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| 2. |
- Gustafsson Asting, Annika, et al.
(författare)
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Genetic Copy Number Variations in Colon Mucosa Indicating Risk for Colorectal Cancer.
- 2014
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Ingår i: Journal of Cancer Therapy. - : Scientific Research Publishing, Inc.. - 2151-1934 .- 2151-1942. ; 5:14
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sporadic colorectal tumors probably carry genetic alterations that may be related to familiar clusters according to risk loci visualized by SNP arrays on normal tissues. The aim of the present study was therefore to search for DNA regions (copy number variations, CNVs) as biomarkers associated to genetic susceptibility for early risk predictions of colorectal cancer. Such sequence alterations could provide additional information on phenotypic grouping of patients. Material and Methods: High resolution 105K oligonucleotide microarrays were used in search for CNV loci in DNA from tumor-free colon mucosa at primary operations for colon cancer in 60 unselected patients in comparison to DNA in buffy coat cells from 44 confirmed tumor-free and healthy blood donors. Array-detected CNVs were confirmed by Multiplex ligation-dependent probe amplification (MLPA). Results: A total number of 205 potential CNVs were present in DNA from colon mucosa. 184 (90%) of the 205 potential CNVs had been identified earlier in mucosa DNA from healthy individuals as reported to the Database of Genomic Variants. Remaining 21 (10%) CNVs were potentially novel sites. Two CNVs (3q23 and 10q21.1) were significantly related to colon cancer, but not confirmed in buffy coat DNA from the cancer patients. Conclusion: Our study reveals two CNVs that indicate increased risk for colon cancer; these DNA alterations may have been acquired by colon stem cells with subsequent appearance among epithelial mucosa cells. Impact: Certain mucosa CNV alterations may indicate individual susceptibility for malignant transformation in relationship to intestinal toxins and bacterial growth.
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| 3. |
- Norberg, Peter, 1974, et al.
(författare)
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Phylogenetic analysis of clinical herpes simplex virus type 1 isolates identified three genetic groups and recombinant viruses.
- 2004
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Ingår i: Journal of virology. - 0022-538X. ; 78:19, s. 10755-64
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Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex virus type 1 (HSV-1) is a ubiquitous human pathogen which establishes lifelong infections. In the present study, we determined the sequence diversity of the complete genes coding for glycoproteins G (gG), I (gI), and E (gE), comprising 2.3% of the HSV-1 genome and located within the unique short (US) region, for 28 clinical HSV-1 isolates inducing oral lesions, genital lesions, or encephalitis. Laboratory strains F and KOS321 were sequenced in parallel. Phylogenetic analysis, including analysis of laboratory strain 17 (GenBank), revealed that the sequences were separated into three genetic groups. The identification of different genogroups facilitated the detection of recombinant viruses by using specific nucleotide substitutions as recombination markers. Seven of the isolates and strain 17 displayed sequences consistent with intergenic recombination, and at least four isolates were intragenic recombinants. The observed frequency of recombination based on an analysis of a short stretch of the US region suggests that most full-length HSV-1 genomes consist of a mosaic of segments from different genetic groups. Polymorphic tandem repeat regions, consisting of two to eight blocks of 21 nucleotides in the gI gene and seven to eight repeats of 3 nucleotides in the gG gene, were also detected. Laboratory strain KOS321 displayed a frameshift mutation in the gI gene with a subsequent alteration of the deduced intracellular portion of the protein. The presence of polymorphic tandem repeat regions and the different genogroup identities can be used for molecular epidemiology studies and for further detection of recombination in the HSV-1 genome.
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| 4. |
- Rekabdar, Elham, 1971, et al.
(författare)
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Dichotomy of glycoprotein g gene in herpes simplex virus type 1 isolates.
- 2002
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Ingår i: Journal of clinical microbiology. - 0095-1137. ; 40:9, s. 3245-51
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Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex virus type 1 (HSV-1) encodes 11 envelope glycoproteins, of which glycoprotein G-1 (gG-1) induces a type-specific antibody response. Variability of the gG-1 gene among wild-type strains may be a factor of importance for a reliable serodiagnosis and typing of HSV-1 isolates. Here, we used a gG-1 type-specific monoclonal antibody (MAb) to screen for mutations in the immunodominant region of this protein in 108 clinical HSV-1 isolates. Of these, 42 isolates showed no reactivity to the anti-gG-1 MAb. One hundred five strains were further examined by DNA sequencing of the middle part of the gG-1 gene, encompassing 106 amino acids including the immunodominant region and epitope of the anti-gG-1 MAb. By phylogenetic comparisons based on the sequence data, we observed two (main) genetic variants of the gG-1 gene among the clinical isolates corresponding to reactivity or nonreactivity to the anti-gG-1 MAb. Furthermore, four strains appeared to be recombinants of the two gG-1 variants. In addition, one strain displayed a gG-1-negative phenotype due to a frameshift mutation, in the form of insertion of a cytosine nucleotide. When immunoglobulin G reactivity to HSV-1 in sera from patients infected with either of the two variants was investigated, no significant differences were found between the two groups, either in a type-common enzyme-linked immunosorbent assay (ELISA) or in a type-specific gG-1 antigen-based ELISA. Despite the here-documented existence of two variants of the gG-1 gene affecting the immunodominant region of the protein, other circumstances, such as early phase of infection, might be sought for explaining the seronegativity to gG-1 commonly found in a proportion of the HSV-1-infected patients.
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| 5. |
- Rekabdar, Elham, 1971
(författare)
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Genetic variants of herpes simplex virus type 1
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Herpes simplex virus type 1 (HSV-1) virus causes oral as well as genital lesions, and, on rare occasions, focal encephalitis and severe neonatal infections. Due to the partly overlapping clinical manifestations of infection with HSV-1 and its closest relative among herpesviruses, HSV-2, diagnostic methods are required to discriminate between infections with these two viruses. To improve our understanding of the genetic basis for such diagnostic procedures, we have employed DNA sequencing to investigate the genetic variability of HSV-1 viruses derived from clinical isolates.The viral envelope glycoprotein G (gG-1) has been suggested as a prototype antigen for HSV-1-specific serodiagnosis, but the interstrain variability of this gene has not been investigated. In a large material of clinical HSV-1 isolates, we found a high degree of sequence variation, especially in the middle part of the gene encoding immunodominant antibody epitopes. By phylogenetic analysis, two main groups of this gene were discovered among the clinical isolates, one represented by laboratory strains Syn 17+ and F being reactive with an anti-gG-1 monoclonal antibody (MAb), and the other variant being unreactive to the same MAb and showing sequence similarity to strain KOS. Five isolates appeared to be recombinants of these two gG-1 variants. Furthermore, one isolate displayed a gG-1-negative phenotype due to a frameshift mutation in the form of an insertion of one cytosine nucleotide. The existence of two main genetic groups of gG-1 did not markedly affect the antibody response to this protein when IgG titers in hosts carrying either of the two variant viruses were compared in a gG-1-based ELISA.To investigate whether a genetic diversity in form of dichotomy into two genogroups also existed in other HSV-1 envelope genes, we sequenced parts or complete genes coding for gB, gI, and gE in a large proportion of the clinical isolates. Surprisingly, the gE/gI genes exhibited sequence diversity that clustered into three main groups as supported by high bootstrap values. Intra- and intergenic recombinants were demonstrated in the gE/gI gene complex. In contrast, phylogenetic analysis did not separate the gB sequences into main genogroups, although a relatively large sequence variability was documented. Our approach of sequencing selected genes or fragments thereof provided insight as regards evolution of investigated genes, while phylogeny of whole-virus genomes remains to be elucidated. Despite that only short regions of the genome were sequenced, the frequent finding of recombinants among our isolates indicate that, besides point and indel mutations, recombination stands out as a major source of HSV genetic variability.Lastly, we investigated the degree of heterogeneity within individual HSV-1 and HSV-2 isolates. The frequencies of negative phenotypes of genes encoding for gG-1, gG-2 and gC-1 were estimated by antibody-staining of viral plaques. DNA-sequencing defined the responsible genetic mechanisms either as frameshift mutations due to insertion or deletion of nt G or C in homopolymer runs, or point mutations within MAb epitopes. Finally, exploiting our previous finding of a dichotomy of the gG-1 gene, we developed a KOS-genovariant-specific PCR. In a large proportion of clinical isolates showing a Syn 17+-like sequence, KOS-like sequences were detected as minority populations. Our results demonstrate a hitherto unknown degree of inter- and intrastrain genetic diversity among HSV strains.
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| 6. |
- Rekabdar, Elham, 1971, et al.
(författare)
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Variability of the glycoprotein G gene in clinical isolates of herpes simplex virus type 1.
- 1999
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Ingår i: Clinical and diagnostic laboratory immunology. - 1071-412X. ; 6:6, s. 826-31
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Tidskriftsartikel (refereegranskat)abstract
- Glycoprotein G (gG) of herpes simplex virus type 1 (HSV-1) has been used as a prototype antigen for HSV-1 type-specific serodiagnosis, but data on the sequence variability of the gene coding for this protein in wild-type strains are lacking. In this study, direct DNA sequencing of the gG-1 genes from PCR products was performed with clinical HSV-1 isolates from 11 subjects as well as with strains Syn 17(+), F, and KOS 321. The reference strains Syn 17(+) and F showed a high degree of conservation, while KOS 321 carried 13 missense mutations and, in addition, 12 silent mutations. Three clinical isolates showed mutations leading to amino acid alterations: one had a mutation of K(122) to N, which is a gG-1-to-gG-2 alteration; another contained all mutations which were observed in KOS 321 except two silent mutations; and the third isolate carried five missense mutations. Two clinical isolates as well as strain KOS 321 showed a mutation (F(111)-->V) within the epitope of a gG-1-reactive monoclonal antibody (MAb). When all viruses were tested for reactivity with the anti-gG-1 MAb, the three strains with the F(111)-->V mutation were found to be unreactive. Furthermore, gG-1 antibodies purified from sera from the two patients carrying strains mutated in this epitope were less reactive when they were tested by an HSV-1-infected-cell assay. Therefore, our finding that the sequence variability of the gG-1 gene also affects B-cell epitope regions of this protein in clinical isolates may have consequences for the use of this protein as a type-specific antigen for serodiagnosis.
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| 7. |
- Sandstedt, Joakim, et al.
(författare)
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Markedly reduced myocardial expression of γ-protocadherins and long non-coding RNAs in patients with heart disease.
- 2021
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Ingår i: International journal of cardiology. - : Elsevier BV. - 1874-1754 .- 0167-5273. ; 344, s. 149-159
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Tidskriftsartikel (refereegranskat)abstract
- Adverse cardiac remodeling and tissue damage following heart disease is strongly associated with chronic low grade inflammation. The mechanisms underlying persisting inflammatory signals are not fully understood, but may involve defective and/or non-responsive transcriptional and post-transcriptional regulatory mechanisms. In the current study, we aimed to identify novel mediators and pathways involved in processes associated with inflammation in the development and maintenance of cardiac disease.We performed RNA sequencing analysis of cardiac tissue from patients undergoing coronary artery bypass grafting (CABG) or aortic valve replacement (AVR) and compared with control tissue from multi-organ donors. Our results confirmed previous findings of a marked upregulated inflammatory state, but more importantly, we found pronounced reduction of non-protein coding genes, particularly long non-coding RNAs (lncRNA), including several lncRNAs known to be associated with inflammation and/or cardiovascular disease. In addition, Gene Set Enrichment Analysis revealed markedly downregulated microRNA pathways, resulting in aberrant expression of other genes, particularly γ-protocadherins.Our data suggest that aberrant expression of non-coding gene regulators comprise crucial keys in the progression of heart disease, and may be pivotal for chronic low grade inflammation associated with cardiac dysfunction. By unmasking atypical γ-protocadherin expression as a prospective genetic biomarker of myocardial dysfunction, our study provides new insight into the complex molecular framework of heart disease. Creating new approaches to modify non-coding gene regulators, such as those identified in the current study, may define novel strategies to shift γ-protocadherin expression, thereby normalizing part of the molecular architecture associated with heart disease.
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| 8. |
- Tajsharghi, Homa, et al.
(författare)
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Mutations and sequence variation in the human myosin heavy chain IIa gene (MYH2)
- 2005
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Ingår i: European Journal of Human Genetics. - : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 13:5, s. 617-22
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Tidskriftsartikel (refereegranskat)abstract
- We recently described a new autosomal dominant myopathy associated with a missense mutation in the myosin heavy chain (MyHC) IIa gene (MYH2). In this study, we performed mutation analysis of MYH2 in eight Swedish patients with familial myopathy of unknown cause. In two of the eight index cases, we identified novel heterozygous missense mutations in MYH2, one in each case: V970I and L1061V. The mutations were located in subfragment 2 of the MyHC and they changed highly conserved residues. Most family members carrying the mutations had signs and symptoms consisting mainly of mild muscle weakness and myalgia. In addition, we analyzed the extent and distribution of nucleotide variation in MYH2 in 50 blood donors, who served as controls, by the complete sequencing of all 38 exons comprising the coding region. We identified only six polymorphic sites, five of which were synonymous polymorphisms. One variant, which occurred at an allele frequency of 0.01, was identical to the L1061V that was also found in one of the families with myopathy. The results of the analysis of normal variation indicate that there is strong selective pressure against mutations in MYH2. On the basis of these results, we suggest that MyHC genes should be regarded as candidate genes in cases of hereditary myopathies of unknown etiology.
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| 9. |
- Westin, Maria, et al.
(författare)
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Mutations in the genes for keratin-4 and keratin-13 in Swedish patients with white sponge nevus
- 2018
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Ingår i: Journal of Oral Pathology & Medicine. - : Wiley. - 0904-2512 .- 1600-0714. ; 47:2, s. 152-157
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundWhite sponge nevus is a rare autosomal dominant disorder that affects the non-keratinised stratified squamous epithelium. Mutations in the genes that encode mucosa-specific keratin-4 and keratin-13 are strongly linked to the manifestation of white sponge nevus. This study involved mutational analysis of the genes encoding keratin-4 and keratin-13 in two Swedish families with white sponge nevus. MethodsThe diagnosis of white sponge nevus was based on disease history, clinical characteristics of the lesions and, in the majority of the cases, histopathological examination. Samples were collected from the affected buccal mucosa using buccal swabs. DNA was subsequently extracted and amplified using touchdown-PCR. The keratin-4 and keratin-13 genes were sequenced, and a genetic analysis was performed. ResultsA novel heterozygous missense mutation was identified in exon 1A of the keratin-4 gene in Family 2. In addition, previously reported heterozygous missense mutations were identified in the keratin-4 (E449K, A72V, Q156R, R208H) and keratin-13 (L115P) genes in both families. ConclusionWe describe a novel heterozygous missense mutation in the keratin-4 gene of a Swedish family with white sponge nevus. Our results support the notion that mutations in keratin-4 and keratin-13 are the underlying cause of white sponge nevus.
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| 10. |
- Wikström, Tove, et al.
(författare)
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Microbial and human transcriptome in vaginal fluid at midgestation: Association with spontaneous preterm delivery.
- 2022
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Ingår i: Clinical and translational medicine. - : Wiley. - 2001-1326. ; 12:9
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Tidskriftsartikel (refereegranskat)abstract
- Intrauterine infection and inflammation caused by microbial transfer from the vagina are believed to be important factors causing spontaneous preterm delivery (PTD). Multiple studies have examined the relationship between the cervicovaginal microbiome and spontaneous PTD with divergent results. Most studies have applied a DNA-based assessment, providing information on the microbial composition but not transcriptional activity. A transcriptomic approach was applied to investigate differences in the active vaginal microbiome and human transcriptome at midgestation between women delivering spontaneously preterm versus those delivering at term.Vaginal swabs were collected in women with a singleton pregnancy at 18 + 0 to 20 + 6 gestational weeks. For each case of spontaneous PTD (delivery<37 + 0weeks) two term controls were randomized (39 + 0 to 40 + 6weeks). Vaginal specimens were subject to sequencing of both human and microbial RNA. Microbial reads were taxonomically classified using Kraken2 and RefSeq as a reference. Statistical analyses were performed using DESeq2. GSEA and HUMAnN3 were used for pathway analyses.We found 17 human genes to be differentially expressed (false discovery rate, FDR<0.05) in the preterm group (n =48) compared to the term group (n =96). Gene expression of kallikrein-2 (KLK2), KLK3 and four isoforms of metallothioneins 1 (MT1s) was higher in the preterm group (FDR<0.05). We found 11 individual bacterial species to be differentially expressed (FDR<0.05), most with a low occurrence. No statistically significant differences in bacterial load, diversity or microbial community state types were found between the groups.In our mainly white population, primarily bacterial species of low occurrence were differentially expressed at midgestation in women who delivered preterm versus at term. However, the expression of specific human transcripts including KLK2, KLK3 and several isoforms of MT1s was higher in preterm cases. This is of interest, because these genes may be involved in critical inflammatory pathways associated with spontaneous PTD.
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