Deep analysis of N-cadherin/ADH-1 interaction: a computational survey

Due to the considerable role of N-cadherin in cancer metastasis, tumor growth, and progression, inhibition of this protein has been highly regarded in recent years. Although ADH-1 has been known as an appropriate inhibitor of N-cadherin in clinical trials, its chemical nature and binding mode with N-cadherin have not been precisely specified yet. Accordingly, in this study, quantum mechanics calculations were used to investigate the chemical nature of ADH-1. These calculations clarify the molecular properties of ADH-1 and determine its reactive sites. Based on the results, the oxygen atoms are suitable for electrophilic reactivity, while the hydrogen atoms that are connected to nitrogen atoms are the favorite sites for nucleophilic reactivity. The higher electronegativity of the oxygen atoms makes them the most reactive portions in this molecule. Molecular docking and molecular dynamics (MD) simulation have also been applied to specify the binding mode of ADH-1 with N-cadherin and determine the important residues of N-cadherin involving in the interaction with ADH-1. Moreover, the verified model by MD simulation has been studied to extract the free energy value and find driving forces. These calculations and molecular electrostatic potential map of ADH-1 indicated that hydrophobic and electrostatic interactions are almost equally involved in the implantation of ADH-1 in the N-cadherin binding site. The presented results not only enable a closer examination of N-cadherin in complex with ADH-1 molecule, but also are very beneficial in designing new inhibitors for N-cadherin and can help to save time and cost in this field.     

A Chronic Autochthonous Fifth Clade Case of Candida auris Otomycosis in Iran

Candida auris, a multidrug-resistant nosocomial pathogen, has emerged globally with high morbidity and mortality among immunocompromised individuals and COVID19 hospitalized patients. Five major clades of C. auris have been previously described. The fifth clade is exclusively found in Iran where C. auris isolates are genetically distinct from other clades by?>?200,000 single-nucleotide polymorphisms. The origin of C. auris remains unclear, and limited clinical data are available at present regarding clade V infection or colonization. Herein, another case of otomycosis in Iran caused by an isolate of C. auris belonging to the fifth clade is reported. Genotyping revealed that the obtained C. auris isolate from Isfahan clustered with earlier clade V isolates from Babol, cities around 600 km separated, which indicates that C. auris clade V is established in Iran. C. auris is thought to exist more commonly in Iran, given that limited diagnostic capacity in the country has probably curbed the identification of more C. auris cases. Therefore, surveillance of the environment, patients and healthcare facilities in different geographical regions in Iran is urgently required.

     

Karyological studies in Hyoscyamus species of Iran

Karyological studies were performed on Hyoscyamus species of Iran. The species studied showed variation with regard to chromosome number and details of karyotype. Two different basic chromosome numbers of x=14 and 17 were recorded for the genus corresponding to the two subgenera of Hyoscyamus . Chromosome numbers of six species are reported for the first time.     

Mosaicism in CRISPR/Cas9-mediated genome editing

The CRISPR/Cas9 system is a rapid, simple, and often extremely efficient gene editing method. This method has been used in a variety of organisms and cell types over the past several years. However, using this technology for generating gene-edited animals involves a number of obstacles. One such obstacle is mosaicism, which is common in founder animals. This is especially the case when the CRISPR/Cas9 system is used in embryos. Here we review the pros and cons of mosaic mutations of gene-edited animals caused by using the CRISPR/Cas9 system in embryos. Furthermore, we will discuss the mechanisms underlying mosaic mutations resulting from the CRISPR/Cas9 system, as well as the possible strategies for reducing mosaicism. By developing ways to overcome mosaic mutations when using CRISPR/Cas9, genotyping for germline gene disruptions should become more reliable. This achievement will pave the way for using the CRISPR technology in the research and clinical applications where mosaicism is an issue.     

Fast Food Intake Increases the Incidence of Metabolic Syndrome in Children and Adolescents: Tehran Lipid and Glucose Study

The aim of the study was to evaluate the association between fast food consumption and incidence of metabolic syndrome (MetS) and its components among children and adolescents over a 3.6 year follow-up. Dietary data of 424 healthy subjects, aged 6–18 years, was collected using a valid and reliable food frequency questionnaire. Metabolic syndrome was defined according to the Cook et al criteria. Consumption of fast foods including hamburgers, sausages, bologna (beef), and fried potatoes was calculated and further categorized to quartiles. Multiple logistic regression models were used to estimate the incidence of MetS and its components in each quartile of fast food intake. The incidence of MetS was 11.3% after a 3.6 year follow up. In the fully adjusted model, compared to the lowest quartile of fast food intake, individuals in the highest had odds ratios of 2.96 (95% CI: 1.02–8.63; P for trend<0.001), 2.82 (95% CI: 1.01–7.87; P for trend = 0.037), and 2.58 (95% CI: 1.01–6.61; P for trend = 0.009) for incidence of MetS, hypertriglyceridemia, and abdominal obesity, respectively. No significant association was found between fast food intakes and other components of MetS. Fast food consumption is associated with the incidence of MetS, abdominal obesity, and hypertriglyceridemia in Tehranian children and adolescents.     

Cytokine response following transthoracic and transhiatal esophagectomy in patients with esophageal cancer

Curative esophageal resection is usually performed using either a transthoracic (TT) or transhiatal (TH) approach. Forty patients with esophageal squamous cell carcinoma who underwent esophagectomies (24 TT and 16 TH), 12 patients who underwent surgery for gastric cancer, and 16 healthy individuals were enrolled in this study. Blood samples were taken from the patients, pre- and post-surgery. The levels of synthesis of T-helper 1 and 2 cytokines were assessed in vitro in the presence of mitogen. Our initial data indicated that at admission, 24 h before surgery, blood cells from both groups of esophageal cancer patients produced significantly lower levels of the Th1 cytokines, IFN-gamma and IL-2 than those from cells of healthy donors. Cells collected from gastric cancer patients prior to surgery produced intermediate levels of IFN-gamma and IL-2: significantly lower than healthy donors, and slightly more (non-significant) than esophageal cancer patients. These results contrast with those for the production of Th2 cytokines prior to surgery, which did not differ significantly between any groups: either the esophageal or gastric cancer patients, or healthy donors. Th1 and Th2 cytokine production was then studied using blood cells collected seven days after surgery. Cells from both groups of esophageal cancer patients, undergoing either TT or TH surgery, produced significantly lower levels of the Th1 cytokines, IFN-gamma and IL-2 than those from cells of gastric cancer patients who had undergone surgery. Postoperative and preoperative production was compared. For patients who had undergone TT esophageal resection, we observed that the post-operative production of IL-2, IL-5 and IL-13 was significantly lower than the pre-operative production of those cytokines. Such reduced post-operative compared to pre-operative production was only significant in patients who had undergone TT esophagectomy. A similar, but non-significant trend was observed in patients who had undergone either TH esophagectomy, or gastrectomy. The results indicate that digestive tract cancer patients, both esophageal and gastric, have (prior to surgery), a significantly reduced, basal, mitogen-induced production of Th1 but not of Th2 cytokine. Post-operatively, a significantly reduced production of Th1 and Th2 cytokines, except for IFN-gamma, was observed only in patients who had undergone surgical esophageal resection using the TT method.     

Vaccinomics approach for developing multi-epitope peptide pneumococcal vaccine

Streptococcus pneumoniae is a leading cause of some diseases such as pneumonia, sepsis, and meningitis mostly in children less than 5?years of age. Presently, two types of pneumococcal vaccine are available on the market: polysaccharide vaccines (PPV) that are based on capsular polysaccharides of at least 92 different serotypes, and protein-conjugated polysaccharide vaccine (PCV). The PPVs such as PPV23 do not stimulate efficient protective immunity in children under 2?years old, while the PCVs such as PCV7, PCV10, and PCV13 that cover 7, 10, and 13 serotypes, respectively, highly protect newborns, but have some disadvantages such as complications in manufacturing, costly production, and also requires refrigeration and multiple injections. Epitope-based vaccines, including varied mixtures of conserved virulence proteins, are a promising alternative to the existing capsular antigen vaccines. In this study, it has been tried to design an efficient subunit vaccine in order to elicit both CTL and HTL responses. The immunodominant epitopes from highly protective antigens of S. pneumoniae (PspA, CbpA, PiuA, and PhtD) were selected from different databanks, such as IEDB, PROPRED, RANKPEP, and MHCPRED. The PspA and CbpA were chosen as CTL epitope stimulants, and PhtD and PiuA were defined as helper epitopes. Because of low immunogenicity of epitope vaccines, PorB protein as a TLR2 agonist was employed to increase the immunogenicity of the vaccine. All the peptide segments were fused to each other by proper linkers, and the physicochemical, structural, and immunological characteristics of the construct were also evaluated. To achieve a high-quality 3?D structure of the protein, modeling, refinement, and validation of the final construct were done. Docking and molecular dynamics analyses demonstrated an appropriate and stable interaction between the vaccine and TLR2 during the simulation period. The computational studies suggested the designed vaccine as a novel construct, capable to elicit efficient humoral and cellular immunities, which are crucial for protection against S. pneumoniae.

Communicated by Ramaswamy H. Sarma     

Computational approach to suggest a new multi-target-directed ligand as a potential medication for Alzheimer’s disease

Abstract

Acetylcholinesterase (AChE) enzyme and myeloid differentiation 2 protein (MD2) are two critical proteins involved in Alzheimer’s disease (AD). Since the nature of the active site of AChE and the binding pocket of MD2 are similar, some ligands can inhibit both of them appropriately. Oxidative stress has also been known as an important cause of AD. Designing an effective common inhibitor with antioxidant activity to inhibit AChE and MD2 proteins is the main goal of this work. In this regard, we used tacrine molecule with a high ligand efficiency (LE) and dehydrozingerone (DHZ) with anti-inflammatory, antioxidant and anti-Alzheimer activities. Some modifications on DHZ structure can increase its antioxidant activity. So, tacrine molecule was combined with modified DHZ to present a new multi-target-directed ligand (MTDL). The ability of the designed ligand to inhibit AChE and MD2 proteins was confirmed by molecular docking, molecular dynamics (MD) simulation, and binding-free energy calculations. Therefore, the designed ligand can target two proteins involved in AD. It can also act as a potent antioxidant. In general, three important causative agents of AD are targeted by the designed ligand. Moreover, the inhibition of MD2, as the main source of oxidative stress, significantly reduces the production of free radicals.     

HPV16 Seropositivity and Subsequent HPV16 Infection Risk in a Naturally Infected Population: Comparison of Serological Assays

Background

Several serological assays have been developed to detect antibodies elicited against infections with oncogenic human papillomavirus (HPV) type 16. The association between antibody levels measured by various assays and subsequent HPV infection risk may differ. We compared HPV16-specific antibody levels previously measured by a virus-like particle (VLP)-based direct enzyme-linked immunoassay (ELISA) with levels measured by additional assays and evaluated the protection against HPV16 infection conferred at different levels of the assays.

Methodology/Principal Findings

Replicate enrollment serum aliquots from 388 unvaccinated women in the control arm of the Costa Rica HPV vaccine trial were measured for HPV16 seropositivity using three serological assays: a VLP-based direct ELISA; a VLP-based competitive Luminex immunoassay (cLIA); and a secreted alkaline phosphatase protein neutralization assay (SEAP-NA). We assessed the association of assay seropositivity and risk of subsequent HPV16 infection over four years of follow-up by calculating sampling-adjusted odds ratios (OR) and HPV16 seropositivity based on standard cutoff from the cLIA was significantly associated with protection from subsequent HPV16 infection (OR = 0.48, CI = 0.27–0.86, compared with seronegatives). Compared with seronegatives, the highest seropositive tertile antibody levels from the direct ELISA (OR = 0.53, CI = 0.28–0.90) as well as the SEAP-NA (OR = 0.20, CI = 0.06, 0.64) were also significantly associated with protection from HPV16 infection.

Conclusions/Significance

Enrollment HPV16 seropositivity by any of the three serological assays evaluated was associated with protection from subsequent infection, although cutoffs for immune protection were different. We defined the assays and seropositivity levels after natural infection that better measure and translate to protective immunity.