AIM:To identify a maculopathy patient caused by new recessive compound heterozygous variants in RP1L1.METHODS:Comprehensive retinal morphological and functional examinations were evaluated for the patient with RP1L1 m...AIM:To identify a maculopathy patient caused by new recessive compound heterozygous variants in RP1L1.METHODS:Comprehensive retinal morphological and functional examinations were evaluated for the patient with RP1L1 maculopathy.Targeted sequence capture array technique was used to screen potential pathologic variants.Polymerase chain reaction and Sanger sequencing were used to confirm the screening results.RESULTS:Fundus examination showed round macular lesions appeared in both eyes.Optical coherence tomography showed that the inner segment/outer segment continuity was disorganized and disruptive in the left eye,but it was uneven and slightly elevated in the right eye.Fundus autofluorescence showed patchy hyper-autofluorescence in the macula.Visual field examination indicates central defects in both eyes.Electroretinogram(ERG)and multifocal ERG showed no obvious abnormalities.Fundus fluorescein angiography in the macula showed obviously irregular hyper-fluorescence in the right eye and slightly hyper-fluorescence in the left eye.We found that the proband carried a missense variant(c.1972C>T)and a deletion variant(c.4717_4718del)of RP1L1,which were originated from the parents and formed compound heterozygous variants.Both variants are likely pathogenic according to the ACMG criteria.Multimodal imaging,ERG and detailed medical history are important diagnostic tools for differentiating between acquired and inherited retinal disorders.CONCLUSION:A maculopathy case with detailed retinal phenotype and new recessive compound heterozygous variants of RP1L1 is identified in a Chinese family,which expands the understanding of phenotype and genotype in RP1L1 maculopathy.展开更多
BACKGROUND The Columbia classification identified five histological variants of focal segmental glomerulosclerosis(FSGS).The prognostic significance of these variants remains controversial.AIM To evaluate the relative...BACKGROUND The Columbia classification identified five histological variants of focal segmental glomerulosclerosis(FSGS).The prognostic significance of these variants remains controversial.AIM To evaluate the relative frequency,clinicopathologic characteristics,and medium-term outcomes of FSGS variants at a single center in Pakistan.METHODS This retrospective study was conducted at the Department of Nephrology,Sindh Institute of Urology and Transplantation,Karachi,Pakistan on all consecutive adults(≥16 years)with biopsy-proven primary FSGS from January 1995 to December 2017.Studied subjects were treated with steroids as a first-line therapy.The response rates,doubling of serum creatinine,and kidney failure(KF)with replacement therapy were compared between histological variants using ANOVA or Kruskal Wallis,and Chi-square tests as appropriate.Data were analyzed by SPSS version 22.0.P-value≤0.05 was considered significant.RESULTS A total of 401 patients were diagnosed with primary FSGS during the study period.Among these,352(87.7%)had a designated histological variant.The not otherwise specified(NOS)variant was the commonest,being found in 185(53.9%)patients,followed by the tip variant in 100(29.1%)patients.Collapsing(COL),cellular(CEL),and perihilar(PHI)variants were seen in 58(16.9%),6(1.5%),and 3(0.7%)patients,respectively.CEL and PHI variants were excluded from further analysis due to small patient numbers.The mean follow-up period was 36.5±29.2 months.Regarding response rates of variants,patients with TIP lesions achieved remission more frequently(59.5%)than patients with NOS(41.8%)and COL(24.52%)variants(P<0.001).The hazard ratio of complete response among patients with the COL variant was 0.163[95%confidence interval(CI):0.039-0.67]as compared to patients with NOS.The TIP variant showed a hazard ratio of 2.5(95%CI:1.61-3.89)for complete remission compared to the NOS variant.Overall,progressive KF was observed more frequently in patients with the COL variant,43.4%(P<0.001).Among these,24.53%of patients required kidney replacement therapy(P<0.001).The hazard ratio of doubling of serum creatinine among patients with the COL variant was 14.57(95%CI:1.87-113.49)as compared to patients with the TIP variant.CONCLUSION In conclusion,histological variants of FSGS are predictive of response to treatment with immunosuppressants and progressive KF in adults in our setup.展开更多
Background Copy number variants(CNV)hold significant functional and evolutionary importance.Numerous ongoing CNV studies aim to elucidate the etiology of human diseases and gain insights into the population structure ...Background Copy number variants(CNV)hold significant functional and evolutionary importance.Numerous ongoing CNV studies aim to elucidate the etiology of human diseases and gain insights into the population structure of livestock.High-density chips have enabled the detection of CNV with increased resolution,leading to the identification of even small CNV.This study aimed to identify CNV in local Italian chicken breeds and investigate their distribution across the genome.Results Copy number variants were mainly distributed across the first six chromosomes and primarily associated with loss type CNV.The majority of CNV in the investigated breeds were of types 0 and 1,and the minimum length of CNV was significantly larger than that reported in previous studies.Interestingly,a high proportion of the length of chromosome 16 was covered by copy number variation regions(CNVR),with the major histocompatibility complex being the likely cause.Among the genes identified within CNVR,only those present in at least five animals across breeds(n=95)were discussed to reduce the focus on redundant CNV.Some of these genes have been associated to functional traits in chickens.Notably,several CNVR on different chromosomes harbor genes related to muscle development,tissue-specific biological processes,heat stress resistance,and immune response.Quantitative trait loci(QTL)were also analyzed to investigate potential overlapping with the identified CNVR:54 out of the 95 gene-containing regions overlapped with 428 QTL associated to body weight and size,carcass characteristics,egg production,egg components,fat deposition,and feed intake.Conclusions The genomic phenomena reported in this study that can cause changes in the distribution of CNV within the genome over time and the comparison of these differences in CNVR of the local chicken breeds could help in preserving these genetic resources.展开更多
Reproduction via cis-binary mechanisms appears to have evolved fairly early in the evolution of complex organisms, and a system committed to prior to evolution of humans. While the evolution of a chromosomal-specific ...Reproduction via cis-binary mechanisms appears to have evolved fairly early in the evolution of complex organisms, and a system committed to prior to evolution of humans. While the evolution of a chromosomal-specific approach has been a successful strategy for survival of a large variety of species including humans, the fidelity of sex determination leading to 100% cis-binary outcomes is not achieved in many species, with evidence for homosexual or bisexual behaviour evident in more than 1500 species. Thus, such outcomes indicates that sex determination is a multi-step process and not a single event, and as such, could lead to the appearance of variants during the process which developed much earlier than humans. Variants could arise either due to intrinsic variation in the steps of determination, or also be influenced by environmental factors of a biological or psychological nature. In contrast to homosexual variants which do not require interventions such as hormone therapy or surgery, expression of gender dysphoria, is more based in psychology, but also has biological underpinnings and can be influenced by such hormonal interventions and surgery. While the numbers of those with gender dysphoria is small (~0.6% - 1.0% of population), the attention given to this issue raises the possibility of biological and psychological environmental factors impacting the emergence of some of those expressing gender dysphoria. Furthermore, transitioning from male-to-female or female-to-male can have consequences regarding disease risks latter in life, including the appearance of autoimmune diseases. This review will attempt to review some of the evidence regarding sex determination, discuss why the system has potentially not been improved upon during evolution, how a potential role for sex chromosome function on neurodevelopment may be central to variation in humans, and how commitment to the current strategy is likely integrated into other sex-related events such as puberty, pregnancy, and menopause to ensure species survival. It will also discuss how variants in sex determination could contribute to sex differences in disease risk and how epigenetic modifications could play a role in such risk. .展开更多
Oligo probe staining is a low-cost and efficient chromosome identification technique.In this study,oligo genomic in situ hybridization(Oligo-GISH)technology was established in peanut.Peanut A and B subgenome-specific ...Oligo probe staining is a low-cost and efficient chromosome identification technique.In this study,oligo genomic in situ hybridization(Oligo-GISH)technology was established in peanut.Peanut A and B subgenome-specific interspersed repeat(IR)oligo probe sets were developed based on clustering and electronic localization of tandem repeat sequences in the reference genome of Tifrunner.The OligoGISH kit was then used to perform staining of 15 Arachis species.The A-subgenome probe set stained the chromosomes of A-and E-genome Arachis species,the B-subgenome probe set stained those of B-,F-,K-,and E-genome species,and neither set stained those of H-genome species.These results indicate the relationships among the genomes of these Arachis species.The Oligo-GISH kit was also used for batch staining of the chromosomes of 389 seedlings from the irradiated M1generation,allowing 67 translocation and deletion lines to be identified.Subsequent Oligo-FISH karyotyping,FISH using single-copy probe libraries,and trait investigation identified seven homozygous chromosomal variants from the M3generation and suggested that there may be genes on chromosome 4B controlling seed number per pod.These findings demonstrate that the IR probe sets and method developed in this study can facilitate research on distant hybridization and genetic improvement in peanut.展开更多
Background Pan-genomics is a recently emerging strategy that can be utilized to provide a more comprehensive characterization of genetic variation.Joint calling is routinely used to combine identified variants across ...Background Pan-genomics is a recently emerging strategy that can be utilized to provide a more comprehensive characterization of genetic variation.Joint calling is routinely used to combine identified variants across multiple related samples.However,the improvement of variants identification using the mutual support information from mul-tiple samples remains quite limited for population-scale genotyping.Results In this study,we developed a computational framework for joint calling genetic variants from 5,061 sheep by incorporating the sequencing error and optimizing mutual support information from multiple samples’data.The variants were accurately identified from multiple samples by using four steps:(1)Probabilities of variants from two widely used algorithms,GATK and Freebayes,were calculated by Poisson model incorporating base sequencing error potential;(2)The variants with high mapping quality or consistently identified from at least two samples by GATK and Freebayes were used to construct the raw high-confidence identification(rHID)variants database;(3)The high confidence variants identified in single sample were ordered by probability value and controlled by false discovery rate(FDR)using rHID database;(4)To avoid the elimination of potentially true variants from rHID database,the vari-ants that failed FDR were reexamined to rescued potential true variants and ensured high accurate identification variants.The results indicated that the percent of concordant SNPs and Indels from Freebayes and GATK after our new method were significantly improved 12%-32%compared with raw variants and advantageously found low frequency variants of individual sheep involved several traits including nipples number(GPC5),scrapie pathology(PAPSS2),sea-sonal reproduction and litter size(GRM1),coat color(RAB27A),and lentivirus susceptibility(TMEM154).Conclusion The new method used the computational strategy to reduce the number of false positives,and simulta-neously improve the identification of genetic variants.This strategy did not incur any extra cost by using any addi-tional samples or sequencing data information and advantageously identified rare variants which can be important for practical applications of animal breeding.展开更多
Background:Atrial septal defect(ASD)is one of the common congenital heart diseases.The MYH6 gene has a critical role in cardiac development but the role of MYH6 promoter variants in patients with ASD has not been expl...Background:Atrial septal defect(ASD)is one of the common congenital heart diseases.The MYH6 gene has a critical role in cardiac development but the role of MYH6 promoter variants in patients with ASD has not been explored.Methods:In 613 subjects including 320 ASD patients,we investigated the MYH6 gene promoter variants and verified the effect on gene expression by using cellular functional experiments and bioinformatics analysis.Results:Eleven variants were identified in the MYH6 gene promoter,of which four variants were found only in ASD patients,and two variants(g.3434G>C and g.4524C>T)were identified for the first time.Cellular functional experiments indicated that all four variants reduced the transcriptional activity of the MYH6 gene promoter(p<0.05).Subsequent analysis through the JASPAR(A database of transcription factor binding profiles)suggests that these variants may alter transcription factor binding sites,which may in turn lead to changes in myocardin subunit expression and ASD formation.Conclusions:Our study for the first time focuses on variants in the promoter region of the MYH6 gene in Chinese patients with ASD and the discovered variants have functional significance.The study provides new insights in the role of the MYH6 gene promoter region to better understand the genetic basis of ASD formation and facilitates clinical diagnosis.展开更多
Objective:To surveill emerging variants by nanopore technology-based genome sequencing in different COVID-19 waves in Sri Lanka and to examine the association with the sample characteristics,and vaccination status.Met...Objective:To surveill emerging variants by nanopore technology-based genome sequencing in different COVID-19 waves in Sri Lanka and to examine the association with the sample characteristics,and vaccination status.Methods:The study analyzed 207 RNA positive swab samples received to sequence laboratory during different waves.The N gene cut-off threshold of less than 30 was considered as the major inclusion criteria.Viral RNA was extracted,and elutes were subjected to nanopore sequencing.All the sequencing data were uploaded in the publicly accessible database,GISAID.Results:The Omicron,Delta and Alpha variants accounted for 58%,22%and 4%of the variants throughout the period.Less than 1%were Kappa variant and 16%of the study samples remained unassigned.Omicron variant was circulated among all age groups and in all the provinces.Ct value and variants assigned percentage was 100%in Ct values of 10-15 while only 45%assigned Ct value over 25.Conclusions:The present study examined the emergence,prevalence,and distribution of SARS-CoV-2 variants locally and has shown that nanopore technology-based genome sequencing enables whole genome sequencing in a low resource setting country.展开更多
The anterior system of the polygon of Willis plays an anastomotic role between the carotid territories and communicates with the posterior system. It ensures adequate cerebral blood flow in the event of internal occlu...The anterior system of the polygon of Willis plays an anastomotic role between the carotid territories and communicates with the posterior system. It ensures adequate cerebral blood flow in the event of internal occlusion. Its ability to redistribute blood flow depends on its morphology, the presence and size of the vessels that constitute it and their variants, knowledge of which is essential. The morphology of the carotid system is not constant and a number of variants are well recognized with greater hemodynamic importance. In this context, we undertook this work which aims to seek the anatomical variants of the anterior part of the PW;to determine the diameters of the vessels of the latter and to correlate these results with epidemiological data. We carried out a retrospective, descriptive and analytical study over a period of 4 months at Fann University Hospital, targeting patients who had undergone brain MRI with a 3D TOF sequence whatever the indication. Patients with lesions of cerebrovascular pathologies such as ischemia, hemorrhage, aneurysm, arteriovenous malformations or presenting a limited analysis examination due to the presence of kinetic or other artifact, were not included. Demographic data and anatomical variants were studied as well as the measurements of any continuous arterial segment greater than 0.8 mm in diameter. Those less than 0.8 mm in diameter were considered hypoplastic. The C3 segment of the internal carotid arteries, the A1 segment of the anterior cerebral arteries, the anterior communicating artery, constituted our main measurement sites. The sex ratio was 1.06, the mean age of the patients was 43 years ± 17.9 with extremes of 11 and 85 years. The anterior configuration of the polygon was complete in 57.5% representing 50% of men and 65.5% of women, in 56% of subjects under 40 years old and 58% in subjects over 40 years old. We noted a predominance of type a in 47% of patients followed by type g found in 35% of patients. The morphology of the anterior system of the Willis polygon is a function of its variants, some of which have greater hemodynamic importance than others. Its knowledge is essential for the management of cerebrovascular diseases.展开更多
BACKGROUND The Omicron variant of severe acute respiratory syndrome coronavirus 2(SARSCoV-2)mainly infects the upper respiratory tract.This study aimed to determine whether the probability of pulmonary infection and t...BACKGROUND The Omicron variant of severe acute respiratory syndrome coronavirus 2(SARSCoV-2)mainly infects the upper respiratory tract.This study aimed to determine whether the probability of pulmonary infection and the cycle threshold(Ct)measured using the fluorescent polymerase chain reaction(PCR)method were related to pulmonary infections diagnosed via computed tomography(CT).AIM To analyze the chest CT signs of SARS-CoV-2 Omicron variant infections with different Ct values,as determined via PCR.METHODS The chest CT images and PCR Ct values of 331 patients with SARS-CoV-2Omicron variant infections were retrospectively collected and categorized into low(<25),medium(25.00-34.99),and high(≥35)Ct groups.The characteristics of chest CT images in each group were statistically analyzed.RESULTS The PCR Ct values ranged from 13.36 to 39.81,with 99 patients in the low,155 in the medium,and 77 in the high Ct groups.Six abnormal chest CT signs were detected,namely,focal infection,patchy consolidation shadows,patchy groundglass shadows,mixed consolidation ground-glass shadows,subpleural interstitial changes,and pleural changes.Focal infections were less frequent in the low Ct group than in the medium and high Ct groups;these infections were the most common sign in the medium and high Ct groups.Patchy consolidation shadows and pleural changes were more frequent in the low Ct group than in the other two groups.The number of patients with two or more signs was greater in the low Ct group than in the medium and high Ct groups.CONCLUSION The chest CT signs of patients with pulmonary infection caused by the Omicron variants of SARSCoV-2 varied depending on the Ct values.Identification of the characteristics of Omicron variant infection can help subsequent planning of clinical treatment.展开更多
Aberrant alternative polyadenylation(APA)events play an important role in cancers,but little is known about whether APA-related genetic variants contribute to the susceptibility to bladder cancer.Previous genome-wide ...Aberrant alternative polyadenylation(APA)events play an important role in cancers,but little is known about whether APA-related genetic variants contribute to the susceptibility to bladder cancer.Previous genome-wide association study performed APA quantitative trait loci(apaQTL)analyses in bladder cancer,and identified 17955 single nucleotide polymorphisms(SNPs).We found that gene symbols of APA affected by apaQTL-associated SNPs were closely correlated with cancer signaling pathways,high mutational burden,and immune infiltration.Association analysis showed that apaQTL-associated SNPs rs34402449 C>A,rs2683524 C>T,and rs11540872 C>G were significantly associated with susceptibility to bladder cancer(rs34402449:OR=1.355,95%confidence interval[CI]:1.159-1.583,P=1.33×10^(−4);rs2683524:OR=1.378,95%CI:1.164-1.632,P=2.03×10^(−4);rs11540872:OR=1.472,95%CI:1.193-1.815,P=3.06×10^(−4)).Cumulative effect analysis showed that the number of risk genotypes and smoking status were significantly associated with an increased risk of bladder cancer(P_(trend)=2.87×10^(−12)).We found that PRR13,being demonstrated the most significant effect on cell proliferation in bladder cancer cell lines,was more highly expressed in bladder cancer tissues than in adjacent normal tissues.Moreover,the rs2683524 T allele was correlated with shorter 3′untranslated regions of PRR13 and increased PRR13 expression levels.Collectively,our findings have provided informative apaQTL resources and insights into the regulatory mechanisms linking apaQTL-associated variants to bladder cancer risk.展开更多
Cancer progression involves the sonic hedgehog(SHH)pathway,in which the receptor PTCH1 actives the downstream pathways.Dysfunction of PTCH1 can lead to nevoid basal cell carcinoma Syndrome(NBCCs)including neoplastic d...Cancer progression involves the sonic hedgehog(SHH)pathway,in which the receptor PTCH1 actives the downstream pathways.Dysfunction of PTCH1 can lead to nevoid basal cell carcinoma Syndrome(NBCCs)including neoplastic disease and congenital disorder.To evaluate the relationship between PTCH1 and cancer,we applied the CRISPR/Cas9 system to knock out PTCH1 in oral nontumorous epithelial cells(GMSM-K).Then we screened six PTCH1 variants associated with cleft lip/palate(CL/P),one of the congenital disorders in NBCCs,and generated PTCH1 variant and wild-type recombinant PTCH1^(−/−)GMSM-K cell lines.Transcriptome sequencing was conducted in these cell lines.The results revealed that differentially expressed genes(DEGs)in PTCH1^(−/−)GMSM-K were enriched in extracellular compartments,contributing epithelial diseases by pathway enrichment analysis.RT-PCR confirmed that KRT34,KRT81,KRT86,PDGFB,and WNT10B genes,associated with extracellular compartments were highly expressed in PTCH1^(−/−).The Kyoto Encyclopedia of Genes and Genomes analysis also suggested that DEGs are closely related to focal adhesion,transcriptional misregulation,and proteoglycans in breast and gastric cancers.Comparative analysis of samples revealed that the CL/P-associated PTCH1 variants A443G and V908G are potentially carcinogenic.These findings provide new insights into the carcinogenic potential of PTCH1 dysfunction.展开更多
Molecular virology methods including polymerase chain reaction,cloning and sequencing have revolutionised our understanding of viral genome variation.In the case of hepatitis B virus(HBV),sequencing studies have ident...Molecular virology methods including polymerase chain reaction,cloning and sequencing have revolutionised our understanding of viral genome variation.In the case of hepatitis B virus(HBV),sequencing studies have identified a number of virus variants normally found during the natural course of chronic infection.The appearance of the precore stop codon(with G-for-A substitution at position 1896)and basal core promoter(BCP)(with A-for-T and G-for-A,at positions 1762 and 1764,respectively)variants which reduce or abrogate hepatitis B e antigen(HBeAg)production,heralds the initiation of the seroconversion phase from HBeAg to antiHBe positivity.The gradual removal of the tolerogenic effect of HBeAg leads to the awakening of the immune response(immune clearance phase).Most patients after HBeAg seroconversion become"inactive HBsAg carriers".However during the course of infection precore and/or BCP variants may emerge and be selected leading to HBeAg negative chronic hepatitis B(CHB)with high viremia levels(reactivation phase).The prevalence of HBeAg negative CHB has been increasing over the last few decades and has become the commonest type of HBV infection in many countries of the world.This probably reflects the aging of existing HBV carriers and the effective prevention measures restricting new HBV infections.Frequent acute exacerbations accompanied by high viral replication,elevated alanine aminotransferase levels and histological activity are a common feature of HBeAg negative CHB leading to cirrhosis much faster than in HBeAg positive CHB patients.展开更多
Gastric cancer remains the third leading cause of mortality from cancer worldwide and carries a poor prognosis,due largely to late diagnosis.The importance of the interaction between Helicobacter pylori(H.pylori)infec...Gastric cancer remains the third leading cause of mortality from cancer worldwide and carries a poor prognosis,due largely to late diagnosis.The importance of the interaction between Helicobacter pylori(H.pylori)infection,the main risk factor,and host-related genetic factors has been studied intensively in recent years.The genetic predisposition for non-hereditary gastric cancer is difficult to assess,as neither the real prevalence of premalignant gastric lesions in various populations nor the environmental risk factors for cancer progression are clearly defined.For non-cardiac intestinal-type cancer,identifying the factors that modulate the progression from inflammation toward cancer is crucial in order to develop preventive strategies.The role of cytokines and their gene variants has been questioned in regard to non-self-limiting H.pylori gastritis and its evolution to gastric atrophy and intestinal metaplasia;the literature now includes various and non-conclusive results on this topic.The influence of the majority of cytokine single nucleotide polymorphisms has been investigated for gastric cancer but not for preneoplastic gastric lesions.Among the investigated gene variants onlyIL10T-819C,IL-8-251,IL-18RAP917997,IL-22 rs1179251,IL1-B-511,IL1-B-3954,IL4R-398 and IL1RN were identified as predictors for premalignant gastric lesions risk.One of the most important limiting factors is the inhomogeneity of the studies(e.g.,the lack of data on concomitant H.pylori infection,methods used to assess preneoplastic lesions,and source population).Testing the modifying effect of H.pylori infection upon the relationship between cytokine gene variants and premalignant gastric lesions,or even testing the interaction between H.pylori and cytokine gene variants in multivariable models adjusted for potential covariates,could increase generalizability of results.展开更多
Coronary artery anomalies and variants are relatively uncommon congenital disorders of the coronary artery anatomy and constitute the second most common cause of sudden cardiac death in young competitive athletes. The...Coronary artery anomalies and variants are relatively uncommon congenital disorders of the coronary artery anatomy and constitute the second most common cause of sudden cardiac death in young competitive athletes. The rapid advancement of imaging techniques, including computed tomography, magnetic resonance imaging, intravascular ultrasound and optical coherence tomography, have provided us with a wealth of new information on the subject. Anomalous origin of a coronary artery from the contralateral sinus is the anomaly most frequently associated with sudden cardiac death, in particular if the anomalous coronary artery has a course between the aorta and the pulmonary artery. However, other coronary anomalies, like anomalous origin of the left coronary artery from the pulmonary artery, atresia of the left main stem and coronary fistulae, have also been implicated in cases of sudden cardiac death. Patients are usually asymptomatic, and in most of the cases, coronary anomalies are discovered incidentally during coronary angiography or on autopsy following sudden cardiac death. However, in some cases, symptoms like angina, syncope, heart failure and myocardial infarction may occur. The aims of this article are to present a brief overview of the diverse coronary variants and anomalies, focusing especially on anatomical features, clinical manifestations, risk of sudden cardiac death and pathophysiologic mechanism of symptoms, as well as to provide valuable information regarding diagnostic workup, follow-up, therapeutic choices and timing of surgical treatment.展开更多
Objective: To analyse the emergence of YMDD motif(tyrosine-methionine-aspartate-aspartate) variants inpatients with hepatitis B treated with lamivudine.Methods: The amino acid substitution from methio-nine or isoleuci...Objective: To analyse the emergence of YMDD motif(tyrosine-methionine-aspartate-aspartate) variants inpatients with hepatitis B treated with lamivudine.Methods: The amino acid substitution from methio-nine or isoleucine at the YMDD motif at the HBVpolymerase gene is a main mutation resistant to lami-vudine treatment. Generated from a fragment of do-main C of the polymerase gene, patients HBV DNA,which had been positive previously became positive a-gain ever since it had been negative during lamivudi-ne therapy. Variants were detected by cleavage of theproducts of the three PCRs with following enzymes:FokI, SspI, Alw441. The results of PCR-RELP wereanalysed by 8. 4% polypropylene acidemide gel elec-trophoresis. PCR-RFLP assay was compared to di-rect sequencing.Results: HBV DNA was positive again in 33 patientsand positive for one year in 2 patients. YMDD vari-ants were detected in serum 14 of 35 patients, YIDDvariants in 4, YVDD variants in 6, and YI/MDD va-riants in 1; all were in concordance with the resultsof direct sequencing. The samples of other 3 patientsshowed YI/VDD mutations, as shown by direct se-quencing. The results of PCR-RFLP assay of themixed sera of YIDD and YVDD variants were similarto those sera of YI/VDD variants.Conclusion: PCR-RFLP is suitable for rapid detec-tion of YMDD variants of viral polymerase in hepati-tis B virus patients treated with lamivudine.展开更多
The goal of this study was to identify MSX1 gene variants in multiple Chinese families with nonsyndromic oligodontia and analyse the functional influence of these variants.Whole-exome sequencing(WES)and Sanger sequenc...The goal of this study was to identify MSX1 gene variants in multiple Chinese families with nonsyndromic oligodontia and analyse the functional influence of these variants.Whole-exome sequencing(WES)and Sanger sequencing were performed to identify the causal gene variants in five families with nonsyndromic oligodontia,and a series of bioinformatics databases were used for variant confirmation and functional prediction.Phenotypic characterization of the members of these families was described,and an in vitro analysis was performed for functional evaluation.Five novel MSX1 heterozygous variants were identified:three missense variants[c.662A>C(p.Q221P),c.670C>T(p.R224C),and c.809C>T(p.S270L)],one nonsense variant[c.364G>T(p.G122*)],and one frameshift variant[c.277delG(p.A93Rfs*67)].Preliminary in vitro studies demonstrated that the subcellular localization of MSX1 was abnormal with the p.Q221P,p.R224C,p.G122*,and p.A93Rfs*67 variants compared to the wild type.Three variants(p.Q221P,p.G122*,and p.A93Rfs*67)were classified as pathogenic or likely pathogenic,while p.S270L and p.R224C were of uncertain significance in the current data.Moreover,we summarized and analysed the MSX1-related tooth agenesis positions and found that the type and variant locus were not related to the severity of tooth loss.Our results expand the variant spectrum of nonsyndromic oligodontia and provide valuable information for genetic counselling.展开更多
AIM:To investigate the association of 10 known common gene variants with susceptibility to type 2diabetes mellitus(T2D)among Omanis.METHODS:Using case-control design,a total of992 diabetic patients and 294 normoglycem...AIM:To investigate the association of 10 known common gene variants with susceptibility to type 2diabetes mellitus(T2D)among Omanis.METHODS:Using case-control design,a total of992 diabetic patients and 294 normoglycemic Omani Arabs were genotyped,by an allelic discrimination assay-by-design TaqMan method on fast real time polymerase chain reaction system,for the following gene variants:KCNJ11(rs5219),TCF7L2(rs7903146),CDKAL1(rs10946398),CDKN2A/B(rs10811661),FTO(rs9939609 and rs8050136),IGF2BP2(rs4402960),SLC30A8(rs13266634)CAPN10(rs3792267)and HHEX(rs1111875).T2D patients were recruited from the Diabetes Clinic(n=243)and inpatients(n=749)at Sultan Qaboos Univesity Hospital(SQUH),Muscat,Oman.Adult control participants(n=294)were volunteers from the community and from those visiting Family Medicine Clinic at SQU,for regular medical checkup.The difficulty in recruiting Omani participants with no family history of diabetes was the main reason behind the small number of control participants in this study.Almost all volunteers questioned had a relativewith diabetes mellitus.Inspite of the small number of normoglycemic controls in this study,this sample was sufficient for detection of genes and loci for common alleles influencing T2D with an odds ratio of≥1.3reaching at least 80%power.Data was collected from June 2010 to February 2012.RESULTS:Using binary logistic regression analysis,four gene variants showed significant association with T2D risk:KCNJ11(rs5219,P=5.8×10^(-6),OR=1.74),TCF7L2(rs7903146,P=0.001,OR=1.46),CDKAL1(rs10946398,P=0.002,OR=1.44)and CDKN2A/B(rs10811661,P=0.020,OR=1.40).The fixation index analysis of these four gene variants indicated significant genetic differentiation between diabetics and controls{[KCNJ11(rs5219),P<0.001],[TCF7L2(rs7903146),P<0.001],[CDKAL1(rs10946398),P<0.05],[CDKN2A/B(rs10811661),P<0.05]}.The highest genotype variation%between diabetics and controls was found at KCNJ11(2.07%)and TCF7L2(1.62%).This study was not able to detect an association of T2D risk with gene variants of IGF2BP2(rs4402960),SLC30A8(rs13266634),CAPN10(rs3792267)and HHEX(rs1111875).Moreover,no association was found between FTO gene variants(rs9939609 and rs8050136)and T2D risk.However,T2D risk was found to be significantly associated with obesity(P=0.002,OR=2.22);and with the Waist-to-Hip ratio(n=532,P=1.9×10^(-7),OR=2.4),[among males(n=234,P=1.2×10^(-4),OR=2.0)and females(n=298,P=0.001,OR=6.3)].CONCLUSION:Results confirmed the association of KCNJ11(rs5219),TCF7L2(rs7903146),CDKAL1(rs10946398)and CDKN2A/B(rs10811661)gene variants with susceptibility to T2D among Omani Arabs.展开更多
BACKGROUND:Pancreaticoduodenectomy is the treatment of choice for periampullary and pancreatic head tumors.In case of hepatic artery abnormalities,early pancreatic transection during pancreaticoduodenectomy may prove ...BACKGROUND:Pancreaticoduodenectomy is the treatment of choice for periampullary and pancreatic head tumors.In case of hepatic artery abnormalities,early pancreatic transection during pancreaticoduodenectomy may prove inappropriate Early retroportal lamina dissection improves exposure of the superior mesenteric vessels and anatomic variants of the hepatic artery,where safeguarding is mandatory.METHOD:We describe our early retroportal lamina approach in patients with anatomic variants of the hepatic artery before pancreatic transection.RESULTS:This approach was used during 42 pancreatico duodenectomies with a hepatic artery anatomic variant which was spared in 40 patients.Arterial reconstruction was performed in 2 patients.Five patients with a hepatic artery variant and adenocarcinoma involving the portomesenteric junction required venous resection and reconstruction.CONCLUSIONS:Early retroportal lamina dissection during pancreaticoduodenectomy in patients with hepatic artery anatomic variants enables easier exposure,avoiding injuries that might compromise the liver arterial supply.When the portomesenteric vein is involved,this approach facilitates en bloc "no touch" venous resection and reconstruction.展开更多
Current therapies for advanced prostate cancer,such as enzalutamide and abiraterone,focus on inhibiting androgen receptor(AR)activity and reducing downstream signaling pathways to inhibit tumor growth.Unfortunately,ca...Current therapies for advanced prostate cancer,such as enzalutamide and abiraterone,focus on inhibiting androgen receptor(AR)activity and reducing downstream signaling pathways to inhibit tumor growth.Unfortunately,cancer cells are very adaptable and,over time,these cells develop mechanisms by which they can circumvent therapeutics.One of the many mechanisms that have been discovered is the generation of AR variants.These variants are generated through alternative splicing of the full length AR and often lack the ligand binding domain.This leads to forms of the AR that are constitutively active that continue to promote prostate cancer cell growth even in the absence of ligand.The high prevalence of AR variants and their role in disease progression have prompted a number of studies investigating ways to inhibited AR variant expression and activity.Among these are the antihelminthic drug,niclosamide,which selectively promotes degradation of AR variants over full length AR and re-sensitizes anti-androgen resistant prostate cancer cells to treatment with enzalutamide and abiraterone.Other AR variant targeting mechanisms include interfering with AR variant co-activators and the development of drugs that bind to the DNA or N-terminal AR domains,which are retained in most AR variants.The clinical efficacy of treating prostate cancer by targeting AR variants is under investigation in several clinical trials.In this review,we provide an overview of the most relevant AR variants and discuss current AR variant targeting strategies.展开更多
基金Supported by Shenzhen Science and Technology Program,Shenzhen,China(No.JCYJ20200109145001814,No.SGDX20211123120001001)the National Natural Science Foundation of China(No.81970790)Sanming Project of Medicine in Shenzhen(No.SZSM202011015).
文摘AIM:To identify a maculopathy patient caused by new recessive compound heterozygous variants in RP1L1.METHODS:Comprehensive retinal morphological and functional examinations were evaluated for the patient with RP1L1 maculopathy.Targeted sequence capture array technique was used to screen potential pathologic variants.Polymerase chain reaction and Sanger sequencing were used to confirm the screening results.RESULTS:Fundus examination showed round macular lesions appeared in both eyes.Optical coherence tomography showed that the inner segment/outer segment continuity was disorganized and disruptive in the left eye,but it was uneven and slightly elevated in the right eye.Fundus autofluorescence showed patchy hyper-autofluorescence in the macula.Visual field examination indicates central defects in both eyes.Electroretinogram(ERG)and multifocal ERG showed no obvious abnormalities.Fundus fluorescein angiography in the macula showed obviously irregular hyper-fluorescence in the right eye and slightly hyper-fluorescence in the left eye.We found that the proband carried a missense variant(c.1972C>T)and a deletion variant(c.4717_4718del)of RP1L1,which were originated from the parents and formed compound heterozygous variants.Both variants are likely pathogenic according to the ACMG criteria.Multimodal imaging,ERG and detailed medical history are important diagnostic tools for differentiating between acquired and inherited retinal disorders.CONCLUSION:A maculopathy case with detailed retinal phenotype and new recessive compound heterozygous variants of RP1L1 is identified in a Chinese family,which expands the understanding of phenotype and genotype in RP1L1 maculopathy.
文摘BACKGROUND The Columbia classification identified five histological variants of focal segmental glomerulosclerosis(FSGS).The prognostic significance of these variants remains controversial.AIM To evaluate the relative frequency,clinicopathologic characteristics,and medium-term outcomes of FSGS variants at a single center in Pakistan.METHODS This retrospective study was conducted at the Department of Nephrology,Sindh Institute of Urology and Transplantation,Karachi,Pakistan on all consecutive adults(≥16 years)with biopsy-proven primary FSGS from January 1995 to December 2017.Studied subjects were treated with steroids as a first-line therapy.The response rates,doubling of serum creatinine,and kidney failure(KF)with replacement therapy were compared between histological variants using ANOVA or Kruskal Wallis,and Chi-square tests as appropriate.Data were analyzed by SPSS version 22.0.P-value≤0.05 was considered significant.RESULTS A total of 401 patients were diagnosed with primary FSGS during the study period.Among these,352(87.7%)had a designated histological variant.The not otherwise specified(NOS)variant was the commonest,being found in 185(53.9%)patients,followed by the tip variant in 100(29.1%)patients.Collapsing(COL),cellular(CEL),and perihilar(PHI)variants were seen in 58(16.9%),6(1.5%),and 3(0.7%)patients,respectively.CEL and PHI variants were excluded from further analysis due to small patient numbers.The mean follow-up period was 36.5±29.2 months.Regarding response rates of variants,patients with TIP lesions achieved remission more frequently(59.5%)than patients with NOS(41.8%)and COL(24.52%)variants(P<0.001).The hazard ratio of complete response among patients with the COL variant was 0.163[95%confidence interval(CI):0.039-0.67]as compared to patients with NOS.The TIP variant showed a hazard ratio of 2.5(95%CI:1.61-3.89)for complete remission compared to the NOS variant.Overall,progressive KF was observed more frequently in patients with the COL variant,43.4%(P<0.001).Among these,24.53%of patients required kidney replacement therapy(P<0.001).The hazard ratio of doubling of serum creatinine among patients with the COL variant was 14.57(95%CI:1.87-113.49)as compared to patients with the TIP variant.CONCLUSION In conclusion,histological variants of FSGS are predictive of response to treatment with immunosuppressants and progressive KF in adults in our setup.
基金supported by the project“Protection of biodiversity of Italian poultry breeds—TuBAvI”,funded in the framework of the PSRN 2014–2020,submeasure 10.2“Support for sustainable conservation,use and development of genetic resources in agriculture”.
文摘Background Copy number variants(CNV)hold significant functional and evolutionary importance.Numerous ongoing CNV studies aim to elucidate the etiology of human diseases and gain insights into the population structure of livestock.High-density chips have enabled the detection of CNV with increased resolution,leading to the identification of even small CNV.This study aimed to identify CNV in local Italian chicken breeds and investigate their distribution across the genome.Results Copy number variants were mainly distributed across the first six chromosomes and primarily associated with loss type CNV.The majority of CNV in the investigated breeds were of types 0 and 1,and the minimum length of CNV was significantly larger than that reported in previous studies.Interestingly,a high proportion of the length of chromosome 16 was covered by copy number variation regions(CNVR),with the major histocompatibility complex being the likely cause.Among the genes identified within CNVR,only those present in at least five animals across breeds(n=95)were discussed to reduce the focus on redundant CNV.Some of these genes have been associated to functional traits in chickens.Notably,several CNVR on different chromosomes harbor genes related to muscle development,tissue-specific biological processes,heat stress resistance,and immune response.Quantitative trait loci(QTL)were also analyzed to investigate potential overlapping with the identified CNVR:54 out of the 95 gene-containing regions overlapped with 428 QTL associated to body weight and size,carcass characteristics,egg production,egg components,fat deposition,and feed intake.Conclusions The genomic phenomena reported in this study that can cause changes in the distribution of CNV within the genome over time and the comparison of these differences in CNVR of the local chicken breeds could help in preserving these genetic resources.
文摘Reproduction via cis-binary mechanisms appears to have evolved fairly early in the evolution of complex organisms, and a system committed to prior to evolution of humans. While the evolution of a chromosomal-specific approach has been a successful strategy for survival of a large variety of species including humans, the fidelity of sex determination leading to 100% cis-binary outcomes is not achieved in many species, with evidence for homosexual or bisexual behaviour evident in more than 1500 species. Thus, such outcomes indicates that sex determination is a multi-step process and not a single event, and as such, could lead to the appearance of variants during the process which developed much earlier than humans. Variants could arise either due to intrinsic variation in the steps of determination, or also be influenced by environmental factors of a biological or psychological nature. In contrast to homosexual variants which do not require interventions such as hormone therapy or surgery, expression of gender dysphoria, is more based in psychology, but also has biological underpinnings and can be influenced by such hormonal interventions and surgery. While the numbers of those with gender dysphoria is small (~0.6% - 1.0% of population), the attention given to this issue raises the possibility of biological and psychological environmental factors impacting the emergence of some of those expressing gender dysphoria. Furthermore, transitioning from male-to-female or female-to-male can have consequences regarding disease risks latter in life, including the appearance of autoimmune diseases. This review will attempt to review some of the evidence regarding sex determination, discuss why the system has potentially not been improved upon during evolution, how a potential role for sex chromosome function on neurodevelopment may be central to variation in humans, and how commitment to the current strategy is likely integrated into other sex-related events such as puberty, pregnancy, and menopause to ensure species survival. It will also discuss how variants in sex determination could contribute to sex differences in disease risk and how epigenetic modifications could play a role in such risk. .
基金supported by National Natural Science Foundation of China(31801397)Fund for Distinguished Young Scholars of Henan Academy of Agricultural Sciences(2020JQ03)+3 种基金Independent Innovation Foundation of Henan Academy of Agricultural Sciences,China(2022ZC69)China Agriculture Research System(CARS-13)Key Scientific and Technological Project of Henan Province(201300111000)Henan Provincial Agriculture Research System(S2012-5)。
文摘Oligo probe staining is a low-cost and efficient chromosome identification technique.In this study,oligo genomic in situ hybridization(Oligo-GISH)technology was established in peanut.Peanut A and B subgenome-specific interspersed repeat(IR)oligo probe sets were developed based on clustering and electronic localization of tandem repeat sequences in the reference genome of Tifrunner.The OligoGISH kit was then used to perform staining of 15 Arachis species.The A-subgenome probe set stained the chromosomes of A-and E-genome Arachis species,the B-subgenome probe set stained those of B-,F-,K-,and E-genome species,and neither set stained those of H-genome species.These results indicate the relationships among the genomes of these Arachis species.The Oligo-GISH kit was also used for batch staining of the chromosomes of 389 seedlings from the irradiated M1generation,allowing 67 translocation and deletion lines to be identified.Subsequent Oligo-FISH karyotyping,FISH using single-copy probe libraries,and trait investigation identified seven homozygous chromosomal variants from the M3generation and suggested that there may be genes on chromosome 4B controlling seed number per pod.These findings demonstrate that the IR probe sets and method developed in this study can facilitate research on distant hybridization and genetic improvement in peanut.
基金Superior Farms sheep producersIBEST for their supportfinancial support from the Idaho Global Entrepreneurial Mission
文摘Background Pan-genomics is a recently emerging strategy that can be utilized to provide a more comprehensive characterization of genetic variation.Joint calling is routinely used to combine identified variants across multiple related samples.However,the improvement of variants identification using the mutual support information from mul-tiple samples remains quite limited for population-scale genotyping.Results In this study,we developed a computational framework for joint calling genetic variants from 5,061 sheep by incorporating the sequencing error and optimizing mutual support information from multiple samples’data.The variants were accurately identified from multiple samples by using four steps:(1)Probabilities of variants from two widely used algorithms,GATK and Freebayes,were calculated by Poisson model incorporating base sequencing error potential;(2)The variants with high mapping quality or consistently identified from at least two samples by GATK and Freebayes were used to construct the raw high-confidence identification(rHID)variants database;(3)The high confidence variants identified in single sample were ordered by probability value and controlled by false discovery rate(FDR)using rHID database;(4)To avoid the elimination of potentially true variants from rHID database,the vari-ants that failed FDR were reexamined to rescued potential true variants and ensured high accurate identification variants.The results indicated that the percent of concordant SNPs and Indels from Freebayes and GATK after our new method were significantly improved 12%-32%compared with raw variants and advantageously found low frequency variants of individual sheep involved several traits including nipples number(GPC5),scrapie pathology(PAPSS2),sea-sonal reproduction and litter size(GRM1),coat color(RAB27A),and lentivirus susceptibility(TMEM154).Conclusion The new method used the computational strategy to reduce the number of false positives,and simulta-neously improve the identification of genetic variants.This strategy did not incur any extra cost by using any addi-tional samples or sequencing data information and advantageously identified rare variants which can be important for practical applications of animal breeding.
基金This study involving human participants was reviewed and approved by the ethics committee of TEDA International Cardiovascular Hospital,China(No.0715-4,2021,02 August 2021)the National Natural Science Foundation of China[82170353&81870288]+4 种基金the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences[2020-PT310-007]Tianjin Municipal and Binhai New Area Health Commissions[KJ20071&2019BWKY010]Tianjin Science and Technology Project[18PTZWHZ00060]TEDA International Cardiovascular Hospital[2021-TD-006&2021-ZX-002&2019-TD-013]Tianjin Key Medical Discipline(Specialty)Construction Project[TJYXZDXK-019A].
文摘Background:Atrial septal defect(ASD)is one of the common congenital heart diseases.The MYH6 gene has a critical role in cardiac development but the role of MYH6 promoter variants in patients with ASD has not been explored.Methods:In 613 subjects including 320 ASD patients,we investigated the MYH6 gene promoter variants and verified the effect on gene expression by using cellular functional experiments and bioinformatics analysis.Results:Eleven variants were identified in the MYH6 gene promoter,of which four variants were found only in ASD patients,and two variants(g.3434G>C and g.4524C>T)were identified for the first time.Cellular functional experiments indicated that all four variants reduced the transcriptional activity of the MYH6 gene promoter(p<0.05).Subsequent analysis through the JASPAR(A database of transcription factor binding profiles)suggests that these variants may alter transcription factor binding sites,which may in turn lead to changes in myocardin subunit expression and ASD formation.Conclusions:Our study for the first time focuses on variants in the promoter region of the MYH6 gene in Chinese patients with ASD and the discovered variants have functional significance.The study provides new insights in the role of the MYH6 gene promoter region to better understand the genetic basis of ASD formation and facilitates clinical diagnosis.
文摘Objective:To surveill emerging variants by nanopore technology-based genome sequencing in different COVID-19 waves in Sri Lanka and to examine the association with the sample characteristics,and vaccination status.Methods:The study analyzed 207 RNA positive swab samples received to sequence laboratory during different waves.The N gene cut-off threshold of less than 30 was considered as the major inclusion criteria.Viral RNA was extracted,and elutes were subjected to nanopore sequencing.All the sequencing data were uploaded in the publicly accessible database,GISAID.Results:The Omicron,Delta and Alpha variants accounted for 58%,22%and 4%of the variants throughout the period.Less than 1%were Kappa variant and 16%of the study samples remained unassigned.Omicron variant was circulated among all age groups and in all the provinces.Ct value and variants assigned percentage was 100%in Ct values of 10-15 while only 45%assigned Ct value over 25.Conclusions:The present study examined the emergence,prevalence,and distribution of SARS-CoV-2 variants locally and has shown that nanopore technology-based genome sequencing enables whole genome sequencing in a low resource setting country.
文摘The anterior system of the polygon of Willis plays an anastomotic role between the carotid territories and communicates with the posterior system. It ensures adequate cerebral blood flow in the event of internal occlusion. Its ability to redistribute blood flow depends on its morphology, the presence and size of the vessels that constitute it and their variants, knowledge of which is essential. The morphology of the carotid system is not constant and a number of variants are well recognized with greater hemodynamic importance. In this context, we undertook this work which aims to seek the anatomical variants of the anterior part of the PW;to determine the diameters of the vessels of the latter and to correlate these results with epidemiological data. We carried out a retrospective, descriptive and analytical study over a period of 4 months at Fann University Hospital, targeting patients who had undergone brain MRI with a 3D TOF sequence whatever the indication. Patients with lesions of cerebrovascular pathologies such as ischemia, hemorrhage, aneurysm, arteriovenous malformations or presenting a limited analysis examination due to the presence of kinetic or other artifact, were not included. Demographic data and anatomical variants were studied as well as the measurements of any continuous arterial segment greater than 0.8 mm in diameter. Those less than 0.8 mm in diameter were considered hypoplastic. The C3 segment of the internal carotid arteries, the A1 segment of the anterior cerebral arteries, the anterior communicating artery, constituted our main measurement sites. The sex ratio was 1.06, the mean age of the patients was 43 years ± 17.9 with extremes of 11 and 85 years. The anterior configuration of the polygon was complete in 57.5% representing 50% of men and 65.5% of women, in 56% of subjects under 40 years old and 58% in subjects over 40 years old. We noted a predominance of type a in 47% of patients followed by type g found in 35% of patients. The morphology of the anterior system of the Willis polygon is a function of its variants, some of which have greater hemodynamic importance than others. Its knowledge is essential for the management of cerebrovascular diseases.
文摘BACKGROUND The Omicron variant of severe acute respiratory syndrome coronavirus 2(SARSCoV-2)mainly infects the upper respiratory tract.This study aimed to determine whether the probability of pulmonary infection and the cycle threshold(Ct)measured using the fluorescent polymerase chain reaction(PCR)method were related to pulmonary infections diagnosed via computed tomography(CT).AIM To analyze the chest CT signs of SARS-CoV-2 Omicron variant infections with different Ct values,as determined via PCR.METHODS The chest CT images and PCR Ct values of 331 patients with SARS-CoV-2Omicron variant infections were retrospectively collected and categorized into low(<25),medium(25.00-34.99),and high(≥35)Ct groups.The characteristics of chest CT images in each group were statistically analyzed.RESULTS The PCR Ct values ranged from 13.36 to 39.81,with 99 patients in the low,155 in the medium,and 77 in the high Ct groups.Six abnormal chest CT signs were detected,namely,focal infection,patchy consolidation shadows,patchy groundglass shadows,mixed consolidation ground-glass shadows,subpleural interstitial changes,and pleural changes.Focal infections were less frequent in the low Ct group than in the medium and high Ct groups;these infections were the most common sign in the medium and high Ct groups.Patchy consolidation shadows and pleural changes were more frequent in the low Ct group than in the other two groups.The number of patients with two or more signs was greater in the low Ct group than in the medium and high Ct groups.CONCLUSION The chest CT signs of patients with pulmonary infection caused by the Omicron variants of SARSCoV-2 varied depending on the Ct values.Identification of the characteristics of Omicron variant infection can help subsequent planning of clinical treatment.
基金The current study was supported by the National Natural Science Foundation of China(Grant Nos.82130096 and 82373537)Collaborative Innovation Center for Cancer Personalized Medicine and Priority Academic Program Development of Jiangsu Higher Education Institutions(Public Health and Preventive Medicine).
文摘Aberrant alternative polyadenylation(APA)events play an important role in cancers,but little is known about whether APA-related genetic variants contribute to the susceptibility to bladder cancer.Previous genome-wide association study performed APA quantitative trait loci(apaQTL)analyses in bladder cancer,and identified 17955 single nucleotide polymorphisms(SNPs).We found that gene symbols of APA affected by apaQTL-associated SNPs were closely correlated with cancer signaling pathways,high mutational burden,and immune infiltration.Association analysis showed that apaQTL-associated SNPs rs34402449 C>A,rs2683524 C>T,and rs11540872 C>G were significantly associated with susceptibility to bladder cancer(rs34402449:OR=1.355,95%confidence interval[CI]:1.159-1.583,P=1.33×10^(−4);rs2683524:OR=1.378,95%CI:1.164-1.632,P=2.03×10^(−4);rs11540872:OR=1.472,95%CI:1.193-1.815,P=3.06×10^(−4)).Cumulative effect analysis showed that the number of risk genotypes and smoking status were significantly associated with an increased risk of bladder cancer(P_(trend)=2.87×10^(−12)).We found that PRR13,being demonstrated the most significant effect on cell proliferation in bladder cancer cell lines,was more highly expressed in bladder cancer tissues than in adjacent normal tissues.Moreover,the rs2683524 T allele was correlated with shorter 3′untranslated regions of PRR13 and increased PRR13 expression levels.Collectively,our findings have provided informative apaQTL resources and insights into the regulatory mechanisms linking apaQTL-associated variants to bladder cancer risk.
基金This work was supported by the Natural Science Foundation of China(Nos.81870747,82170916)Clinical Medicine Plus X–Young Scholars Project(PKU2021LCXQ003)the Fundamental Research Funds for the Central Universities(BMU2021YJ001).
文摘Cancer progression involves the sonic hedgehog(SHH)pathway,in which the receptor PTCH1 actives the downstream pathways.Dysfunction of PTCH1 can lead to nevoid basal cell carcinoma Syndrome(NBCCs)including neoplastic disease and congenital disorder.To evaluate the relationship between PTCH1 and cancer,we applied the CRISPR/Cas9 system to knock out PTCH1 in oral nontumorous epithelial cells(GMSM-K).Then we screened six PTCH1 variants associated with cleft lip/palate(CL/P),one of the congenital disorders in NBCCs,and generated PTCH1 variant and wild-type recombinant PTCH1^(−/−)GMSM-K cell lines.Transcriptome sequencing was conducted in these cell lines.The results revealed that differentially expressed genes(DEGs)in PTCH1^(−/−)GMSM-K were enriched in extracellular compartments,contributing epithelial diseases by pathway enrichment analysis.RT-PCR confirmed that KRT34,KRT81,KRT86,PDGFB,and WNT10B genes,associated with extracellular compartments were highly expressed in PTCH1^(−/−).The Kyoto Encyclopedia of Genes and Genomes analysis also suggested that DEGs are closely related to focal adhesion,transcriptional misregulation,and proteoglycans in breast and gastric cancers.Comparative analysis of samples revealed that the CL/P-associated PTCH1 variants A443G and V908G are potentially carcinogenic.These findings provide new insights into the carcinogenic potential of PTCH1 dysfunction.
文摘Molecular virology methods including polymerase chain reaction,cloning and sequencing have revolutionised our understanding of viral genome variation.In the case of hepatitis B virus(HBV),sequencing studies have identified a number of virus variants normally found during the natural course of chronic infection.The appearance of the precore stop codon(with G-for-A substitution at position 1896)and basal core promoter(BCP)(with A-for-T and G-for-A,at positions 1762 and 1764,respectively)variants which reduce or abrogate hepatitis B e antigen(HBeAg)production,heralds the initiation of the seroconversion phase from HBeAg to antiHBe positivity.The gradual removal of the tolerogenic effect of HBeAg leads to the awakening of the immune response(immune clearance phase).Most patients after HBeAg seroconversion become"inactive HBsAg carriers".However during the course of infection precore and/or BCP variants may emerge and be selected leading to HBeAg negative chronic hepatitis B(CHB)with high viremia levels(reactivation phase).The prevalence of HBeAg negative CHB has been increasing over the last few decades and has become the commonest type of HBV infection in many countries of the world.This probably reflects the aging of existing HBV carriers and the effective prevention measures restricting new HBV infections.Frequent acute exacerbations accompanied by high viral replication,elevated alanine aminotransferase levels and histological activity are a common feature of HBeAg negative CHB leading to cirrhosis much faster than in HBeAg positive CHB patients.
基金Supported by an Internal Research Grant from the University of Medicine,Pharmacy,Sciences and Technology of Targu Mure,No.615/12/17.01.2019
文摘Gastric cancer remains the third leading cause of mortality from cancer worldwide and carries a poor prognosis,due largely to late diagnosis.The importance of the interaction between Helicobacter pylori(H.pylori)infection,the main risk factor,and host-related genetic factors has been studied intensively in recent years.The genetic predisposition for non-hereditary gastric cancer is difficult to assess,as neither the real prevalence of premalignant gastric lesions in various populations nor the environmental risk factors for cancer progression are clearly defined.For non-cardiac intestinal-type cancer,identifying the factors that modulate the progression from inflammation toward cancer is crucial in order to develop preventive strategies.The role of cytokines and their gene variants has been questioned in regard to non-self-limiting H.pylori gastritis and its evolution to gastric atrophy and intestinal metaplasia;the literature now includes various and non-conclusive results on this topic.The influence of the majority of cytokine single nucleotide polymorphisms has been investigated for gastric cancer but not for preneoplastic gastric lesions.Among the investigated gene variants onlyIL10T-819C,IL-8-251,IL-18RAP917997,IL-22 rs1179251,IL1-B-511,IL1-B-3954,IL4R-398 and IL1RN were identified as predictors for premalignant gastric lesions risk.One of the most important limiting factors is the inhomogeneity of the studies(e.g.,the lack of data on concomitant H.pylori infection,methods used to assess preneoplastic lesions,and source population).Testing the modifying effect of H.pylori infection upon the relationship between cytokine gene variants and premalignant gastric lesions,or even testing the interaction between H.pylori and cytokine gene variants in multivariable models adjusted for potential covariates,could increase generalizability of results.
文摘Coronary artery anomalies and variants are relatively uncommon congenital disorders of the coronary artery anatomy and constitute the second most common cause of sudden cardiac death in young competitive athletes. The rapid advancement of imaging techniques, including computed tomography, magnetic resonance imaging, intravascular ultrasound and optical coherence tomography, have provided us with a wealth of new information on the subject. Anomalous origin of a coronary artery from the contralateral sinus is the anomaly most frequently associated with sudden cardiac death, in particular if the anomalous coronary artery has a course between the aorta and the pulmonary artery. However, other coronary anomalies, like anomalous origin of the left coronary artery from the pulmonary artery, atresia of the left main stem and coronary fistulae, have also been implicated in cases of sudden cardiac death. Patients are usually asymptomatic, and in most of the cases, coronary anomalies are discovered incidentally during coronary angiography or on autopsy following sudden cardiac death. However, in some cases, symptoms like angina, syncope, heart failure and myocardial infarction may occur. The aims of this article are to present a brief overview of the diverse coronary variants and anomalies, focusing especially on anatomical features, clinical manifestations, risk of sudden cardiac death and pathophysiologic mechanism of symptoms, as well as to provide valuable information regarding diagnostic workup, follow-up, therapeutic choices and timing of surgical treatment.
文摘Objective: To analyse the emergence of YMDD motif(tyrosine-methionine-aspartate-aspartate) variants inpatients with hepatitis B treated with lamivudine.Methods: The amino acid substitution from methio-nine or isoleucine at the YMDD motif at the HBVpolymerase gene is a main mutation resistant to lami-vudine treatment. Generated from a fragment of do-main C of the polymerase gene, patients HBV DNA,which had been positive previously became positive a-gain ever since it had been negative during lamivudi-ne therapy. Variants were detected by cleavage of theproducts of the three PCRs with following enzymes:FokI, SspI, Alw441. The results of PCR-RELP wereanalysed by 8. 4% polypropylene acidemide gel elec-trophoresis. PCR-RFLP assay was compared to di-rect sequencing.Results: HBV DNA was positive again in 33 patientsand positive for one year in 2 patients. YMDD vari-ants were detected in serum 14 of 35 patients, YIDDvariants in 4, YVDD variants in 6, and YI/MDD va-riants in 1; all were in concordance with the resultsof direct sequencing. The samples of other 3 patientsshowed YI/VDD mutations, as shown by direct se-quencing. The results of PCR-RFLP assay of themixed sera of YIDD and YVDD variants were similarto those sera of YI/VDD variants.Conclusion: PCR-RFLP is suitable for rapid detec-tion of YMDD variants of viral polymerase in hepati-tis B virus patients treated with lamivudine.
基金supported by the National Natural Science Foundation of China(81970902,81771054,and 81600846).
文摘The goal of this study was to identify MSX1 gene variants in multiple Chinese families with nonsyndromic oligodontia and analyse the functional influence of these variants.Whole-exome sequencing(WES)and Sanger sequencing were performed to identify the causal gene variants in five families with nonsyndromic oligodontia,and a series of bioinformatics databases were used for variant confirmation and functional prediction.Phenotypic characterization of the members of these families was described,and an in vitro analysis was performed for functional evaluation.Five novel MSX1 heterozygous variants were identified:three missense variants[c.662A>C(p.Q221P),c.670C>T(p.R224C),and c.809C>T(p.S270L)],one nonsense variant[c.364G>T(p.G122*)],and one frameshift variant[c.277delG(p.A93Rfs*67)].Preliminary in vitro studies demonstrated that the subcellular localization of MSX1 was abnormal with the p.Q221P,p.R224C,p.G122*,and p.A93Rfs*67 variants compared to the wild type.Three variants(p.Q221P,p.G122*,and p.A93Rfs*67)were classified as pathogenic or likely pathogenic,while p.S270L and p.R224C were of uncertain significance in the current data.Moreover,we summarized and analysed the MSX1-related tooth agenesis positions and found that the type and variant locus were not related to the severity of tooth loss.Our results expand the variant spectrum of nonsyndromic oligodontia and provide valuable information for genetic counselling.
基金Supported by The Research Council(TRC),Muscat,Oman,No.RC/MED/BIOC/10/01
文摘AIM:To investigate the association of 10 known common gene variants with susceptibility to type 2diabetes mellitus(T2D)among Omanis.METHODS:Using case-control design,a total of992 diabetic patients and 294 normoglycemic Omani Arabs were genotyped,by an allelic discrimination assay-by-design TaqMan method on fast real time polymerase chain reaction system,for the following gene variants:KCNJ11(rs5219),TCF7L2(rs7903146),CDKAL1(rs10946398),CDKN2A/B(rs10811661),FTO(rs9939609 and rs8050136),IGF2BP2(rs4402960),SLC30A8(rs13266634)CAPN10(rs3792267)and HHEX(rs1111875).T2D patients were recruited from the Diabetes Clinic(n=243)and inpatients(n=749)at Sultan Qaboos Univesity Hospital(SQUH),Muscat,Oman.Adult control participants(n=294)were volunteers from the community and from those visiting Family Medicine Clinic at SQU,for regular medical checkup.The difficulty in recruiting Omani participants with no family history of diabetes was the main reason behind the small number of control participants in this study.Almost all volunteers questioned had a relativewith diabetes mellitus.Inspite of the small number of normoglycemic controls in this study,this sample was sufficient for detection of genes and loci for common alleles influencing T2D with an odds ratio of≥1.3reaching at least 80%power.Data was collected from June 2010 to February 2012.RESULTS:Using binary logistic regression analysis,four gene variants showed significant association with T2D risk:KCNJ11(rs5219,P=5.8×10^(-6),OR=1.74),TCF7L2(rs7903146,P=0.001,OR=1.46),CDKAL1(rs10946398,P=0.002,OR=1.44)and CDKN2A/B(rs10811661,P=0.020,OR=1.40).The fixation index analysis of these four gene variants indicated significant genetic differentiation between diabetics and controls{[KCNJ11(rs5219),P<0.001],[TCF7L2(rs7903146),P<0.001],[CDKAL1(rs10946398),P<0.05],[CDKN2A/B(rs10811661),P<0.05]}.The highest genotype variation%between diabetics and controls was found at KCNJ11(2.07%)and TCF7L2(1.62%).This study was not able to detect an association of T2D risk with gene variants of IGF2BP2(rs4402960),SLC30A8(rs13266634),CAPN10(rs3792267)and HHEX(rs1111875).Moreover,no association was found between FTO gene variants(rs9939609 and rs8050136)and T2D risk.However,T2D risk was found to be significantly associated with obesity(P=0.002,OR=2.22);and with the Waist-to-Hip ratio(n=532,P=1.9×10^(-7),OR=2.4),[among males(n=234,P=1.2×10^(-4),OR=2.0)and females(n=298,P=0.001,OR=6.3)].CONCLUSION:Results confirmed the association of KCNJ11(rs5219),TCF7L2(rs7903146),CDKAL1(rs10946398)and CDKN2A/B(rs10811661)gene variants with susceptibility to T2D among Omani Arabs.
文摘BACKGROUND:Pancreaticoduodenectomy is the treatment of choice for periampullary and pancreatic head tumors.In case of hepatic artery abnormalities,early pancreatic transection during pancreaticoduodenectomy may prove inappropriate Early retroportal lamina dissection improves exposure of the superior mesenteric vessels and anatomic variants of the hepatic artery,where safeguarding is mandatory.METHOD:We describe our early retroportal lamina approach in patients with anatomic variants of the hepatic artery before pancreatic transection.RESULTS:This approach was used during 42 pancreatico duodenectomies with a hepatic artery anatomic variant which was spared in 40 patients.Arterial reconstruction was performed in 2 patients.Five patients with a hepatic artery variant and adenocarcinoma involving the portomesenteric junction required venous resection and reconstruction.CONCLUSIONS:Early retroportal lamina dissection during pancreaticoduodenectomy in patients with hepatic artery anatomic variants enables easier exposure,avoiding injuries that might compromise the liver arterial supply.When the portomesenteric vein is involved,this approach facilitates en bloc "no touch" venous resection and reconstruction.
基金This work was supported in part by grants NIH/NCI,CA168601,CA179970,DOD PC150229the U.S.Department of Veterans Affairs,Office of Research&Development BL&D grant number I01BX0002653(A.C.G),a Research Career Scientist Award(A.C.G).
文摘Current therapies for advanced prostate cancer,such as enzalutamide and abiraterone,focus on inhibiting androgen receptor(AR)activity and reducing downstream signaling pathways to inhibit tumor growth.Unfortunately,cancer cells are very adaptable and,over time,these cells develop mechanisms by which they can circumvent therapeutics.One of the many mechanisms that have been discovered is the generation of AR variants.These variants are generated through alternative splicing of the full length AR and often lack the ligand binding domain.This leads to forms of the AR that are constitutively active that continue to promote prostate cancer cell growth even in the absence of ligand.The high prevalence of AR variants and their role in disease progression have prompted a number of studies investigating ways to inhibited AR variant expression and activity.Among these are the antihelminthic drug,niclosamide,which selectively promotes degradation of AR variants over full length AR and re-sensitizes anti-androgen resistant prostate cancer cells to treatment with enzalutamide and abiraterone.Other AR variant targeting mechanisms include interfering with AR variant co-activators and the development of drugs that bind to the DNA or N-terminal AR domains,which are retained in most AR variants.The clinical efficacy of treating prostate cancer by targeting AR variants is under investigation in several clinical trials.In this review,we provide an overview of the most relevant AR variants and discuss current AR variant targeting strategies.
