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分子生物学:开放获取

体积 5, 问题 3 (2016)

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The Role of Human Endogenous Retroviruses (HERV-K) in the Pathogenesis of Human Cancers

William Simmons

Transmission of oncogenic retroviruses demonstrated in 1908. Much work was done around that period since by other researchers who demonstrated transfer of Sarcoma in chickens through filtrates. Although the name ‘retroviruses’ was coined as late as 1974, retroviral diseases were distinguished much earlier. Human endogenous retroviruses (HERVs) are natural components of the human genome and are considered remnants of ancient germ line infections by exogenous retroviruses. The human genome sequencing project revealed that 8 to 9% of the human genome is of retroviral origin. About 800 of these elements (class II HERVs) are beta-retrovirus-like and therefore distantly related to exogenous MMTV (an accepted aetiological agent for mammary tumour in mice). The majority of HERVs are noninfectious and replication-defective retroviral fossils. Some members of each HERV family however have been found to still be transcriptionally active. Furthermore, tissue-specific HERV expression profiles could be established for all human tissues investigated so far, confirming that HERVs are permanent components of the human transcriptome. A prevalence of HERV transcripts, in particular class II elements, such as members of the HML-2 family have been reported for various cancer tissues. In this review we focus our attention therefore on the association of class II HERVs with cancers. We also discuss the importance of this group of HERVs to humans, their relationship with other triggering factors (e.g. other viruses); and if there is to date a definitive causal role in cancer. We outlined the future perspectives with respect to HERVs and its contribution to human cancers, the methods of diagnosing and prognosticating; and plans to forestall attendant disease linked to these viruses by vaccine route, for example. The active sub-species purported to cause diseases in humans are the HERV-K and HERV-W.

研究文章

Type-Specific HPV Concordance in a Group of Stable Sexual Partners from Bogota, Colombia

Vargas H

Human Papillomavirus (HPV) is one of the most important sexually transmitted infections (STIs) worldwide. However, little information is currently available about the patterns of infection among sexual partners. Therefore, the objective of this study was to characterize type-specific HPV genital infection positivity and concordance in a group of 25 male sexual partners of 25 women with cervical intraepithelial lesions. Overall, 56% of men and 80% of women were positive for at least one HPV type. The prevalent high risk viral type in both men and women was HPV-16, with frequencies of 21.4% and 25%, respectively. On the other hand, the correlation of infection among partners was 40% for HPV positivity and 28% for type-specific HPV concordance. These results confirm the high positivity of HPV infection in both women and men reported in the literature, and the existence of a type-specific concordance in stable couples, suggesting the important role of men as a viral reservoir that contributes not only to the transmission of HPV but also to maintain the infection in their sexual partners.

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The Frequency and Effects of CCR5 Delta 32 Allele in Gondar Population

Adugnaw Admas

HIV is the virus that causes AIDS. Its infection occurs by binding to CD4+ receptor and chemokine receptor 5 (CCR5). Recent studies have shown that reasons for progression and non-progression are multi factorial and may involve genetic, virological and immunological factors that influence HIV disease progression in various ways.

Chemokine receptors act as important co receptors mediating the entry of the human immunodeficiency virus type 1 (HIV-1) into susceptible cells. The Δ32 mutation at the CCR5 locus is a well-studied example of natural selection acting in humans. Homozygous carriers of the Δ32 mutation are resistant to HIV-1.

The aim of the present study was to assess the frequency of CCR5-Δ32 (Chemokine receptor delta 32 allele) in HIV-1 untreated individuals who visited Gondar university teaching hospital.

3 ml blood samples of fifty HIV-1 untreated seropositive individual and equal numbers of age and sex match seronegative individual who are exposed and uninfected were collected using EDTA coated vacutenous tubes. DNA from 1 ml blood samples was isolated using phenol-chloroform method.

Specially designed primers, both forward and reverse was used to amplify the alleles of CCR5 using PCR (Polymerase chain reaction). Desirable data regarding study subjects were collected by using specifically designed questioner. SPSS 16 and EPI-info version 3.2 were used to analyze the data.

The frequency of the homozygous CCR5 mutant allele was zero in the study population and there was statistically no significance difference between the frequency of the heterozygous allele among cases and controls. There was no homozygous mutant allele both in cases and controls in the present study. This may be due to small sample size and thus another study on the same population with large sample size is warranted to further confirm the result.

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RNA Interference (RNAi) as a metronome of the circadian cadence

Utpal Bhadra, Paromita Das and Manika Pal-Bhadra

The circadian clock of an organism is intricately entwined between a multitude of intercellular and intracellular networks consolidating the physiological activities into a refined rhythmic pattern. The key to these rhythms lie in their exceptional competence in either self-sustaining or in resetting themselves to the most suitable stimuli, neglecting the irrelevant ones. Apart from the prevalent notion about the dominant role of transcription and translation in the clock regulation, recent findings have unfurled the importance of post-transcription and post-translation in modulating the same. This review aims at evolving a new player in clock control via the incredible phenomena of RNA interference (RNAi), which is executed mainly through the microRNAs and the long non-coding RNAs. It enlightens us with replete evidences that effectively establish the cryptic yet enigmatic role of different core components of RNA interference and their machinery in the modulation of all the unexplored facets for the sustenance and constancy of the biological rhythm.

研究文章

Association of Angiotensin Converting Enzyme Gene Polymorphism and Possible High Risk Factors with Essential Arterial Hypertension in Egyptian Patients

Eman R Abdel-hamid

Background: Hypertension (HT) is a public health challenge due to its high prevalence, and being a major risk factor for cardiovascular diseases. HT is a multifactorial disorder with genetic and environmental interactive factors.

Aim: This study aims to evaluate association of angiotensin converting enzyme gene polymorphism (I/D) with blood pressure among Egyptian patients with essential hypertension and the interrelationship with other clinical parameters.

Subjects and methods: Eighty four patients with essential hypertension were included in this cross sectional descriptive study. Venous blood samples were withdrawn for DNA extraction, determination of different genotypes of ACE gene (I/D) polymorphism by polymerase chain reaction (PCR) and measuring serum ACE levels, lipid profile, blood sugar and creatinin.

Results: The frequency of different ACE genotypes were; 41.7% homozygous (DD), 45.2% heterozygous (ID) and 13.1% homozygous (II) indicating that (D) allele is significantly associated with essential hypertension. Also serum ACE level was significantly correlated with ACE (I/D) polymorphism (p=0.001). Patients with DD genotype had the highest serum ACE level followed by patients with ID genotype and patients with II genotype had the lowest serum ACE level.

Conclusion: ACE (I/D) polymorphism is associated with increased serum ACE activity and consequently with increased risk for essential hypertension and its complications.

研究文章

Age Dependent Accumulation of Spontaneous DNA Damage in Liver of Transgenic Mice over Expressing Ribosomal Protein S3

Vijay Hegde, Sridevi Yadavilli and Walter A Deutsch

Oxidative stress has been associated with the aging process and increased cancer incidence mainly due to accumulation of free radical dependent cellular damage. Reactive oxygen species (ROS) induced formation of 7,8-dihydro-8-oxoguanine (8-oxodG) has the potential to mispair with Adenine during DNA replication in key genes involved in the development of cancer. Human ribosomal protein S3 (RPS3) participates in a variety of reactions beyond its role in protein synthesis, such as processing of oxidative DNA damage. We have shown ex vivo that oxidative stress causes RPS3 to translocate to the nucleus, bind to sites of 8-oxodG with an extraordinarily high binding affinity and interferes with 8-oxodG repair in vitro. Furthermore, our in vivo studies using RPS3 over expressing transgenic mice showed translocation of RPS3 to the nucleus in mouse embryonic fibroblasts (MEFs) and co-localization to 8-oxodG foci with an increase in DNA damage. In this study, we show age dependent accumulation of DNA damage (double strand breaks [DSBs] and fragmented DNA) in aging (15-month old) transgenic mice over expressing RPS3. We also observed increase in DNA damage particularly 8-oxodG, in the liver of older transgenic mice which showed a pre-neoplastic pathology and presence of hepatic tumors. The older transgenic livers had significantly higher p53 expression compared to age matched wild-type mice. These results provide evidence for role of RPS3 over expression interfering with DNA repair and predisposing animals to carcinogenesis but also underscore the role of RPS3 expression plays in the DNA damage signaling pathway and in maintenance of genome integrity by channeling cells either towards cell survival (DNA repair) or cell death (apoptosis).

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DNA Methylation Signature of Post-injury Neointimal Cells During Vascular Remodeling in the Rat Balloon Injury Model

Qing Song, Li Ma

Vascular smooth muscle cell (VSMC) accumulation in the neointimal is a common feature in vascular diseases such as atherosclerosis, transplant arteriosclerosis and restenosis. In this study, we isolated the neointimal cells and uninjured residential vascular smooth muscle cells by laser micro dissection and carried out single-cell whole-genome methylation sequencing. We also sequenced the bisulfite converted genome of circulating bone-marrow-derived cells such as peripheral blood mononuclear cells (PBMC) and bone marrow mononuclear cells (BMMC). We found totally 2,360 differential methylation sites (DMS) annotated to 1,127 gene regions. The majority of differentially methylated regions (DMRs) were located in intergenic regions, outside those CpG islands and island shores. Interestingly, exons have less DMRs than promotors and introns, and CpG islands contain more DMRs than islands shores. Pearson correlation analysis showed a clear clustering of neointimal cells with PBMC/BMMC. Gene set enrichment analysis of differentially methylated CpG sites revealed that many genes were important for regulation of VSMC differentiation and stem cell maintenance. In conclusion, our results showed that neointimal cells are more similar to the progenitor cells in methylation profile than the residential VSMCs at the 30th day after the vascular injury.

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OncoLncs: Long Non-Coding RNAs with Oncogenic Functions

Esra Bozgeyik, Emine Bayraktar, Arturo Chavez-Reyes and Cristian Rodriguez-Aguayo

A decade before the discovery of non-coding transcripts, approximately 98% of the human genome was known as “transcriptional noise” or “junk DNA”. However, with the recent findings, non-coding transcripts are continuously turning into functional non-coding RNAs (ncRNA). NcRNAs comprise multiple classes of RNA transcripts that are not transcribed into proteins but have shown to regulate the transcription, stability, or translation of protein-coding genes in the mammalian genome. Nowadays the most studied ncRNAs are called miRNAs. They have been involved in the biogenesis and development of cancer. More recently, long non-coding RNAs (lncRNAs) were discovered and they have been shown not only to play a role in transcriptional and translational regulation, but also be involved in several diseases including cancer. LncRNAs are RNA transcripts longer than 200 nucleotides that do not encode proteins. The accumulating body of evidence suggests that lncRNAs play important roles in a variety of biological processes. They have been reported to be altered in many pathological states including cancer. LncRNAs with oncogenic functions (we may call; OncoLncs) were reported to be overexpressed in cancer cells and involved in the hallmarks of cancer including sustained proliferation, invasion, and metastasis. The field of regulatory RNAs is continuously growing especially the lncRNAs. Thus, in this comprehensive review, we discussed the advances on OncoLncs field in the malignant transformation of cancer and the therapeutics opportunities.

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