Distribution of Disease-Causing Mutations through Different Protein Domains in Patients with Severe Combined Immunodeficiency

Background and Aim: Severe combined immunodeficiency (SCID) has been described as the most severe form of primary immunodeficiency disorders (PID). The disease can be caused by mutations in more than 20 different genes with prevalence of 1 in 50000 to 100000 live births. In the present study, we described the protein domain position of variants in 14 main genes in patients with SCID. We also aimed to investigate the correlation between the variant distribution of protein domains and its pathogenicity and clinical outcome of the variant. Materials and Methods: Molecular genetic analysis including Sanger sequencing, targeted gene panel and whole exome sequencing were performed on 50 patients with SCID. Moreover, protein domains characteristics were extracted from different databases such as Uniprot and PDB and the reported mutations were obtained from HGMD and ENSEMBL databases. Results: Our results showed that the mortality rate had a significant correlation with severity of clinical manifestations in the patients (p-value=0.000). There was also a significant relationship between the protein type and mutation severity (p-value=0.001) and severity of clinical manifestations (p-value=0.025). However, there was no significant relationship between the mortality rate and occurrence of mutations in different domains of proteins (p-value=0.304) and the severity of mutations (p-value= 0.586). Conclusion: In severe genetic diseases such as SCID, mutations in related genes have affected the structure of the protein enough to cause severe symptoms. However, there are differences in the pathogenicity of the mutations based on their location on the protein domains. In order to determine these variations and predict the outcome of mutations, it is necessary to use in silico and laboratory methods along with statistical and data mining tools to track these minor differences

Human APOBEC3 Variations and Viral Infection

Human APOBEC3 (apolipoprotein B mRNA-editing catalytic polypeptide-like 3) enzymes are capable of inhibiting a wide range of endogenous and exogenous viruses using deaminase and deaminase-independent mechanisms. These enzymes are essential components of our innate immune system, as evidenced by (a) their strong positive selection and expansion in primates, (b) the evolution of viral counter-defense mechanisms, such as proteasomal degradation mediated by HIV Vif, and (c) hypermutation and inactivation of a large number of integrated HIV-1 proviruses. Numerous APOBEC3 single nucleotide polymorphisms, haplotypes, and splice variants have been identified in humans. Several of these variants have been reported to be associated with differential antiviral immunity. This review focuses on the current knowledge in the field about these natural variations and their roles in infectious diseases

Nationwide Prevalence of Diabetes and Prediabetes and Associated Risk Factors Among Iranian Adults: Analysis of Data from PERSIAN Cohort Study

Introduction Over the past decades prevalence of diabetes has increased in Iran and other countries. This study aimed to update the prevalence of diabetes and prediabetes in Iran and to determine associated sociodemographic risk factors, as well as diabetes awareness and control. Methods This is a nationally representative cross-sectional survey that included 163,770 Iranian adults aged 35-70 years, from different ethnic backgrounds, between 2014 and 2020. Diabetes was diagnosed at fasting blood sugar of >= 6.99 mmol/L (126 mg/dL), or receiving blood glucose-lowering treatment. Multivariable logistic regression was applied to detect determinants associated with prevalence of diabetes and prediabetes, as well as predictors of diabetes awareness and glycemic control. Results Sex- and age-standardized prevalence of diabetes and prediabetes was 15.0% (95% CI 12.6-17.3) and 25.4% (18.6-32.1), respectively. Among patients with diabetes, 79.6% (76.2-82.9) were aware of their diabetes. Glycemic control was achieved in 41.2% (37.5-44.8) of patients who received treatment. Older age, obesity, high waist to hip ratio (WHR), and specific ethnic background were associated with a significant risk of diabetes and prediabetes. Higher awareness of diabetes was observed in older patients, married individuals, those with high WHR, and individuals with high wealth score. Moreover, glycemic control was significantly better in women, obese individuals, those with high physical activity, educational attainment, and specific ethnic background. Conclusions The prevalence of diabetes and prediabetes is increasing at an alarming rate in Iranian adults. High proportion of uncontrolled patients require particular initiatives to be integrated in the health care system

Computational Design of TrkB Peptide Inhibitors and Their Biological Effects on Ovarian Cancer Cell Lines

Abstract There are large numbers of different intracellular signaling pathways regulated by Tyrosine kinases (Trk) receptors. Trk receptors, especially TrkB, are also frequently overexpressed in a variety of human malignant tumors. In this study, we have computationally designed small peptide-based inhibitors of TrkB and investigated their effects on the proliferation and apoptosis of two ovarian cancer cell lines. Molecular docking of TrkB with its ligand and antagonist, BDNF and Cyclotraxin B respectively, was carried out using HADDOCK program. A peptide library was constructed based on the critical residues involved in the TrkB binding site. After docking and optimization, two selected peptides were purchased and their effects on the viability and apoptosis of the cells were evaluated by performing MTT (3-[4,5-dimethylthiazol- 2-yl]-2,5-diphenyltetrazolium bromide) test and flow cytometry assay. Subsequently, the levels of expression and phosphorylation statues of TrkB and its two downstream genes including MAPK3 and eIF4E were assessed with western blot. We found that designed peptides effectively reduced TrkB, MAPK3 and eIF4E phosphorylation, reduced cell viability and induced apoptosis in the treated cells when compared to untreated cells. In conclusion, the BDNF/TrkB signaling is shown to be attenuated substantially in the presence of peptide inhibitors suggesting a strong inhibitory potential of the designed peptides for Trk famil

Molecular investigation of association between common IL-6 polymorphism with cytomegalovirus (CMV) infection and recurrent miscarriage in Iranian women

Background: Recurrent pregnancy loss (RPL) is described as two or more spontaneous abortions. To date, scientists in various fields of knowledge, such as genetics, endocrinology, anatomy, immunology, and microbiology, have identified some important factors that affect abortions; nonetheless, the precise basic etiology is not determined in up to 50% of RPL cases. Human cytomegalovirus (CMV) infection and host genetic background, like IL-6 SNP polymorphisms, play important roles in RPL etiology. Objective: This study aimed to evaluate the relationships among single nucleotide polymorphisms (-634C/G and -174 G/C) in the IL-6 gene with CMV infection and the risk of RPL for early detection and treatment. Materials and methods: This case-control study was carried on 80 Iranian females with RPL and 80 healthy females as controls. DNA was extracted from samples and CMV and IL6 SNPs were detected using Tetra ARMS-PCR. Statistics were analyzed by Epi Info TM and SPSS software by X2 test for the roles of CMV detection and two polymorphisms in RPL. Results: The results indicated an increased rate of CMV infection in the RPL group (44%) compared to the control group (25.45%). The prevalence of IL-6-634C/G genotype among RPL patients with CMV infection was 80%, while the frequency of this genotype among RPL patients without CMV infection was 50%. Furthermore, no substantial relation was found between IL-6-174 G/C genotypes and RPL (p = 0.005). Conclusion: This study not only indicated a significant role for CMV in RPL, but also showed an association between CMV and allele G in IL6-634 among Iranian women. In addition, the findings suggested the use of CMV and IL-6-634 GG genotypes as diagnostic and prognostic biomarkers for RPL in the Iranian population. Keywords: Cytomegalovirus (CMV); IL-6-634C>G polymorphism; Polymerase chain reaction (PCR); Recurrent pregnancy loss (RPL)

Human APOBEC3 Variations and Viral Infection

Human APOBEC3 (apolipoprotein B mRNA-editing catalytic polypeptide-like 3) enzymes are capable of inhibiting a wide range of endogenous and exogenous viruses using deaminase and deaminase-independent mechanisms. These enzymes are essential components of our innate immune system, as evidenced by (a) their strong positive selection and expansion in primates, (b) the evolution of viral counter-defense mechanisms, such as proteasomal degradation mediated by HIV Vif, and (c) hypermutation and inactivation of a large number of integrated HIV-1 proviruses. Numerous APOBEC3 single nucleotide polymorphisms, haplotypes, and splice variants have been identified in humans. Several of these variants have been reported to be associated with differential antiviral immunity. This review focuses on the current knowledge in the field about these natural variations and their roles in infectious diseases

Identification of novel bacterial DNA gyrase inhibitors: An in silico study

Owing to essential role in bacterial survival, DNA gyrase has been exploited as a validated drug target. However, rapidly emerging resistance to gyrase-targeted drugs such as widely utilized fluoroquinolones reveals the necessity to develop novel compounds with new mechanism of actions against this enzyme. Here, an attempt has been made to identify new drug-like molecules for Shigella flexneri DNA gyrase inhibition through in silico approaches. The structural similarity search was carried out using the natural product simocyclinone D8, a unique gyrase inhibitor, to virtually screen ZINC database. A total of 11830 retrieved hits were further screened for selection of high-affinity compounds by implementing molecular docking followed by investigation of druggability according to Lipinski’s rule, biological activity and physiochemical properties. Among the hits initially identified, three molecules were then confirmed to have reasonable gyrase-binding affinity and to follow Lipinski’s rule. Based on these in silico findings, three compounds with different chemical structures from previously identified gyrase inhibitors were proposed as potential candidates for the treatment of fluoroquinolone-resistant strains and deserve further investigations

Assessment of Mini-dose Succinylcholine Effect on Facilitating Laryngeal Mask Airway Insertion

Introduction: Laryngeal Mask Airway (LMA) has gained wide acceptance for routine airway management and with increasing emphasis on day care surgery it is widely used. The aim of this study was to assess the effects of mini dose succinylcholine (0.1mg/kg) with semi-inflated cuff on facilitation of laryngeal mask airway insertion in order to achieve more satisfaction yet less complications . Methods: In a randomized double-blinded study, sixty ASA 1, 2 and 3 patients aged 20-60 years scheduled for urologic surgical procedures were included. Thirty patients received succinylcholine (Group S), and thirty received 0.9% sodium choride as a placebo (Group C). Results: Coughing occured in 33.3% of patients in the control group and there was no incidence in succ group (P=0.002). Head or limb movement occurred in 70% of the patients in the control group vs. 10% in succ group (P<0.001). Laryngospasm occurred in 36.6 % of the patients in the control group but there was no incidence in succ group (P=0.004). Additional propofol was required in 53% of the patients in control group vs. 10% for succ group (P=0.001). Ease of insertion and first successfull attempt of LMA were achieved in 93.3% and 90% of the patients respectively in group S (P<0.05). Myalgia and sore throat occurred in 66.7 % of patients in the group C in comparison with 33.3% in group S (P=0.06). Conclusion: The combination of propofol with mini dose succinylcholine, provided a significantly better method for LMA insertion, while reduced propofol doses were needed and number of attempts decreased