A meta-analysis on the relationship between media with violence and aggression in Iranian sports.

The present research aimed to conduct a systematic study on violence and aggression in the context of Iranian sports and perform a meta-analysis to investigate the association between the media and violence and aggression in sports. The research encompassed all relevant studies available in scientific databases within Iran (such as Magiran, Seyed, Civilica, Normagz, Humane resource study, and police publications), as well as dissertations from the information and scientific documents database. The selected timeframe for this analysis covered the years 2001 to 2018 in the Iranian context. Through this process, 209 studies related to the subject were identified, out of which 10 studies were included in the meta-analysis based on the research protocol investigating the relationship between media and violence and aggression in sports. Data analysis was performed using SPSS25 and CMA2 software. The results showed several variables played prominent roles in the researches on violence and aggression in sports, including media performance, referees' performance, stadium amenities, law enforcement and security factors, external and internal stadium environment, coach's behavior, social control, family influence, education, socio-economic factors, substance abuse, players' behavior, influence of friends, managerial aspects, and cultural and political factors. Inferential statistics indicated effect size for the relationship between media and violence and aggression, under the fixed model, was determined to be 0.259, and under the random model, it was 0.306, both of which were statistically significant. Consequently, based on the findings from the meta-analysis, a significant direct relationship between media and violence and aggression in sports was established.

Evaluation of the paired-Cas9 nickase and RNA-guided FokI genome editing tools in precise integration of an anti-CD52 bicistronic monoclonal antibody expression construct at Chinese hamster ovary cells 18S rDNA locus.

INTRODUCTION: The aim of this study was to compare two CRISPR/Cas9-based orthogonal strategies, paired-Cas9 nickase (paired-Cas9n) and RNA-guided FokI (RFN), in targeting 18S rDNA locus in Chinese hamster ovary (CHO) cells and precisely integrating a bicistronic anti-CD52 monoclonal antibody (mAb) expression cassette into this locus. METHODS: T7E1 and high-resolution melt (HRM) assays were used to compare the ability of mentioned systems in inducing double-strand break (DSB) at the target site. Moreover, 5'- and 3'-junction polymerase chain reactions (PCR) were used to verify the accuracy of the targeted integration of the mAb expression cassette into the 18S rDNA locus. Finally, anti-CD52 mAb gene copy number was measured and, its expression was analyzed using ELISA and western blot assays. RESULTS: Our results indicated that both paired-Cas9n and RFN induced DSB at the target site albeit RFN performance was slightly more efficient in HRM analysis. We also confirmed that the anti-CD52 mAb cassette was accurately integrated at the 18S rDNA locus and the mAb was expressed successfully in CHO cells. CONCLUSION: Taken together, our findings elucidated that both paired-Cas9n and RFN genome editing tools are promising in targeting the 18S rDNA locus. Site specific integration of the bicistronic anti-CD52 mAb expression cassette at this locus in the CHO-K1 cells was obtained, using RFN. Moreover, proper expression of the anti-CD52 mAb at the 18S rDNA target site can be achieved using the bicistronic internal ribosome entry site (IRES)-based vector system.

CRISPR/Cas9-mediated deletion of a GA-repeat in human GPM6B leads to disruption of neural cell differentiation from NT2 cells.

The human neuron-specific gene, GPM6B (Glycoprotein membrane 6B), is considered a key gene in neural cell functionality. This gene contains an exceptionally long and strictly monomorphic short tandem repeat (STR) of 9-repeats, (GA)9. STRs in regulatory regions, may impact on the expression of nearby genes. We used CRISPR-based tool to delete this GA-repeat in NT2 cells, and analyzed the consequence of this deletion on GPM6B expression. Subsequently, the edited cells were induced to differentiate into neural cells, using retinoic acid (RA) treatment. Deletion of the GA-repeat significantly decreased the expression of GPM6B at the RNA (p < 0.05) and protein (40%) levels. Compared to the control cells, the edited cells showed dramatic decrease of the astrocyte and neural cell markers, including GFAP (0.77-fold), TUBB3 (0.57-fold), and MAP2 (0.2-fold). Subsequent sorting of the edited cells showed an increased number of NES (p < 0.01), but a decreased number of GFAP (p < 0.001), TUBB3 (p < 0.05), and MAP2 (p < 0.01), compared to the control cells. In conclusion, CRISPR/Cas9-mediated deletion of a GA-repeat in human GPM6B, led to decreased expression of this gene, which in turn, disrupted differentiation of NT2 cells into neural cells.

Synthetic miR-21 decoy circularized by tRNA splicing mechanism inhibited tumorigenesis in glioblastoma in vitro and in vivo models.

Glioblastoma multiforme (GBM) is the deadliest primary central nervous system tumor. miRNAs (miRs), a class of non-coding RNAs, are considered pivotal post-transcriptional regulators of cell signaling pathways. miR-21 is a reliable oncogene that promotes tumorigenesis of cancer cells. We first performed an in silico analysis on 10 microarray datasets retrieved from TCGA and GEO databases to elucidate top differentially expressed miRs. Furthermore, we generated a circular miR-21 decoy, CM21D, using the tRNA-splicing mechanism in GBM cell models, U87 and C6. The inhibitory efficacy of CM21D with that of a linear form, LM21D, was compared under in vitro conditions and an intracranial C6 rat glioblastoma model. miR-21 significantly overexpressed in GBM samples and confirmed in GBM cell models using qRT-PCR. CM21D was more efficient than LM21D at inducing apoptosis, inhibiting cell proliferation and migration, and interrupting the cell cycle by restoring the expression of miR-21 target genes at RNA and protein levels. Moreover, CM21D suppressed tumor growth more effectively than LM21D in the C6-rat GBM model (p < 0.001). Our findings validate miR-21 as a promising therapeutic target for GBM. The introduced CM21D by sponging miR-21 reduced tumorigenesis of GBM and can be considered a potential RNA-base therapy to inhibit cancers.

Overexpression of VEGF in dermal fibroblast cells accelerates the angiogenesis and wound healing function: in vitro and in vivo studies.

Fibroblasts are the main cells of connective tissue and have pivotal roles in the proliferative and maturation phases of wound healing. These cells can secrete various cytokines, growth factors, and collagen. Vascular endothelial growth factor (VEGF) is a unique factor in the migration process of fibroblast cells through induces wound healing cascade components such as angiogenesis, collagen deposition, and epithelialization. This study aimed to create VEGF165 overexpressing fibroblast cells to evaluate angiogenesis function in wound healing. In vitro, a novel recombinant expression vector, pcDNA3.1(-)-VEGF, was produced and transfected into the fibroblast cells. Following selecting fibroblast cells with hygromycin, recombinant cells were investigated in terms of VEGF expression by quantifying and qualifying methods. Mechanical, physical, and survival properties of polyurethane-cellulose acetate (PU-CA) scaffold were investigated. Finally, in vivo, the angiogenic potential was evaluated in four groups containing control, PU-CA, PU-CA with fibroblast cells, and VEGF-expressing cells on days 0, 2, 5, 12 and 15. Wound biopsies were harvested and the healing process was histopathologically evaluated on different days. qRT-PCR showed VEGF overexpression (sevenfold) in genetically-manipulated cells compared to fibroblast cells. Recombinant VEGF expression was also confirmed by western blotting. Manipulated fibroblast cells represented more angiogenesis than other groups on the second day after surgery, which was also confirmed by the antiCD31 antibody. The percentage of wound closure area on day 5 in genetically-manipulated Hu02 and Hu02 groups showed a significant reduction of wound area compared to other groups. These findings indicate that overexpression of VEGF165 in fibroblast cells results in enhanced angiogenesis and formation of granulated tissue in the early stage of the healing process, which can show its therapeutic potential in patients with impaired wound healing and also provide functional support for gene therapy.

Advance trends in targeting homology-directed repair for accurate gene editing: An inclusive review of small molecules and modified CRISPR-Cas9 systems.

Introduction: Clustered regularly interspaced short palindromic repeat and its associated protein (CRISPR-Cas)-based technologies generate targeted modifications in host genome by inducing site-specific double-strand breaks (DSBs) that can serve as a substrate for homology-directed repair (HDR) in both in vitro and in vivo models. HDR pathway could enhance incorporation of exogenous DNA templates into the CRISPR-Cas9-mediated DSB site. Owing to low rate of HDR pathway, the efficiency of accurate genome editing is diminished. Enhancing the efficiency of HDR can provide fast, easy, and accurate technologies based on CRISPR-Cas9 technologies. Methods: The current study presents an overview of attempts conducted on the precise genome editing strategies based on small molecules and modified CRISPR-Cas9 systems. Results: In order to increase HDR rate in targeted cells, several logical strategies have been introduced such as generating CRISPR effector chimeric proteins, anti-CRISPR proteins, modified Cas9 with donor template, and using validated synthetic or natural small molecules for either inhibiting non-homologous end joining (NHEJ), stimulating HDR, or synchronizing cell cycle. Recently, high-throughput screening methods have been applied for identification of small molecules which along with the CRISPR system can regulate precise genome editing through HDR. Conclusion: The stimulation of HDR components or inhibiting NHEJ can increase the accuracy of CRISPR-Cas-mediated engineering systems. Generating chimeric programmable endonucleases provide this opportunity to direct DNA template close proximity of CRISPR-Cas-mediated DSB. Small molecules and their derivatives can also proficiently block or activate certain DNA repair pathways and bring up novel perspectives for increasing HDR efficiency, especially in human cells. Further, high throughput screening of small molecule libraries could result in more discoveries of promising chemicals that improve HDR efficiency and CRISPR-Cas9 systems.

Dysregulation of long noncoding RNA MEG3 and NLRC5 expressions in patients with relapsing-remitting multiple sclerosis: is there any correlation?

Long noncoding RNA MEG3 and NLRC5 genes are both involved in the immune system and the regulation of NLRC5 by MEG3 is documented in rheumatoid arthritis. Therefore, we intended to evaluate the association between the expressions of MEG3 and NLRC5 in multiple sclerosis (MS). Forty relapsing and remitting MS (RRMS) patients (20 in each group) and twenty healthy individuals were enrolled. The expression level of MEG3 and NLRC5 was assessed in peripheral blood mononuclear cells. Sub-group analysis demonstrated that the expression level of MEG3 is reduced in the relapse patient group compared to remission and healthy groups (p < 0.001). The expression level of NLRC5 was higher in whole patients compared with healthy controls (p < 0.05). Moreover, a negative correlation was observed between the expression of these two genes (r = -0.73, p < 0.0001). To conclude, our findings showed the dysregulation of MEG3 and NLRC5 expressions in RRMS patients. Also, the converse association of MEG3 and NLRC5 reflects that the role of MEG3 in MS development is probably mediated by modulation of NLRC5.

Editing SOX Genes by CRISPR-Cas: Current Insights and Future Perspectives.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and its associated proteins (Cas) is an adaptive immune system in archaea and most bacteria. By repurposing these systems for use in eukaryote cells, a substantial revolution has arisen in the genome engineering field. In recent years, CRISPR-Cas technology was rapidly developed and different types of DNA or RNA sequence editors, gene activator or repressor, and epigenome modulators established. The versatility and feasibility of CRISPR-Cas technology has introduced this system as the most suitable tool for discovering and studying the mechanism of specific genes and also for generating appropriate cell and animal models. SOX genes play crucial roles in development processes and stemness. To elucidate the exact roles of SOX factors and their partners in tissue hemostasis and cell regeneration, generating appropriate in vitro and in vivo models is crucial. In line with these premises, CRISPR-Cas technology is a promising tool for studying different family members of SOX transcription factors. In this review, we aim to highlight the importance of CRISPR-Cas and summarize the applications of this novel, promising technology in studying and decoding the function of different members of the SOX gene family.

Investigation of rs531564 Polymorphism in the Primary MicroRNA-124 Gene in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis: Association with Disease Susceptibility and Clinical Characteristics.

MicroRNA-124 (miR-124) is known as an important regulator of the immune system and inflammatory response. Studies have reported that this miRNA is dysregulated in autoimmune disorders such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). A functional analysis demonstrated that rs531564 (C>G) affects the biogenesis of primary microRNA transcript-124 (pri-miR-124) and changes the expression of mature miR-124. In the present study, for the first time, we intended to evaluate the possible association between rs531564 polymorphism with SLE and RA risk.  In this case-control study, 110 patients with SLE, 115 patients with RA, and 120 healthy subjects were enrolled to evaluate rs531564 genotypes with real-time polymerase chain reaction (PCR) high resolution melting method. Our findings demonstrated that frequency of GC genotype and G allele were considerably higher in the control group than RA patients, demonstrating that that GC genotype and G allele have a protective effect for healthy individuals (GC vs CC; OR: 0.29; 95%CI [0.12,0.67] and G vs C; OR: 0.42; 95%CI [0.23,0.78]). However, no significant correlation was confirmed between allele and genotype frequencies of rs531564 with SLE risk (p>0.05). However, the G allele in rs531564 polymorphism was associated with serum level of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti-dsDNA antibody, C3, C4, and creatinine, and frequency of renal involvements in SLE patients (p<0.05). Moreover, in RA patients, the G was correlated with lower concentration ESR and CRP (p<0.001).  Our findings propose a considerable association between rs531564 polymorphism in the pri-miR-124 gene with susceptibility and clinical characteristics of RA and SLE in the Iranian population.

Common therapeutic advances for Duchenne muscular dystrophy (DMD).

Background and purpose: Duchenne muscular dystrophy (DMD), a lethal X-linked recessive muscle dystrophy, is resulted in by different mutations including mostly frame-shifting gross deletions and duplications and rarely point mutations in DMD gene. Increasing weakness, progressive loss of skeletal muscle mass, and later-onset cardiomyopathy are serious clinical symptoms which ultimately lead to cardiac and respiratory failure, and premature death in DMD patients by age of 30. DMD is a prevalent genetic disorder and considers as an interesting target for gene therapy approaches. Massive gene size and existence of enormous number of muscle tissues are terrific hindrance against DMD treatments, nevertheless enormous efforts have been executed in the fields of gene replacement therapy, gene editing strategies, cell-based treatments, and small drug medications. Hot spot exons skipping and suppression of premature stop codons are the most interesting treatments for restoring functional DMD product, dystrophin protein. Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas) systems are the most interesting genome editing platforms that are able to restore open reading frame of DMD gene. CRISPR-Cas9 and CRISPR-Cpf1 are two main genome editing sub-types that successfully used in mdx mice.Conclusions: This review aims to present recent progresses and future prospects over three main DMD therapeutic subgroups including gene therapy, cell therapy, and pharmacological therapy.

Development of an improved lentiviral based vector system for the stable expression of monoclonal antibody in CHO cells.

Therapeutic monoclonal antibodies (mAbs) have become the dominant products in biopharmaceutical industry. Mammalian cell expression systems including Chinese hamster ovary (CHO) cells are the most commonly used hosts for the production of complex recombinant proteins. However, development of stable, high producing CHO cell lines suffers from the low expression level and instability of the transgene. The increasing efforts in the development of novel therapeutic antibodies and the advent of biosimilars have revealed the necessity for the development of improved platforms for rapid production of products for initial characterization and testing. In line with this premise, vector design and engineering has been applied to improve the expression level and stability of the transgene. This study reports the application of an improved lentiviral vector system containing the human interferon-ß scaffold attachment region (IFN-SAR) for the development of antibody producing stable CHO cells. mAb expressing clones producing 1100 µg/L of IgG1 monoclonal antibody were isolated without extensive screening of a large number of clones. Our results here indicate the positive effects of IFN-SAR on stable mAb expression using lentiviral based expression vectors. We also observed that although IFN-SAR can improve light chain (LC) and heavy chain (HC) gene copy numbers in stable cell pools, mAb expression in single cell clones was not affected by the transgene copy number.

The Augmenting Effects of the tDNA Insulator on Stable Expression of Monoclonal Antibody in Chinese Hamster Ovary Cells.

Cell line development is one of the most critical steps in the production of complex recombinant therapeutic proteins such as monoclonal antibodies in mammalian cells. Generation of industrial cell lines is mainly based on the time-consuming and laborious process of selection and screening of a large number of clones. With the increasing demand for therapeutic proteins during the past years, more effort is invested to improve the efficiency of cell line development. In line with this premise, several studies employed expression vector engineering strategies based on incorporation of epigenetic regulatory elements, which can enhance the expression level and stability of the transgenes. Main examples of such elements include ubiquitous chromatin opening elements, scaffold or matrix attachment regions, stabilizing antirepressor elements, and insulators. This work evaluates the utility of the tDNA insulator element for stable expression of an IgG1 monoclonal antibody as well as the enhanced green fluorescent protein (EGFP) reporter gene in Chinese hamster ovary (CHO) cells. Initial analysis of EGFP transfected cells showed improved mean fluorescent intensity in cell pools and single cell clones when tDNA element was included in the expression vector. Our results also indicated up to nine- and sixfold enhancements in antibody titer and specific productivity of clones derived from tDNA containing vectors, respectively. Moreover, improved single cell cloning efficiency was observed for transfectants generated using tDNA harboring expression constructs. Our study clearly shows the beneficial effects of the tDNA insulator on monoclonal antibody expression in CHO cells.

Evaluation of different vector design strategies for the expression of recombinant monoclonal antibody in CHO cells.

Monoclonal antibodies (mAbs) have emerged as the most promising category of recombinant proteins due to their high efficiency for the treatment of a wide range of human diseases. The complex nature of mAbs creates a great deal of challenges in both upstream and downstream manufacturing processes. Proportional expression and correct folding and assembly of the light chain and heavy chain are required for efficient production of the mAbs. In this regard, expression vector design has proven to have profound effects on the antibody expression level as well as its stability and quality. Here, we have explored the efficiency of different vector design strategies for the expression of a recombinant IgG1 antibody in Chinese hamster ovary (CHO) cells. The antibody expression level was analyzed in transient expression and stable cell pools followed by expression analysis on single-cell clones. While detectable amounts of antibody were observed in all three systems, dual-promoter single-vector system showed the highest expression level in transient and stable expression as well as the highest productivity among clonal cells. Our results here show the importance of vector design for successful production of whole mAbs in CHO cells.

Duchenne muscular dystrophy: an updated review of common available therapies.

BACKGROUND AND PURPOSE: Duchenne muscular dystrophy (DMD) is a lethal progressive pediatric muscle disorder and genetically inherited as an X-linked disease that caused by mutations in the dystrophin gene. DMD leads to progressive muscle weakness, degeneration, and wasting; finally, follows with the premature demise in affected individuals due to respiratory and/or cardiac failure typically by age of 30. For decades, scientists tried massively to find an effective therapy method, but there is no absolute cure currently for patients with DMD, nevertheless, recent advanced progressions on the treatment of DMD will be hopeful in the future. Several promising gene therapies are currently under investigation. These include gene replacement, exon skipping, suppression of stop codons. More recently, a promising gene editing tool referred to as CRISPR/Cas9 offers exciting perspectives for restoring dystrophin expression in patients with DMD. This review intents to briefly describe these methods and comment on their advances. Since DMD is a genetic disorder, it should be treated by replacing the deficient DMD copy with a functional one. However, there are different types of mutations in this gene, so such therapeutic approaches are highly mutation specific and thus are personalized. Therefore, DMD has arisen as a model of genetic disorder for understanding and overcoming of the challenges of developing personalized genetic medicines, consequently, the lessons learned from these approaches will be applicable to many other disorders. CONCLUSIONS: This review provides an update on the recent gene therapies for DMD that aim to compensate for dystrophin deficiency and the related clinical trials.

The Impact of CRISPR-Cas System on Antiviral Therapy.

Clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein nuclease (Cas) is identified as an adaptive immune system in archaea and bacteria. Type II of this system, CRISPR-Cas9, is the most versatile form that has enabled facile and efficient targeted genome editing. Viral infections have serious impacts on global health and conventional antiviral therapies have not yielded a successful solution hitherto. The CRISPR-Cas9 system represents a promising tool for eliminating viral infections. In this review, we highlight 1) the recent progress of CRISPR-Cas technology in decoding and diagnosis of viral outbreaks, 2) its applications to eliminate viral infections in both pre-integration and provirus stages, and 3) various delivery systems that are employed to introduce the platform into target cells.

The Conspicuity of CRISPR-Cpf1 System as a Significant Breakthrough in Genome Editing.

Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas) is a microbial adaptive immune system. CRISPR-Cas systems are classified into two main classes and six types. Cpf1 is a putative type V (class II) CRISPR effector, which has revolutionized the genome editing approaches through multiple distinct features such as using T-rich protospacer-adjacent motif, applying a short guide RNA lacking trans-activating crRNA, introducing a staggered double-strand break, and possessing RNA processing activity in addition to DNA nuclease activity. In the present review, we attempt to highlight most recent advances in CRISPR-Cpf1 (CRISPR-Cas12a) system in particular, considering ground expeditions of the nature and the biology of this system, introducing novel Cpf1 variants that have broadened the versatility and feasibility of CRISPR-Cpf1 system, and lastly the great impact of the CRISPR-Cpf1 system on the manipulation of the genome of prokaryotic, mammalian, and plant models is summarized. With regard to recent developments in utilizing the CRISPR-Cpf1 system in genome editing of various organisms, it can be concluded with confidence that this system is a reliable molecular toolbox of genome editing approaches.

Humanizing glycosylation pathways in eukaryotic expression systems.

Glycosylation represents the most widespread posttranslational modifications, found in a broad spectrum of natural and therapeutic recombinant proteins. It highly affects bioactivity, site-specificity, stability, solubility, immunogenicity, and serum half-life of glycoproteins. Numerous expression hosts including yeasts, insect cells, transgenic plants, and mammalian cells have been explored for synthesizing therapeutic glycoproteins. However, glycosylation profile of eukaryotic expression systems differs from human. Glycosylation strategies have been proposed for humanizing the glycosylation pathways in expression hosts which is the main theme of this review. Besides, we also highlighted the glycosylation potential of protozoan parasites by emphasizing on the mammalian-like glycosylation potential of Leishmania tarentolae known as Leishmania expression system.

The CRISPR Growth Spurt: from Bench to Clinic on Versatile Small RNAs.

Clustered regulatory interspaced short palindromic repeats (CRISPR) in association with CRISPR-associated protein (Cas) is an adaptive immune system, playing a pivotal role in the defense of bacteria and archaea. Ease of handling and cost effectiveness make the CRISPR-Cas system an ideal programmable nuclease tool. Recent advances in understanding the CRISPR-Cas system have tremendously improved its efficiency. For instance, it is possible to recapitulate the chronicle CRISPR-Cas from its infancy and inaugurate a developed version by generating novel variants of Cas proteins, subduing off-target effects, and optimizing of innovative strategies. In summary, the CRISPR-Cas system could be employed in a number of applications, including providing model systems, rectification of detrimental mutations, and antiviral therapies.

Association Study of IL-4 -590 C/T and DDX39B -22 G/C Polymorphisms with the Risk of Late-Onset Alzheimer's Disease in Iranian Population.

Interleukin-4 (IL-4), an important anti-inflammatory cytokine, is elucidated to regulate amyloid ß-induced production of the inflammatory cytokines such as IL-1 and IL-6. It is assumed that IL-4 may involve in the inflammation pathology of surrounding senile plaques in Alzheimer's disease (AD) patients. DEAD (Asp-Glu-Ala-Asp) box polypeptide 39B (DDX39B), appears to be involved in regulation of the inflammatory cytokines which are in correlation with AD pathology. This study was conducted to investigate the two single nucleotide polymorphisms (SNPs), IL-4 -590 C/T and DDX39B -22 G/C, association with the risk of late-onset AD (LOAD) in Iranian population. In the present study, therefore, a cohort of 153 LOAD cases and 153 age-matched unrelated, non-dementia control subjects were analyzed for the two polymorphisms by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP). Our results successfully demonstrate a protective association between the IL-4 -590 T allele, IL-4 -590 C/T heterozygous genotype (P= 0.01, OR= 0.53 and P= 0.041; OR= 0.56, respectively) and LOAD in Iranian population. A resemblance significant association was detected in female population when subjects were stratified by sex: the IL-4 -590 T allele (P= 0.02, OR= 0, 40) and the heterozygous genotype (P= 0.009, OR= 0.29). However, no significant association was observed between the DDX39B -22 G/C polymorphism in the cases and controls. Furthermore, it is clarified that the protective effect of IL-4 -590 is independent from APOE protective genotypes. Accordingly, the IL-4 -590 T allele may be applied as a protective marker in the development of LOAD in Iranian population.

Exceptional expansion and conservation of a CT-repeat complex in the core promoter of PAXBP1 in primates.

Adaptive evolution may be linked with the genomic distribution and function of short tandem repeats (STRs). Proximity of the core promoter STRs to the +1 transcription start site (TSS), and their mutable nature are characteristics that highlight those STRs as a novel source of interspecies variation. The PAXBP1 gene (alternatively known as GCFC1) core promoter contains the longest STR identified in a Homo sapiens gene core promoter. Indeed, this core promoter is a stretch of four consecutive CT-STRs. In the current study, we used the Ensembl, NCBI, and UCSC databases to analyze the evolutionary trend and functional implication of this CT-STR complex in six major lineages across vertebrates, including primates, non-primate mammals, birds, reptiles, amphibians, and fish. We observed exceptional expansion (≥4-repeats) and conservation of this CT-STR complex across primates, except prosimians, Microcebus murinus and Otolemur garnettii (Fisher exact P<4.1×10(-7)). H. sapiens has the most complex STR formula, and longest repeats. Macaca mulatta and Callithrix jacchus monkeys have the simplest STR formulas, and shortest repeat numbers. CT≥4-repeats were not detected in non-primate lineages. Different length alleles across the PAXBP1 core promoter CT-STRs significantly altered gene expression in vitro (P<0.001, t-test). PAXBP1 has a crucial role in craniofacial development, myogenesis, and spine morphogenesis, properties that have been diverged between primates and non-primates. To our knowledge, this is the first instance of expansion and conservation of a STR complex co-occurring specifically with the primate lineage.