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This study aimed to investigate the association between serum levels and polymorphic variants of IL-35 with susceptibility, clinical features, and disease severity in multiple sclerosis (MS) patients. This case–control study recruited 186 MS patients and 195 sex- and age-matched healthy controls. Serum levels and polymorphic variants of IL-35 were determined by ELISA and restriction fragment length polymorphism (RFLP)-PCR or high resolution melting (HRM) analysis methods, respectively. In addition, by in silico analysis, we evaluated the location and function of the polymorphism. Serum levels of IL-35 were significantly lower in the patients than those of healthy controls (49.3 ± 3.7 vs. 69.5 ± 7.8, p = 0.009). EBI3 rs4740 polymorphism of IL-35 was associated with 2.2-fold increased risk of MS susceptibility (95% CI, 1.3–3.9, p = 0.005). However, there were no differences in the genotype distribution and allele frequencies of IL-35 rs568408 between the patients and controls (p > 0.05). In silico results showed that variation in IL-12A and EBI3 may affect on protein pathways of the cells and different components of the immune system such as NF-κB and INF-γ. The results show that IL-35 polymorphisms might be a genetic risk factor for the development of MS.

Background: Oral squamous cell carcinoma (OSCC) is one of the most common malignancies and is a serious problem worldwide. The role of HPV in oral cavity squamous cell carcinoma has beenstudied in several researches. Objective: The aim of the present review and meta-analysis was to investigate the relation between human papillomavirus (HPV) and oral cancer. Study design: Relevant studies were found using online international databases and suitable studies were selected and assessed by two independent researchers. The quality of all papers were determined by a checklist. Heterogeneity assay among the primary studies was evaluated by Cochran's Q test and I2 index. The statistical analyses were done using Stata SE, V.11 software. Trim and Fill method was applied to confirm the validity of the results.Results: This meta- analysis consists of 8 primary studies on the incidence of HPV infection in Iranian patients with oral diseases. The odds ratio between HPV infection and risk of oral cancer was 4.00 (95%CI: 2.31, 6.93).Conclusion: This meta- analysis showed associations between prevalence of HPV infection and oral cancer among Iranian patients. The chance of developing oral cancer among HPV positive patients was higher than that in HPV negative patients.

Background To date, no specific vaccine or drug has been proven to be effective against SARS-CoV-2 infection. Therefore, we implemented an immunoinformatic approach to design an efficient multi-epitopes vaccine against SARS-CoV-2. Results The designed-vaccine construct consists of several immunodominant epitopes from structural proteins of spike, nucleocapsid, membrane, and envelope. These peptides promote cellular and humoral immunity and interferon-gamma responses. Also, these epitopes have a high antigenic capacity and are not likely to cause allergies. To enhance the vaccine immunogenicity, we used three potent adjuvants: Flagellin of Salmonella enterica subsp. enterica serovar Dublin, a driven peptide from high mobility group box 1 as HP-91, and human beta-defensin 3 protein. The physicochemical and immunological properties of the vaccine structure were evaluated. The tertiary structure of the vaccine protein was predicted and refined by Phyre2 and Galaxi refine and validated using RAMPAGE and ERRAT. Results of ElliPro showed 246 sresidues from vaccine might be conformational B-cell epitopes. Docking of the vaccine with toll-like receptors (TLR) 3, 5, 8, and angiotensin-converting enzyme 2 approved an appropriate interaction between the vaccine and receptors. Prediction of mRNA secondary structure and in silico cloning demonstrated that the vaccine can be efficiently expressed in Escherichia coli. Conclusion Our results demonstrated that the multi-epitope vaccine might be potentially antigenic and induce humoral and cellular immune responses against SARS-CoV-2. This vaccine can interact appropriately with the TLR3, 5, and 8. Also, it has a high-quality structure and suitable characteristics such as high stability and potential for expression in Escherichia coli .

Introduction Trichophyton mentagrophytes and T. interdigitale are important causative agents of superficial mycoses, demonstrating emergent antifungal drug resistance. We studied the antifungal susceptibility profiles in Iranian isolates of these two species. Methods A total of 96 T. interdigitale and 45 T. mentagrophytes isolates were subjected to molecular typing by ribosomal ITS region. Antifungal susceptibility profiles for terbinafine, griseofulvin, clotrimazole, efinaconazole, luliconazole, amorolfine and ciclopirox were obtained by CLSI broth microdilution method. The squalene epoxidase (SQLE) gene was subjected to sequencing for mutations, if any, in isolates exhibiting elevated MICs for terbinafine. Results Luliconazole and efinaconazole showed the lowest MIC values against T. mentagrophytes and T. interdigitale isolates. There were five isolates with terbinafine MICs ≥32 µg/mL in our sample. They belonged to T. mentagrophytes type VIII and harbored two alternative SQLE gene sequence variants, leading to Phe397Leu and Ala448Thr or Leu393Ser and Ala448Thr substitutions in the enzyme. All terbinafine resistant strains could be inhibited by luliconazole and efinaconazole. Conclusion This study documented a step in the global spread of resistance mechanisms in T. mentagrophytes. However, treatment alternatives for resistant isolates were available.

Background: The Methicillin-resistant Staphylococcus aureus (MRSA) strains cause wide spectrum infections in hospitals and are responsible for the majority of the community-acquired infections. The emergence of community-acquired MRSA in patients without risk factors represents a high risk for public health. Objectives: In this study, we aimed to molecular typing the nasal carriage MRSA strains harbored mecA gene isolated from healthy children living in the North of Iran and also to determine the pattern of vancomycin susceptibility in these isolates. Methods: The MRSA strains were identified using standard microbiological and molecular procedures. The antibiotic susceptibility test was performed according to the clinical and laboratory standards institute. The MRSA strains were characterized by spa typing. Results: In total, 14 different patterns of spa genes were obtained from MRSA isolates in this study, which included t790 (23.07%), t2962 (15.38%), t267 (15.38%), t159 (7.69%) and t701, t094, t1816, t11332, t937, t2135, t180, t160 [1 (3.84%) isolate per each type]. The rate of resistant isolates to cefoxitin, , cefalotin, clindamycin, cefazolin, co-amoxiclav, co-trimoxazole, and cephalexin antibiotics were 69.23%, 100%, 46.15%, 96.15%, 100%, 3.48%, and 100%, respectively. In total, six (23.07%) revealed vancomycin-intermediate resistant phenotype and five (19.23%) isolates revealed vancomycin-resistant S. aureus phenotype. Conclusions: This study showed the different variants of MRSA strains based on molecular typing, among healthy children. Continuous surveillance studies to monitor MRSA should be encouraged to gain a better understanding of the circulating MRSA strains and prevent community spread of this pathogen.

BackgroundRobust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness.MethodsWe conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 (IFI27) in COVID-19 patients.FindingsWe show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression is associated with the presence of a high viral load. We further demonstrate that systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 severity. For clinical outcome prediction (e.g. respiratory failure), IFI27 expression displays a high positive (0.83) and negative (0.95) predictive value, outperforming all other known predictors of COVID-19 severity. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For example, in the pandemic H1N1/09 swine influenza virus infection, IFI27-like genes were highly upregulated in the blood samples of severely infected patients.InterpretationThese data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet-to-be discovered respiratory virus.Research in contextEvidence before this studyWe searched the scientific literature using PubMed to identify studies that used the IFI27 biomarker to predict outcomes in COVID-19 patients. We used the search terms “IFI27”, “COVID-19, “gene expression” and “outcome prediction”. We did not identify any study that investigated the role of IFI27 biomarker in outcome prediction. Although ten studies were identified using the general terms of “gene expression” and “COVID-19”, IFI27 was only mentioned in passing as one of the identified genes. All these studies addressed the broader question of the host response to COVID-19; none focused solely on using IFI27 to improve the risk stratification of infected patients in a pandemic.Added value of this studyHere, we present the findings of a multi-cohort study of the IFI27 biomarker in COVID-19 patients. Our findings show that the host response, as reflected by blood IFI27 gene expression, accurately predicts COVID-19 disease progression (positive and negative predictive values; 0.83 and 0.95, respectively), outperforming age, comorbidity, C-reactive protein and all other known risk factors. The strong association of IFI27 with disease severity occurs not only in SARS-CoV-2 infection, but also in other respiratory viruses with pandemic potential, such as the influenza virus. These findings suggest that host response biomarkers, such as IFI27, could help identify high-risk COVID-19 patients - those who are more likely to develop infection complications - and therefore may help improve patient triage in a pandemic.Implications of all the available evidenceThis is the first systemic study of the clinical role of IFI27 in the current COVID-19 pandemic and its possible future application in other respiratory virus pandemics. The findings not only could help improve the current management of COVID-19 patients but may also improve future pandemic preparedness.

To investigate the efficacy of short-term treatment with ciprofloxacin in alteration of gut microbiota pattern and reduction of seizure frequency in adult patients with drug-resistant epilepsy.In a prospective study, we investigated the effect of a 5-day course of treatment with ciprofloxacin on gut microbiota pattern and seizure frequency of 23 adults with drug-resistant epilepsy. Fecal samples were collected before and after treatment and were analyzed for microbial load and species. Changes in seizure frequency were registered for 12 weeks. Responders were defined as patients who experienced ≥50 % seizure reduction in comparison to baseline. Outcome measures were specified as alteration in fecal microbial burden in days 5-7 and responder rate in 4th and 12th weeks.The mean baseline frequency of seizures was5.6 ±7.7 per week. All patients were on polytherapy with a mean of 3 ± 1.2 anti-seizure medications. Microbial analysis showed a considerable increase in Bacteroidetes/Firmicutes ratio after treatment. Seizure frequency significantly decreased at the end of first week and the therapeutic effect continued to week 12 (P0.001). The responder rate at 4th and 12th weeks were 69.6 % and 73.9 % respectively with a more prominent response in patients with symptomatic generalized epilepsy (P:0.06).Alteration of abnormal gut microbiota pattern by methods such as short-course antibiotic therapy, prescription of probiotics and fecal microbiota transplant might be effective in treatment of drug-resistant epilepsy.

BACKGROUND AND OBJECTIVE Although HLA matching is considered as a key genetic predictor of allo-HSCT outcomes, genetic polymorphisms in non-HLA genes, especially in genes encoding immunoregulatory proteins, have also been proposed as additional risk factors linked to the occurrence of transplant complications. This study aimed to carry out a systematic review and meta-analysis from all eligible cohort studies to determine the effect of CTLA-4 gene polymorphisms, including rs231775, rs3087243, rs4553808, rs5742909, and rs733618, on clinical outcomes in patients receiving an allo-HSCT. METHODS A systematic literature search in PubMed, Web of Science, and Scopus was performed to identify the relevant studies, and related information was extracted. The effect size (ES) and corresponding 95% confidence intervals (CIs) were calculated to estimate the association. RESULTS 16 studies were eligible and included in the meta-analysis. The pooled results showed that only the dominant models of rs3087243 were significantly associated with chronic GVHD (cGVHD), while other SNPs were not significantly associated with overall survival, disease-free survival, relapse, and GVHD. CONCLUSIONS Our study represents, for the first time, a comprehensive meta-analysis on the role of CTLA-4 polymorphisms on outcomes after allo-HSCT. The results indicate that the CT60 CTLA-4 polymorphism could be a significant risk factor for cGVHD.

Purpose: Regarding the role of B- and T-lymphocyte attenuator/Herpesvirus entry mediator (BTLA/HVEM) in tumorigenesis, this research was conducted to determine the HVEM/BTLA expression in development of gastric cancer.Methods: The statistical population of this study consisted of 114 patients, who were divided into 3 groups of non-ulcer dyspepsia (NUD; n=32), intestinal metaplasia (IM; n=19), and gastric cancer (GC; n=63). BTLA and HVEM in gastric biopsies were evaluated using SYBR Green-based on real-time PCR and immunohistochemistry. In this research, soluble HVEM (sHVEM) concentration and anti-Helicobacter pylori IgG antibody were assessed in sera of all study subjects. Results: Our result showed that in contrast to mRNA, HVEM protein expression was significantly higher in the GC group, compared to that in the NUD and IM groups (Pp = 0.005). The sHVEM concentration was also higher in the GC group than in the NUD groups (P=0.001). Conclusions: High expression of BTLA/HVEM and sHVEM suggested that this inhibitory pathway is involved in immune regulation and progression of IM and GC. Therefore, these molecules can be used for the diagnosis and prognosis of GC.

The host resistance against Toxoplasma gondii (T. gondii) infection is related to the initiation of the immune response. The study aimed to investigate the role of the leucine-rich repeat family, pyrin domain -containing protein 12 (NLRP12), and cytoplasmic nucleotide-binding domain in the inflammasome-mediated cell death during murine toxoplasmosis. Groups of BALB/c mice (n = 10) were inoculated intraperitoneally with live tachyzoites, excretory-secretory antigens (ESAs) of T. gondii RH strain, and RPMI. The gene expression levels of NLRP12, caspase-3, caspase-1, IL-1β, IL-18, ASC, and Bcl-2 were measured in the peritoneal cells using quantitative real-time PCR, while the determination of NLRP12 protein level was measured by Western blot. Also, the intracellular reactive oxygen species (ROS) production was investigated. Quantitative and comparative analyses showed that injection of tachyzoites significantly increased NLRP12, caspase-3, caspase-1, IL-1β, IL-18, and ASC genes mRNA expression levels (p

Introduction and objectives Allergic asthma is a chronic inflammatory disorder of the airways. Th1, Th2 and Th17 cells are the main cells involved in the pathophysiology of asthma. The function of these cells is affected by T-bet, GATA3 and RORγt transcription factors (respectively). Therefore, the aim of this study was to evaluate the effect of ginger (officinal Roscoe) extract on the expression of T-bet, GATA-3 and ROR-γ in peripheral blood mononuclear cells (PBMC) of asthmatic patients, in comparison with healthy volunteers as controls. Materials and methods In this case-control study, a total of 50 individuals including 25 patients with severe, moderate and mild allergic asthma and 25 unrelated healthy controls were involved. The PBMCs were isolated and divided into four groups: negative control, two positive controls (Budesonide and PHA) and ginger-extract treated group. After cell treatment and incubation for 48 h, PBMCs were isolated and cDNA was synthesized. Gene expressions of T-bet, GATA3 and ROR-γt were evaluated by Real-time PCR. Results According to the results of this study, hydroalcoholic extract of ginger could reduce the expression of GATA-3, ROR-γt, and T-bet in PBMCs of asthmatic patients in comparison with untreated PBMCs (P values = 0.001, 0.001, and 0.002, respectively). It was also shown that the ginger extract could affect T-bet/GATA-3, T-bet/ROR-γt, and ROR-γt/GATA-3 expression ratios. Conclusions This study showed that the use of ginger extract could control asthma and decrease the severity of this disease by affecting the main cells involving the symptoms of asthma in the airways.

Aspergillus clavatus is a common environmental species known to cause occupational allergic disease in grain handlers. We have recently observed azole-resistant isolates of this fungus as a cause o...

Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that causes coronavirus disease 2019 (COVID-19) is a public health problem and may have co-infection with other pathogens such as influenza virus.Objective This study aims to assess the co-infection of SARS-CoV-2 with influenza among COVID-19 cases.Material and methods The all relevant studies were collected from international databases. For improving the quality of the present literature, the all studies were evaluated by two reviewers in order to confirm all of the studies have inclusion criteria. Finally, all articles with sufficient quality scores were included in meta-analysis. Assessment of heterogeneity among the studies of primary studies was performed using the statistic chi‐squared test (Cochran's Q) and I2 index. In this results, random or fixed effect model were used for determination of heterogeneity test. All statistical analyses were performed using Comprehensive Meta-Analysis (CMA), V.2 software.Results This meta- analysis included 9 primary studies investigating the co-infection of SARS-CoV-2 with influenza among COVID-19 cases. Pooled prevalence (95% confidence interval) of co-infection is shown that the prevalence of influenza A is higher than influenza B. 2.3(0.5-9.3) vs 0.1 (0.4-3.3). Using the fixed effect model the frequency of fever was (80.6% [95% CI 76.1–84.40, p < 0.153]) and it is shown that fever is the most prevalent symptom in patients.Conclusion Patients admitted to hospital with COVID-19 also infected with influenza virus. Thus, the current research provides a better understanding about the control and treatment of co-infection with SARS-CoV-2 and the influenza virus.

Objectives Human papillomavirus infection (HPV) is the most common viral infection which is causes of cervical, penal, vulvar, anal and, oropharyngeal cancer. E7 protein of HPV is a suitable target for induction of T cell responses and controlling HPV-related cancer. The aim of the current study was to designed and evaluated a novel fusion protein containing the different E7 proteins of the HPV 16, 18, 6 and 11, linked to the cell-penetrating peptide HIV-1 Tat 49-57, in order to improve cytotoxic immune responses in in-vitro and in-vivo. Results In this study whole sequence of HPV16,18,6,11 E7-Tat (47-57) and HPV16,18,6,11 E7 cloned into the vector and expressed in E.coli (BL21). The purified protein was confirmed by SDS page and western blotting and then injected into the C57BL/6 mice. The efficiency of the fusion protein vaccine was assessed by antibody response assay, cytokine assay (IL-4 and IFN-γ), CD+8 cytotoxicity assay and tumor challenge experiment. Result showed that fusion proteins containing Adjuvant (IFA,CFA) could express higher titer of antibody. Also, we showed that vaccination with E7-Tat and, E7-Tat-ADJ induced high frequencies of E7-specific CD8+ T cells and CD107a expression as well as IFN-γ level and enhanced long-term survival in the therapeutic animal models. Conclusion Our finding suggested that this novel fusion protein vaccine was able to induce therapeutic efficacy and immunogenicity by improving CD8+ T cell in TC-1 tumor bearing mice; so this vaccine may be appreciated for research against HPV and tumor immunotherapies.

In recent years, the prevalence of resistance to aminoglycosides among clinical isolates of Pseudomonas aeruginosa is increasing. The aim of this study was to investigate the role of aminoglycoside-modifying enzymes (AMEs) in resistance to aminoglycosides in clinical isolates of P. aeruginosa. The clinical isolates were collected from different hospitals. Disk agar diffusion test was used to determine the antimicrobial resistance pattern of the clinical isolates, and the minimum inhibitory concentration of aminoglycosides was detected by microbroth dilution method. The PCR was performed for discovery of aminoglycoside-modifying enzyme-encoding genes. Among 100 screened isolates, 43 (43%) isolates were resistant to at least one tested aminoglycosides. However, 13 (13%) isolates were resistant to all tested aminoglycosides and 37 isolates were detected as multidrug resistant (MDR). The resistance rates of P. aeruginosa isolates against tested antibiotics were as follows: ciprofloxacin (41%), piperacillin-tazobactam (12%), cefepime (32%), piperacillin (26%), and imipenem (31%). However, according to the MIC method, 13%, 32%, 33%, and 37% of the isolates were resistant to amikacin, gentamicin, tobramycin, and netilmicin, respectively. The PCR results showed that AAC(6 ′ )-Ib was the most commonly (26/43, 60.4%) identified AME-encoding gene followed by AAC(6 ′ )-IIa (41.86%), APH(3 ′ )-IIb (34.8%), ANT(3 ″ )-Ia (18.6), ANT(2 ″ )-Ia (13.95%), and APH(3 ″ )-Ib (2.32%). However, APH(3 ′ )-Ib was not found in any of the studied isolates. The high prevalence of AME-encoding genes among aminoglycoside-resistant P. aeruginosa isolates in this area indicated the important role of AMEs in resistance to these antibiotics similar to most studies worldwide. Due to the transmission possibility of these genes between the Gram-negative bacteria, we need to control the prescription of aminoglycosides in hospitals.

Background: Coronavirus is a single-stranded RNA virus, causing an epidemic of pneumonia and acute respiratory distress syndrome (ARDS) worldwide in late 2019. Objectives: In addition to the clinical symptoms, laboratory diagnosis can greatly help diagnose the diseases; therefore, this study aimed to analyze laboratory parameters in patients with COVID-19. Methods: In this cross-sectional study, the laboratory data of 2563 patients with COVID-19 admitted to hospitals affiliated with Mazandaran University of Medical Sciences were extracted from hospital information systems (HIS). The data were recorded on Excel and analyzed through t-test, chi-squared, and Fisher’s exact tests in SPSS 19 at the significance level of P < 0.05. Results: Out of 2563 patients with a mean age of 55.1 ± 16.7 years, 1409 (55%) were male, and 1154 (45%) were female with a mean age of 55.7 ± 16.8, and 54.3 ± 16.6 years, respectively. As the most frequent clinical findings, ESR, CRP, and LDH were increased by 83.5%, 71%, and 69.3% of the patients, respectively. Other research findings included lymphopenia, disturbed INR, abnormal SGOT, abnormal alkaline phosphatase (ALP), and increased lactate dehydrogenase (LDH), which were significantly higher in men than in women and was different between age groups. Conclusions: Conducting simple, convenient, and inexpensive laboratory tests can be helpful in the diagnosis of COVID-19.

The role of immune checkpoint receptors in T-cell exhaustion has been demonstrated in several cancers. We investigated the co-expression of TIGIT/PD-1 and LAG-3/PD-1 cells in patients with chronic lymphocytic leukemia (CLL). The frequencies of TIGIT+PD-1+CD8+and LAG-3+PD-1+CD8+cells and relative mRNA expression of LSECtin and CD155 were examined in PBMCs from 33 CLL patients and 20 controls. The percentage of TIGIT+PD-1+CD8+cells was significantly higher in CLL patients than in control subjects, with the preference in advanced-stage patients. However, LAG-3+PD-1+CD8+cell percentage was significantly lower in CLL patients than in the control subjects, and no significant differences were found between the early and advanced stages of the disease. An increase in the mRNA expression level of LSECtin, but not that of CD155, was observed in CLL patients compared to the control subjects. Collectively, a higher co-expression of PD-1 and TIGIT on CD8+ T-cells in CLL compared to control subjects suggests an important role of TIGIT in T-cell exhaustion in CLL patients especially those with advanced disease.

Malignant melanoma is a devastating disease. Because of its aggressiveness, it also serves as a model tumor for investigating novel therapeutic avenues. In recent years, scientific evidence has shown that cold atmospheric plasma (CAP) might be a promising modality in cancer therapy. In this study, we aimed to evaluate the effect of CAP generated by an argon plasma jet alone or in combination with dacarbazine (DAC) on melanoma cells in vitro and in vivo. The effects of the CAP on inducing lipid peroxidation and nitric oxide production were higher in B16 melanoma cells in comparison to non-malignant L929 cells. Assays on cell growth, apoptosis, and expression of genes related to, e.g., autophagic processes, showed CAP to have a substantial impact in melanoma cells while there were only minoreffects in L929 cells. In vivo, both CAP monotherapy and combination with DAC significantly decreased tumor growth. These results suggest that CAP not only selectively induces cell death in melanoma but also holds promises in combination with chemotherapy that might lead to improved tumor control.

The Outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in late 2019 in China and many other countries around the world necessitate immediate action to develop new drugs against the virus. Repurposing of existing drugs for new targets is a fast, safe and unexpansive approach for this goal. Studies have shown that naproxen could specifically interact with the RNA binding domain of nueclporteins of RNA viruses such as the influenza virus. Therefore, this study aimed to evaluate the binding properties of naproxen to the nucleocapsid protein of SARS-CoV-2. 3D structure of N and C terminal domains of SARS-CoV- 2 nucleocapsid were constructed and each were docked with naproxen and analyzed during 100 ns of molecular dynamics. The results showed that naproxen interacts with the N terminal domain of the nucleocapsid via two salt bridges with Arg 88 and 92 and a network of h-bonds. Molecular dynamics analysis was also revealed that all the coordinations of naproxen with N terminal domain were kept during 100 ns of simulation time. The results of this study provide insights how naproxen can specifically interact with the conserved RNA binding module of the nucleocapsid of SARS-CoV-2 that would inhibit the packaging of viral genome into capsid and virus assembly. Therefore we recommend evaluating the antiviral effects of naproxen against SARS-CoV-2 in in vitro studies and clinical trials.

The molecular epidemiology and antifungal susceptibility of Aspergillus nidulans species complex has not been well studied. To evaluate the genetic diversity and antifungal susceptibility patterns of clinical and environmental isolates of A. nidulans complex. Sixty clinical and environmental isolates of Aspergillus section Nidulantes were collected from five countries (Iran, The Netherlands, Spain, Portugal and Greece). The species were molecularly identified by sequencing of β-tubulin gene. The genetic diversity of A nidulans complex isolates (n = 54) was determined with a microsatellite genotyping assay. Antifungal susceptibility profile was determined using EUCAST method. The isolates were classified as A nidulans (46.7%), A spinulosporus (26.6%), A quadrilineatus (10%), A pachycristatus (3.3%), A rugulosus (3.3%), A unguis (5%), A creber, (1.7%), A olivicola (1.7%) and A sydowii (1.7%). Thirty-four sequence types (STs) were identified among the 54 A nidulans complex isolates. A high level of genetic diversity was found among A nidulans sensu stricto strains but low diversity was found among A spinulosporus strains. Amphotericin B showed high MICs to all species. The most active azole was posaconazole (GM = 0.64 mg/L), while itraconazole showed the highest MICs among azoles (GM = 2.95 mg/L). A spinulosporus showed higher MICs than A nidulans sensu stricto for all antifungals except for micafungin and anidulafungin. Interspecies variations may result in differences in antifungal susceptibility patterns and challenge antifungal therapy in infections caused by A nidulans. Differences in the distribution of STs or persistence of multiple STs might be related to the sources of isolation and niche specialisation. This project was supported in part by a research project from the Fondo de Investigación Sanitaria (PI16CIII/00035) and a research fund (No. 2819) from Invasive Fungi Research Center of Mazandaran University of Medical Sciences, Sari, Iran. info:eu-repo/semantics/publishedVersion

Aspergillus flavus is one of the most important agents of invasive and non-invasive aspergillosis, especially in tropical and subtropical regions of the world, including Iran. Aspergillus oryzae is closely related to A. flavus, and it is known for its economic importance in traditional fermentation industries. Reports of infection due to A. oryzae are scarce. Several studies reported that differentiating these two species in clinical laboratories is not possible using MALDI-TOF or by targeting fungal barcode genes, such as Internal Transcribed Spacer (ITS) and β-tubulin (benA). The species-level identification of causative agents and the determination of antifungal susceptibility patterns can play significant roles in the outcome of aspergillosis. Here, we aimed to investigate the discriminatory potential of cyp51A PCR-sequencing versus that of the ITS, benA and calmodulin (CaM) genes for the differentiation of A. flavus from A. oryzae. In a prospective study investigating the molecular epidemiology of A. flavus in Iran between 2008 and 2018, out of 200 clinical isolates of A. flavus, 10 isolates showed &gt, 99% similarity to both A. flavus and A. oryzae. Overall, the ITS, β-tubulin and CaM genes did not fulfil the criteria for differentiating these 10 isolates. However, the cyp51A gene showed promising results, which warrants further studies using a larger set of isolates from more diverse epidemiological regions of the world.

Environmental contaminants in hospital settings play a major role in the spreading of pathogenic bacteria during outbreaks. The aim of this study was to evaluate the antibiotic resistance and virulence-related genes among Enterococcus strains isolated from hospital environment. Throughout this cross-sectional work, 388 samples were collected from hospital environment. Totally, 88 Enterococcus positive strains were characterized with diagnostic and confirmatory tests. Antibiogram was done according to the CLSI guideline. Genes encoding antibiotic resistance and virulence factors were detected by multiplex PCR. Out of 90 tested isolates, 53.33% and 46.6% of them were identified as E. faecium and E. faecalis, respectively. Also, multidrug resistance phenotype observed in 66.6% and 37.5% of E. faecalis and E. faecium strains, respectively. Distribution of resistance genes was as follows: ermB (66.6%), tetM and tetL (60%), aac(6′)-Ie-aph(2″)-Ia (28.8%), aph (3′)-IIIa (26.6%), and vanA, vanB (8.8%). Moreover, 97.7% and 17.7% of the isolates, carried virulence factors of esp and ace, respectively. This report showed that the environmental Enterococcus are the major sources of resistance genes that can transfer them to the clinical isolates of bacteria in hospital settings.

Post-traumatic stress disorder (PTSD) is a condition that develops after an individual has experienced a major trauma. Currently, selective serotonin reuptake inhibitors (SSRIs) like fluoxetine are the first-line choice in PTSD drug treatment but their moderate response rates and side effects indicate an urgent need for the development of new treatment. Physical activity is known to improve symptoms of certain neuropsychiatric disorders. The present study investigated the effects of moderate treadmill exercise, the antidepressant fluoxetine and the combined treatment on behavioural deficits, and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. We also examined alternations in hippocampal brain-derived neurotrophic factor (BDNF) and mRNA expression of apoptosis - related proteins in a rat model of PTSD: the single prolonged stress (SPS) model. Rats were exposed to SPS (restraint for 2 h, forced swimming for 20 min and ether anaesthesia) and were then kept undisturbed for 14 days. After that, SPS rats were subjected to chronic treatment with fluoxetine (10 mg/kg/day, for 4 weeks), moderate treadmill running (4 weeks, 5 day per week) and the combined treatment (fluoxetine plus treadmill exercise), followed by behavioural, biochemical and apoptosis markers assessments. SPS rats exhibited increased anxiety levels in the elevated plus maze and light/dark box, impaired fear conditioning and extinction in inhibitory avoidance (IA) task, impaired spatial memory in a recognition location memory task and enhanced negative feedback on the HPA axis following a dexamethasone suppression test. SPS rats also showed reduced hippocampal BDNF and enhanced apoptosis. Moderate treadmill exercise, fluoxetine and the combined treatment alleviated the SPS-induced alterations in terms of anxiety levels, HPA axis inhibition, IA conditioning and extinction, hippocampal BDNF and apoptosis markers. Furthermore, the combined treatment was more effective than fluoxetine alone, but in most tests, the effects of the combined treatment were similar to those of exercise alone, suggesting that exercise is the main factor in the beneficial effects of the combined therapy in PTSD patients.

Background:Most of the anticancer chemotherapies are hampered via the development of multidrug resistance (MDR), which is the resistance of tumor cells against cytotoxic effects of multiple chemotherapeutic agents. Overexpression and/or over-activation of ATP-dependent drug efflux transporters is a key mechanism underlying MDR development. Moreover, enhancement of drug metabolism, changes in drug targets and aberrant activation of the main signaling pathways, including Wnt, Akt and NF-κB are also responsible for MDR.Methods:In this study, we have reviewed the roles of Wnt signaling in MDR as well as its potential therapeutic significance. Pubmed and Scopus have been searched using Wnt, β-catenin, cancer, MDR and multidrug resistance as keywords. The last search was done in March 2019. Manuscripts investigating the roles of Wnt signaling in MDR or studying the modulation of MDR through the inhibition of Wnt signaling have been involved in the study. The main focus of the manuscript is regulation of MDR related transporters by canonical Wnt signaling pathway.Result and Conclusion:Wnt signaling has been involved in several pathophysiological states, including carcinogenesis and embryonic development. Wnt signaling is linked to various aspects of MDR including P-glycoprotein and multidrug resistance protein 1 regulation through its canonical pathways. Aberrant activation of Wnt/β- catenin signaling leads to the induction of cancer MDR mainly through the overexpression and/or over-activation of MDR related transporters. Accordingly, Wnt/β-catenin signaling can be a potential target for modulating cancer MDR.

Background\ud Insecticide resistance of Anopheles stephensi, the main malaria vector in eastern Afghanistan, has been reported previously. This study describes the biochemical and molecular mechanisms of resistance to facilitate effective vector control and insecticide resistance management.\ud \ud Methods\ud Mosquito larvae were collected from the provinces of Kunar, Laghman and Nangarhar from 2014 to 2017. The susceptibility of the reared 3–4 days old adults was tested with deltamethrin 0.05%, bendiocarb 0.1%, malathion 5%, permethrin 0.75% and DDT 4%. Cytochrome P450 content and general esterase, glutathione S-transferase (GST) and acetylcholinesterase (AChE) activities were measured in the three field populations and the results were compared with those of the laboratory susceptible An. stephensi Beech strain. Two separate allele-specific PCR assays were used to identify L1014, L1014F and L1014S mutations in the voltage gated sodium channel gene of An. stephensi. Probit analysis, ANOVA and Hardy–Weinberg equilibrium were used to analyse bioassay, biochemical assay and gene frequency data respectively.\ud \ud Results\ud The population of An. stephensi from Kunar was susceptible to bendiocarb, apart from this, all populations were resistant to all the other insecticides tested. The differences between all values for cytochrome P450s, general esterases, GSTs and AChE inhibition rates in the Kunar, Laghman and Nangarhar populations were statistically significant when compared to the Beech strain, excluding GST activities between Kunar and Beech due to the high standard deviation in Kunar. The three different sodium channel alleles [L1014 (wild type), L1014F (kdr west) and L1014S (kdr east)] were all segregated in the Afghan populations. The frequencies of kdr east mutation were 22.9%, 32.7% and 35% in Kunar, Laghman and Nangarhar populations respectively. Kdr west was at the lowest frequency of 4.44%.\ud \ud Conclusions\ud Resistance to different groups of insecticides in the field populations of An. stephensi from Kunar, Laghman and Nangarhar Provinces of Afghanistan is caused by a range of metabolic and site insensitivity mechanisms, including esterases, cytochrome P450s and GSTs combined with AChE and sodium channel target site insensitivity. The intensity and frequency of these mechanisms are increasing in these populations, calling for urgent reorientation of vector control programmes and implementation of insecticide resistance management strategies.dr

Cutaneous leishmaniasis (CL) is considered one of the main health problems in Iran. Therefore, it is required for control and therapeutic purposes, an accurate and fast tool for the diagnosis and identification of Leishmania species. In the present study, three techniques, including microscopic examination, conventional PCR, and high-resolution melting (HRM)–PCR, have been evaluated, to find the most accurate and rapid test. In total, 105 skin scraping smears were taken from suspected dermal lesions of patients belonging to two known endemic CL areas, Gonbad and Bam districts, in Iran. Subsequently, the specimens were analyzed with microscopic, conventional PCR, and HRM–PCR techniques. Most positive samples (89.5%) were observed using HRM–PCR, and among the three techniques, HRM–PCR was the most sensitive (89%, 95% CI 81–94) technique. Microscopic examination test had the lowest sensitivity (57%, 95% CI 47–66%). The highest agreement among positive samples was observed between HRM–PCR and conventional PCR tests. Our results showed that the HRM–PCR technique is the most accurate and sensitive test for recognizing CL, and also a valuable alternative test for conventional PCR to detect various species.

Background:\ud \ud Oncogenic human papilloma viruses (HPV) are the cause of various types of cancer, specifically cervical cancer. L1 protein is the main protein of HPV capsid which targeted in many vaccine-producing attempts. However, they have not enough coverage on the various high risk HPV types. Therefore, having a low cost potent HPV vaccine to protect against all members of the ɑ-papillomaviridea family will be promising. In this study, L1 protein-based peptide vaccine was designed using immunoinformatics methods which provides physicochemical properties such as stability in room temperature, potential of antigenicity, non-allergic properties and no requirement with eukaryotic host system.\ud \ud Results:\ud \ud The designed vaccine has two HPV conserved epitopes with lengths 18 and 27 amino acids in all members of α-papillomaviridea. These peptides promote humoral and cellular immunity and INF-γ responses. In order to ensure strong induction of immune responses, Flagellin, a Toll like receptor 5(TLR-5) agonist, and a short synthetic toll like receptor 4 (TLR-4) agonist were also joined to the epitopes. Structure of the designed- vaccine was validated using Rampage and ERRAT and a high quality 3D structure of the vaccine protein was provided. Docking studies demonstrated an appropriate and stable interaction between the vaccine and TLR-5.\ud \ud Conclusions:\ud \ud The vaccine is expected to have a high quality structure and suitable properties including high stability, solubility and a high potential to be expressed in 'E.coli'. High potentiality of the vaccine in inducing humoral and cellular immune responses, may be considered as an anti-tumor vaccine.

Human papillomavirus (HPV) causes cervical carcinoma, which and is the third most common cancer, accounting for 275,000 deaths annually worldwide. Adjuvants have a key role in promotion of vaccine efficacy; therefore, using prophylactic and therapeutic vaccines combined with adjuvant could be of great benefit in prevention and treatment of cervical cancer. There are different types of adjuvants, including MF59TM adjuvants, RNA-based, JY (interleukin2/chitosan), cholera toxin (CT), heat-labile enterotoxin (LT), Freund's adjuvant, alum, SA-4-1BBL, λ-carrageenan (λ-CGN), heat shock proteins (HSPs), juzen-taiho-to (JTT) and hochu-ekki-to (HET), ISCOM and ISCOMATRIX™, very small size proteoliposomes (VSSPs), granulocyte macrophage colony-stimulating factor (GM-CSF), and Toll-like receptors (TLRs). Adjuvants have various functions, especially in therapeutic vaccines, and they lead to an increase in cytotoxic T lymphocytes (CTLs), so they are important in the design of vaccines. Here, we review the currently used adjuvants and their combinations with HPV protein vaccines in order to introduce an appropriate adjuvant for HPV vaccines.

Background In recent years, cold physical plasma gained significant interest as a new anticancer tool. Cold plasmas are versatile apparatuses in medicine and material processing. Among different cold plasma devices, the argon plasma jet is an effective apparatus and favorite for researches in plasma medicine science. Methods We developed an argon plasma jet for cancer treatments. Using optical emission spectroscopy, the newly developed plasma jet produced a substantial amount of hydroxyl radicals and other reactive oxygen and nitrogen species known to show cytotoxic effects at higher concentrations. In this work, we studied the efficacy of the argon-based plasma jet treatment in murine B16 melanoma cells in vitro and in vivo. In vitro, cell viability, apoptotic gene expression, and cell death patterns were assessed at 24 h and compared against non-malignant murine dermal fibroblasts (MDF). In vivo, B16 cells inoculated into the flank of the mice developed melanoma tumors, which were plasma-treated for 5 min on days 1, 5, and 10 or were left untreated. Results Melanoma cells were significantly more sensitive to plasma treatment than MDF under the same in vitro conditions (p= 0.00023). The results revealed that the argon-based plasma jet damaged B16 melanoma cells in vitro selectively without a detrimental effect on non-malignant MDF cells. In the animal model, the tumor volume was significantly reduced after three treatments with the plasma jet(p Conclusions The argon plasma jet showed therapeutic anti-melanoma efficacy in vitro and in vivo, which may spur new research lines in melanoma therapy.

Background Benzo(a)pyrene (BaP) as an environmental pollutant is ubiquitous in the environment and it has destructive effects on human health. So far, various studies have demonstrated that BaP can cause adverse effects on the female reproductive system, but the existing information is limited about the effects of BaP on the endometrial receptivity and embryo implantation. Objective The aim of this study was to investigate the effects of BaP on the endometrial receptivity and implantation in mice. Materials and methods In this experimental study, 40 pregnant BALB/c mice were divided into 5 groups (n = 8/each) as follows: experimental groups received the doses of 100 µg/kg, 200 µg/kg, and 500 µg/kg BaP dissolved in corn oil, the control group received normal saline and sham group received corn oil. Pregnant mice administered these solutions from Day 1 to Day 5 of gestation by gavage. On Day 6, the mice were sacrificed. Then their embryos were counted and the hormonal, histomorphological and molecular analyses were performed on the mocusa of uterine tube. Results The data revealed that BaP reduces estrogen and progesterone levels, decreases the number of implantation site, endometrium thickness, uterine lumen diameter, stromal cells and endometrial glands, and blood vessels in the endometrium. However, the expression of Activin receptor-like kinase 5 and E-cadherin genes was not changed by BaP with different doses. Conclusion The finding of this study showed that BaP can change estrogen and progesterone levels, and endometrial morphology leads to impairing the endometrial receptivity and decreasing the number of implantation site.

Evaluating the expression of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) may be useful for predicting the best models and achieving more accurate results in cancer research. Therefore, the aim of the present study was to analyze the LGR5 expression levels in different cell lines. Eight commonly used cell lines were assessed (COS-7, NIH3T3, HEK293, VERO, HeLa, BHK, HepG2 and AGS). All the cell lines were cultured in RPMI-1640 medium contain 10% fetal calf serum at 37°C in humidified conditions with 5% CO2. According to the western blotting results, LGR5 was expressed in all cell lines. Densitometry results of LGR5 expression in the different cell lines showed that high LGR5 expression levels were apparent in BHK, AGS, VERO and NIH3T3 cell lines compared with the other cell lines. The results indicate that for the normal and cancer cell lines, BNK and AGS may be a better choice, respectively, for in vitro cancer studies.

Glutamatergic system is involved in pathological effects of organophosphorus (OP) compounds. We aimed to determine in vivo effects of paraoxon, the bioactive metabolite of parathion, on the expression of glutamate transporters as well as Bax and Bcl2 in rat cerebral cortex. Male Wistar rats received an intraperitoneal (i.p.) injection of one of three doses of paraoxon (0.3, 0.7, or 1mg/kg) or corn oil as vehicle (1ml/kg). After 4 or 18h, cerebral cortices were dissected out and used for quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blot assays to measure mRNA and protein levels, respectively. The cortical glial glutamate transporters (GLAST and GLT-1) were up-regulated in animals treated with 0.7mg/kg of paraoxon, but down-regulated in 1mg/kg group. Neuronal glutamate transporter (EAAC1) was unchanged in 0.7mg/kg treated rats, while reduced in 1mg/kg group. No significant difference was found in the mRNA and protein expression of EAAC1 in animals intoxicated with 0.3mg/kg of paraoxon. Paraoxon (1mg/kg) resulted in an up-regulation of Bax and down-regulation of Bcl2 mRNA levels in the rat cerebral cortex. These results indicate that paraoxon can differentially regulate expression of glutamate transporters at mRNA and protein levels in the cerebral cortex. Changes in the expression of glutamate transporters are closely related to paraoxon-induced seizure activity.

Several approaches have been used to improve the immunogenicity of DNA vaccines. In the current study, we constructed the plasmid encoding T. gondii dense granule 14 (GRA14) and investigated the immunological properties of calcium phosphate nanoparticles (CaPNs) as nano-adjuvant to enhance the protective efficacy of pcGRA14. BALB/c mice intramuscularly injected three times at two-week intervals and the immune responses were evaluated using lymphocyte proliferation assay, cytokine and antibody measurements, survival times, and parasite load of mice challenged with the virulent T. gondii RH strain. The results showed that the immune responses were induced in mice receiving pcGRA14 DNA vaccine. Interestingly, pcGRA14 coated with nanoparticles led to statistically significant enhancements of cellular and humoral immune responses against Toxoplasma infection (P0.05). After challenge with RH strain of T. gondii, immunized mice with pcGRA14 showed prolong survival time compared to control groups (P0.05). In addition, pcGRA14 coated with nano-adjuvant exhibited the lowest parasitic load in the infected mice tissues. For the first time, our data indicate that the pcGRA14 coated with CaPN was more effective for stimulation of immune responses and should be considered as an adjuvant in the design of vaccines against toxoplasmosis.