndrome.And to emphasize that genetic testing is a confirmat...Objective To characterize a novel frameshift mutation of the epithelial sodium channel(ENaC)βsubunit in a Chinese family with clinical suspicion of Liddle syndrome.And to emphasize that genetic testing is a confirmatory evidence of the diagnosis of Liddle syndrome.Methods DNA samples from the proband with early-onset,treatment-resistant hypertension and hypokalemia and 31 additional relatives were all sequenced for mutations in exon 13 of theβ-ENaC andγ-ENaC genes,using amplification by polymerase chain reaction and direct DNA sequencing.展开更多
Objective Neurofibromatosis typeⅠ(NF1)is an autosomal dominant disorder which is caused by loss-of-function mutations in neurofibromin 1 gene(NF1).Clinically,NF1 mainly manifests several typical features,such as mult...Objective Neurofibromatosis typeⅠ(NF1)is an autosomal dominant disorder which is caused by loss-of-function mutations in neurofibromin 1 gene(NF1).Clinically,NF1 mainly manifests several typical features,such as multiple neurofibromas and café-au-lait spots,as well as axillary freckling and Lisch nodules in iris.The aim of the current study is to identification a splicing mutation and genotype-phenotype correlation.展开更多
Background:The literature recommends that reduced dosage of CPT-11 should be applied in patients with UGT1 A1 homozygous mutations,but the impact of UGT1 A1 heterozygous mutations on the adverse reactions of CPT-11 is...Background:The literature recommends that reduced dosage of CPT-11 should be applied in patients with UGT1 A1 homozygous mutations,but the impact of UGT1 A1 heterozygous mutations on the adverse reactions of CPT-11 is still not fully clear.Methods:A total of 107 patients with UGT1 A1 heterozygous mutation or wild-type,who were treated with CPT-11 from January 2018 to September 2021 in Peking University Third Hospital,were retrospectively enrolled.The adverse reaction spectra of patients with UGT1 A1*6 and UGT1 A1*28 mutations were analyzed.Adverse reactions were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events(NCI-CTCAE) 5.0.The efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors(RECIST) 1.1.The genotypes of UGT1 A1*6 and UGT1 A1*28 were detected by digital fluorescence molecular hybridization.Results:There were 43 patients with UGT1 A1*6 heterozygous mutation,26 patients with UGT1 A1*28 heterozygous mutation,8 patients with UGT1 A1*6 and UGT1 A1*28 double heterozygous mutations,61 patients with heterozygous mutation at any gene locus of UGT1 A1*6 and UGT1 A1*28.Logistic regression analysis showed that the presence or absence of vomiting(P=0.013) and mucositis(P=0.005) was significantly correlated with heterozygous mutation of UGT1 A1*28,and the severity of vomiting(P<0.001) and neutropenia(P=0.021) were significantly correlated with heterozygous mutation of UGT1 A1*6.In colorectal cancer,UGT1 A1*6 was significantly correlated to diarrhea(P=0.005),and the other adverse reactions spectrum was similar to that of the whole patient cohort,and efficacy and prognosis were similar between patients with different genotypes and patients treated with reduced CPT-11 dosage or not.Conclusion:In clinical use,heterozygous mutations of UGT1 A1*6 and UGT1 A1*28 are related to the risk and severity of vomiting,diarrhea,neutropenia and mucositis in patients with Pan-tumor and colorectal cancer post CPT-11 therpy.In colorectal cancer,UGT1 A1*6 is significantly related to diarrhea post CPT-11 use,efficacy and prognosis is not affected by various genotypes or CPT-11 dosage reduction.展开更多
Background and Objective Marfan syndrome,a variable and heritable disorder of fibrous connective tissue,characterized by affecting skeletal,ocular and cardiovascular systems.With the research advancement of genetic me...Background and Objective Marfan syndrome,a variable and heritable disorder of fibrous connective tissue,characterized by affecting skeletal,ocular and cardiovascular systems.With the research advancement of genetic mechanism,the diagnosis of Marfan syndrome,based on clinical manifestations and genetic evidence,is more accurate.The aim of this study is identification of genetic pathogenesis in a Chinese family.展开更多
基金supported by the National Natural Science Foundation(82271057)the Natural Science Foundation of Hunan Province(2023JJ30818),China。
文摘Objective:Keratoconus(KC)is a progressive corneal ectasia disorder,arising from a myriad of causes including genetic predispositions,environmental factors,biomechanical influences,and inflammatory reactions.This study aims to identify potential pathogenetic gene mutations in patients with sporadic KC in the Han Chinese population.Methods:Twenty-five patients with primary KC as well as 50 unrelated population matched healthy controls,were included in this study to identify potential pathogenic gene mutations among sporadic KC patients in the Han Chinese population.Sanger sequencing and whole-exome sequencing(WES)were used to analyze mutations in the zinc finger protein 469(ZNF469)gene.Bioinformatics analysis was conducted to explore the potential role of ZNF469 in KC pathogenesis.Results:Five novel heterozygous missense variants were identified in KC patients.Among them,2 compound heterozygous variants,c.8986G>C(p.E2996Q)with c.11765A>C(p.D3922A),and c.4423C>G(p.L1475V)with c.10633G>A(p.G3545R),were determined to be possible pathogenic factors for KC.Conclusion:Mutations in the ZNF469 gene may contribute to the development of KC in the Han Chinese population.These mutation sites may provide valuable information for future genetic screening of KC patients and their families.
基金supported by the National Key Research and Development Program of China(2021YFC2700202,2022YFA0806303 and 2022YFC2702601)the Global Select Project of the Institute of Health and Medicine,Hefei Comprehensive National Science Center(DJK-LX-2022010)+1 种基金USTC Research Funds of the Double First-Class Initiative(the Joint Fund for New Medicine of USTC)(YD9100002034)the Fundamental Research Funds for the Central Universities(WK9100000004).
文摘Multiple morphological abnormalities of the sperm flagella(MMAF)are characterized by bent,irregular,short,coiled,and absent flagella.MMAF is caused by a variety of genes,some of which have been identified.However,the underlying genetic factors responsible for the majority of MMAF cases are still largely unknown.The glutamine-rich 2(QRICH2)gene plays an essential role in the development of sperm flagella by regulating the expression of essential sperm flagellar biogenesis-associated proteins,and genetic variants of QRICH2 have been identified as the primary cause of MMAF in humans and mice.Here,we recruited a Pakistani consanguineous family to identify the genetic variant causing infertility in patients with MMAF.Whole-exome sequencing and Sanger sequencing were conducted to identify potentially pathogenic variants causing MMAF in infertile patients.Hematoxylin and eosin(HE)staining was performed to analyze sperm morphology.Quantitative polymerase chain reaction,western blot,and immunofluorescence staining analyses were conducted to observe the expression of QRICH2 in spermatozoa.A novel homozygous missense variant(c.4618C>T)in QRICH2 was identified in the affected patients.Morphological analysis of spermatozoa revealed the MMAF phenotype in infertile patients.qPCR revealed a significant reduction in the level of sperm QRICH2 mRNA,and immunofluorescence staining revealed a lack of sperm QRICH2 expression.Additionally,patients harboring a homozygous QRICH2 mutation presented reduced expression of outer dense fiber 2(ODF2)in sperm,whereas sperm expression of A-kinase anchor protein 4(AKAP4)was normal.These findings expand our understanding of the genetic causes of MMAF-associated male infertility and emphasize the importance of genetic counseling.
基金supported by the National Natural Science Foundation(81971696)the Natural Science Foundation of Hunan Province(2022JJ30861),China.
文摘Methylenetetrahydrofolate reductase(MTHFR)deficiency is a rare autosomal recessive genetic disorder caused by mutations in the MTHFR gene,leading to a variety of clinical manifestations.In October 2022,the Second Xiangya Hospital of Central South University admitted a 21-year-old male patient with neuropsychiatric disorders,presenting primarily with cognitive decline,limb tremors,abnormal mental and behavioral symptoms,seizures,and gait disturbances.These symptoms had gradually developed over 5 years,worsening significantly in the past year.The patient’s plasma homocysteine levels were 10 times higher than normal,and brain MRI revealed brain atrophy and significant abnormal signals in the bilateral paraventricular nuclei and heads of the bilateral caudate nuclei.Further genetic testing identified a paternal mutation c.1604G>A(p.R535Q)and a maternal mutation c.227T>G(p.L76R)of the MTHFR gene.After betaine supplementation,the plasma homocysteine levels decreased within a week,and the symptoms improved.The patient was ultimately diagnosed with severe hyperhomocysteinemia due to MTHFR deficiency.The c.227T>G(p.L76R)mutation represents a novel missense mutation in the MTHFR gene associated with MTHFR deficiency,but further research is needed to confirm its potential pathogenicity.Early treatment with betaine can fully reverse the symptoms.
文摘Background and objective EGFR-tyrosine kinase inhibitors(EGFR-TKIs) were used to treat non-small cell lung cancer(NSCLC) patients with EGFR mutation positive. This study aims to compare the effectiveness of first line TKIs;gefitinib, erlotinib, and afatinib in the treatment of advanced stage NSCLC patients with EGFR mutation positive in the Indonesian population.Methods A retrospective cohort study of 88 NSCLC patients with EGFR mutation positive treated with gefitinib(n=59), erlotinib(n=22), and afatinib(n=7) was performed in national cancer hospital in Indonesia.Inclusion criteria were stage IIIb or IV NSCLC with adenocarcinoma subtype. Subjects less than 18 years or with a history of other malignancy were excluded. Outcomes were treatment response, progression-free survival(PFS), and mortality rate. Results Complete response, partial response, and stable disease were shown in 1.1%, 35.2%, and 31.8% of subjects, respectively. There were 31.8% of subjects developed progressive disease during treatment. Regarding EGFR mutation positive profile, a total of 56.8% subjects had deletion in exon 19, 42% subjects had mutation in exon 21, and rare mutation in exon 18 was found in 3.4% of total subjects. Demography and clinical characteristics had no significant association with the risk of progressive disease. The median PFS of subjects was 11 months(95%CI: 6.8-15.2 months). There was no statistical difference of PFS between treatment groups.Conclusion Gefitinib, erlotinib, and afatinib have similar effectiveness in advanced stage NSCLC with EGFR mutation positive. Afatinib tends to be associated with longer PFS but further investigation is required.
文摘Nine strains resistant to five fluoroquinolones （Ciprofloxacin, Ofloxacin, Enrofloxacin, Danofloxacin, Sarafloxacin） were isolated from clinical samples and extracted the chromosomal DNA of these strains. Designed primers to amplify the Quinolone-resistance-determining region （QRDR） of gyrA and par（？,, then the PCR products were sequenced and analyzed. In comparision with NCTC5776, a single mutation was found at base 371 in gyrA of strain 38 which changed from C to T, and a single mutation was found at base 350 in gyrA of strain 60 which changed from A to C. No mutation was found in gyrA of the rest The mutation of strain 38 led to an amino acid substitution of Arg99Cys and the mutation of 60 led to an amino acid substitution of Met 92 Leu. No mutation was found in parC QRDR of all the isolates. These results indicats that the DNA gyrase will be the primary target to salmonella of fluoroquinolone.
文摘An adaptive genetic algorithm with diversity-guided mutation, which combines adaptive probabilities of crossover and mutation was proposed. By means of homogeneous finite Markov chains, it is proved that adaptive genetic algorithm with diversity-guided mutation and genetic algorithm with diversity-guided mutation converge to the global optimum if they maintain the best solutions, and the convergence of adaptive genetic algorithms with adaptive probabilities of crossover and mutation was studied. The performances of the above algorithms in optimizing several unimodal and multimodal functions were compared. The results show that for multimodal functions the average convergence generation of the adaptive genetic algorithm with diversity-guided mutation is about 900 less than that of (adaptive) genetic algorithm with adaptive probabilities and genetic algorithm with diversity-guided mutation, and the adaptive genetic algorithm with diversity-guided mutation does not lead to premature convergence. It is also shown that the better balance between overcoming premature convergence and quickening convergence speed can be gotten.
基金Supported by Program for Innovative Research Team of Northeast Agricultural University
文摘In order to screen a high-yield spergualin-production strain and an optimal fermentation medium, large numbers of isolates were selected after ultraviolet （UV） mutation and self-tolerant mutation of Bacillus laterosporus A7. A high-yield strain A-94-7 was obtained and the spergualin productivity was 4. 1-fold of the parent strain. The genetic stability of the high-yield strain Bacillus laterosporus A-94-7 was very good. Aider fermentation medium optimization, Bacillus laterosporus A-94-7 was able to produce 380 mg· L^-1 The spergualin productivity in Bacillus laterosporus A7 was increased 4.75-fold by mutation and medium optimization.
基金Project(50321402)supported by the National Natural Science Foundation of ChinaProject(2004CB619201)supported by the Major State Basic Research and Development Program of China
文摘Mixed microorganisms with elevated activity of chalcocite-leaching were screened by mutation methods. The original microorganisms collected from acid mine drainage of different sites were mixed and then treated with mutagens NO2^- , diethyl sulfate （DES）, UV and their combinations, respectively. Five groups of mixed microorganisms with much stronger ore-leaching ability were obtained by screening on the leaching media. Among them, group E of mixed microorganisms （treated with 1% DES for 60 min） with the best perfonnance on chalcocite-leaching, increases the content of Cu^2＋ by 101.4% in 20 d of leaching compared with the control culture. In addition, group E is more tolerant to Cu^2＋ in media than the control without mutation treatment. Analysis for the diversity of microbial clones indicates that half of operational taxonomic units （OTUs） in group E are Acidithiobacillus ferrooxidans. These observations suggest that group E might have potentials for industrial application.
基金Supported by the National Natural Science Foundation of China (11171244)
文摘By means of mathematical modeling methods, we analyzed the relationship between the resistance to fluoroquinolones and GyrA mutation of Salmonella from animal isolates. We found that considering the influence of the resistance to ciprofloxacin hydrochloride, enrofloxacin, ofloxacin, pefloacin mesylate and norfloxacin nicotinate of the five types of fluoroquinolones to GyrA mutation of animal Salmonella, the resistance of pefloacin mesylate had the most significant effect, while the resistance of ciprofloxacin hydrochloride and enrofloxacin were the least significant factors. Nearly half of the Salmonella supports such a rule that the MIC of norfloxacin nicotinate reaching 64 or 128 might lead to the mutation Ser83→Phe, MIC exceeding 512 might lead to the mutation Ser83→Gly; 60% of the sample supported that the MIC of enrofloxacin reaching 32 or 64 might lead to the mutation Asp87 →Asn. 80% of them agreed to the fact that the MIC of neither ciprofloxacin hydrochloride under 64 nor pefloacin mesylate below 512 might result in the gene mutation in 119 site. All Salmonella isolates supported the conclusion that the mutation Alal19→Val took place, if and only if the MIC of norfloxacin nicotinate exceeded 512.
文摘Background and objective:Epidermal growth factor receptor(EGFR)mutations are often associated with non-EGFR genetic alterations,which maybe a reason for the poor efficacy of EGFR tyrosine kinase inhibitors(TKIs).Here we conducted this study to explore whether EGFR-TKIs combined with chemotherapy would benefit advanced lung adenocarcinoma patients with both sensitive EGFR mutation and concomitant non-EGFR genetic alterations.Materials and methods:Cases of advanced lung adenocarcinoma with EGFR mutation combined with concomitant nonEGFR genetic alterations were retrospectively collected.And the patients were required to receive first-line EGFR-TKIs and chemotherapy combination or EGFR-TKIs monotherapy.Demographic,clinical and pathological data were collected,and the electronic imaging data were retrieved to evaluate the efficacy and time of disease progression.Survival data were obtained through face-to-face or telephone follow-up.The differences between the two groups in objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS)and overall survival(OS)were investigated.Results:107 patients were included,including 63 cases in the combination group and 44 cases in the monotherapy group.The ORR were 78%and 50%(P=0.003),and DCR were 97%and 77%(P=0.002),respectively.At a median follow-up of 13.7 mon,a PFS event occurred in 38.1%and 81.8%of patients in the two groups,with median PFS of18.8 mon and 5.3 mon,respectively(P<0.000,1).Median OS was unreached in the combination group,and 27.8 mon in the monotherapy group(P=0.31).According to the Cox multivariate regression analysis,combination therapy was an independent prognostic factor of PFS.Conclusion:In patients with EGFR-mutant advanced lung adenocarcinoma with concomitant non-EGFR genetic alterations,combination of TKIs and chemotherapy was significantly superior to EGFR-TKIs monotherapy,which should be the preferred treatment option.
基金Supported by National-Natural Science Found for Distinguished Young Scholars of China （61025015）, the Foundation for Innovative Research Groups of National Natural Science Foundation of China （61321003） and the China Scholarship Council
基金supported by National High Technology Research and Development Program of China(No. 2006AA 10Z 139)National Key Basic Research and Development Program of China(No.2006CB 102105)+3 种基金National Key Technology R&D Program of China(No. 2008BADB2B01,2006BAD01A 11,2006BAD 13B08)National Natural Science Foundation of China(No. 30540052)Beijing Natural Sciences Foundation of China(No.6062023)the special fund for basic scientific research of Institute of Animal Science,Chinese Academy of Agricultural Sciences(No.ywf-rc-1)
文摘PCR-SSCP was used to detect mutations of bone morphogenetic protein 15(BMP15) gene in both high prolificacy(Small Tail Han sheep,Hu sheep,Jining Grey goat and Boer goat) and low prolificacy breeds(Dorset sheep,Texel sheep,Inner Mongolia Cashmere goat and Angora goat).Both the nucleotide sequences and the amino acid sequences were compared in amplification fragments of both Small Tail Han sheep and Jining Grey goat.The results indicated that none of the four sheep and the four goat breeds carried the same FecX<sup>R</sup> mutation of the BMP15 gene as do Rasa Aragonesa sheep.The nucleotide sequence of Small Tail Han sheep was completely identical with that of the sheep BMP15 sequence(GenBank AF236079,NM<sub>0</sub>01114767).Three base substitutions(T529G,C530G and T576C) and two amino acid changes(V155G and S171P) were found in Jining Grey goat compared with Small Tail Han sheep.The FecX<sup>R</sup> mutation of the BMP15 gene had no significant effect on high prolificacy of Small Tail Han sheep, Hu sheep,Jining Grey goat and Boer goat.
基金Program for Innovative Research Team of Northeast Agricultural University
文摘The aim of this work was to develop a mutation and selection procedure to select the high-yield strain, and this strain could alleviate the inhibition in the biosynthesis of ramoplanin caused by L-leucine. In this experiment, the strain Actinoplanes sp. C6-78-14 that produced 384.8 mg of total productivity per liter was isolated. Its ramoplanin productivity was 4.13-fold higher than that of the parent strain A ctinoplanes sp. C2-9-45. The subculture experiments showed that the hereditary character of C6-78-14 was stable. Subsequent media studies with strain Actinoplanes sp. C6-78-14 showed that adding 0.001% FeSO4· 7H2O, 0.001% CoCl2· 6H2O and 0.001% CuSO4· 5H2O to fermentation medium respectively could enhance the ramoplanin production, and the production of each group was increased by 10%, 15% and 20% compared with the control group.
文摘A novel multi-chip module(MCM) interconnect test generation scheme based on ant algorithm(AA) with mutation operator was presented.By combing the characteristics of MCM interconnect test generation,the pheromone updating rule and state transition rule of AA is designed.Using mutation operator,this scheme overcomes ordinary AA’s defects of slow convergence speed,easy to get stagnate,and low ability of full search.The international standard MCM benchmark circuit provided by the MCNC group was used to verify the approach.The results of simulation experiments,which compare to the results of standard ant algorithm,genetic algorithm(GA) and other deterministic interconnecting algorithms,show that the proposed scheme can achieve high fault coverage,compact test set and short CPU time,that it is a newer optimized method deserving research.
文摘Objective To characterize a novel frameshift mutation of the epithelial sodium channel(ENaC)βsubunit in a Chinese family with clinical suspicion of Liddle syndrome.And to emphasize that genetic testing is a confirmatory evidence of the diagnosis of Liddle syndrome.Methods DNA samples from the proband with early-onset,treatment-resistant hypertension and hypokalemia and 31 additional relatives were all sequenced for mutations in exon 13 of theβ-ENaC andγ-ENaC genes,using amplification by polymerase chain reaction and direct DNA sequencing.
文摘Objective Neurofibromatosis typeⅠ(NF1)is an autosomal dominant disorder which is caused by loss-of-function mutations in neurofibromin 1 gene(NF1).Clinically,NF1 mainly manifests several typical features,such as multiple neurofibromas and café-au-lait spots,as well as axillary freckling and Lisch nodules in iris.The aim of the current study is to identification a splicing mutation and genotype-phenotype correlation.
文摘Background:The literature recommends that reduced dosage of CPT-11 should be applied in patients with UGT1 A1 homozygous mutations,but the impact of UGT1 A1 heterozygous mutations on the adverse reactions of CPT-11 is still not fully clear.Methods:A total of 107 patients with UGT1 A1 heterozygous mutation or wild-type,who were treated with CPT-11 from January 2018 to September 2021 in Peking University Third Hospital,were retrospectively enrolled.The adverse reaction spectra of patients with UGT1 A1*6 and UGT1 A1*28 mutations were analyzed.Adverse reactions were evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events(NCI-CTCAE) 5.0.The efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors(RECIST) 1.1.The genotypes of UGT1 A1*6 and UGT1 A1*28 were detected by digital fluorescence molecular hybridization.Results:There were 43 patients with UGT1 A1*6 heterozygous mutation,26 patients with UGT1 A1*28 heterozygous mutation,8 patients with UGT1 A1*6 and UGT1 A1*28 double heterozygous mutations,61 patients with heterozygous mutation at any gene locus of UGT1 A1*6 and UGT1 A1*28.Logistic regression analysis showed that the presence or absence of vomiting(P=0.013) and mucositis(P=0.005) was significantly correlated with heterozygous mutation of UGT1 A1*28,and the severity of vomiting(P<0.001) and neutropenia(P=0.021) were significantly correlated with heterozygous mutation of UGT1 A1*6.In colorectal cancer,UGT1 A1*6 was significantly correlated to diarrhea(P=0.005),and the other adverse reactions spectrum was similar to that of the whole patient cohort,and efficacy and prognosis were similar between patients with different genotypes and patients treated with reduced CPT-11 dosage or not.Conclusion:In clinical use,heterozygous mutations of UGT1 A1*6 and UGT1 A1*28 are related to the risk and severity of vomiting,diarrhea,neutropenia and mucositis in patients with Pan-tumor and colorectal cancer post CPT-11 therpy.In colorectal cancer,UGT1 A1*6 is significantly related to diarrhea post CPT-11 use,efficacy and prognosis is not affected by various genotypes or CPT-11 dosage reduction.
文摘Background and Objective Marfan syndrome,a variable and heritable disorder of fibrous connective tissue,characterized by affecting skeletal,ocular and cardiovascular systems.With the research advancement of genetic mechanism,the diagnosis of Marfan syndrome,based on clinical manifestations and genetic evidence,is more accurate.The aim of this study is identification of genetic pathogenesis in a Chinese family.
