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The most significant factors that lead to cancer-related death in breast cancer (BC) patients include drug resistance, migration, invasion, and metastasis. Several signaling pathways are involved in the development of BC. The different types of BC are initially sensitive to chemotherapy, and drug resistance can occur through multiple molecular mechanisms. Regardless of developing targeted Therapy, due to the heterogenic nature and complexity of drug resistance, it is a major clinical challenge with the low survival rate in BC patients. The deregulation of several signaling pathways, particularly the Hippo pathway (HP), is one of the most recent findings about the molecular mechanisms of drug resistance in BC, which are summarized in this review. Given that HP is one of the recent cancer research hotspots, this review focuses on its implication in BC drug resistance. Unraveling the different molecular basis of HP through its crosstalk with other signaling pathways, and determining the effectiveness of HP inhibitors can provide new insights into possible therapeutic strategies for overcoming chemoresistance in BC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In the last few decades, DNA-based self-assembly tiles has become a hot field in research due to its special applications and advantages. The regularity and strong design methods comprise other DNA-based digital circuit design methods. In addition to the obvious advantages of this method, there are challenges in performing computations based on self-assembly tiles, which have hindered the development and construction of large computing circuits with this method. The first challenge is the creation of crystals from DNA molecules in the output, which has led to the impossibility of cascading. The second challenge of this method is the uncontrollability of the reactions of the tiles, which increases the percentage of computing errors. In this article, these two challenges have been solved by changing the structure of leading tiles so that without the activator strand, tiles remain inactive and cannot be connected to other tiles. Also, when the tiles are activated, single-strand DNA will be released after connecting to other tiles, which will be used as the output of the circuit. This output gives the possibility of cascading to self-assembly designed circuits. The method introduced in this article can be a beginning for the re-development of DNA-based circuit design with the self-assembly tile method.

Background: Understanding the genetic underpinnings of protein networks conferring stemness is of broad interest for basic and translational research., Methods: We used multi-omics analyses to identify and characterize stemness genes, and focused on the zinc finger protein 982 (Zfp982) that regulates stemness through the expression of Nanog, Zfp42, and Dppa3 in mouse embryonic stem cells (mESC)., Results: Zfp982 was expressed in stem cells, and bound to chromatin through a GCAGAGKC motif, for example near the stemness genes Nanog, Zfp42, and Dppa3. Nanog and Zfp42 were direct targets of ZFP982 that decreased in expression upon knockdown and increased upon overexpression of Zfp982. We show that ZFP982 expression strongly correlated with stem cell characteristics, both on the transcriptional and morphological levels. Zfp982 expression decreased with progressive differentiation into ecto-, endo- and mesodermal cell lineages, and knockdown of Zfp982 correlated with morphological and transcriptional features of differentiated cells. Zfp982 showed transcriptional overlap with members of the Hippo signaling pathway, one of which was Yap1, the major co-activator of Hippo signaling. Despite the observation that ZFP982 and YAP1 interacted and localized predominantly to the cytoplasm upon differentiation, the localization of YAP1 was not influenced by ZFP982 localization., Conclusions: Together, our study identified ZFP982 as a transcriptional regulator of early stemness genes, and since ZFP982 is under the control of the Hippo pathway, underscored the importance of the context-dependent Hippo signals for stem cell characteristics., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Host genetic characteristics and environmental factors interactions may play a crucial role in cervical carcinogenesis. We investigated the impact of functional genetic variants of four xenobiotic-metabolizing genes (AhR, CYP1A1, GSTM1, and GSTT1) on cervical cancer development in Tunisian women., Methods: The AhR gene polymorphism was analyzed using the tetra-primer ARMS-PCR, whereas the CYP1A1 polymorphism genotypes were identified by PCR-RFLP. A multiplex ligation-dependent polymerase chain reaction approach was applied for the analysis of GSTM1 and GSTT1 polymorphisms., Results: The homozygous A/A genotype of the AhR gene (rs2066853) and the heterozygous T/C genotype of the CYP1A1 SNP (CYP1A1-MspI) appeared to be associated with an increased risk of cervical tumorigenesis (OR a = 2.81; OR a = 5.52, respectively). Furthermore, a significantly increased risk of cervical cancer was associated with the GSTT1 null genotype (OR a = 2.65). However, the null GSTM1 genotype showed any significant association with the risk of cervical cancer compared to the wild genotype (OR a = 1.18; p = 0.784). Considering the combined effect, we noted a significantly higher association with cancer risk for individuals with at least two high-risk genotypes of CYP1A1/GSTT1 (OR a = 4.2), individuals with at least two high-risk genotypes of CYP1A1/GSTT1/AhR (OR a = 11.3) and individuals with at least two high-risk genotypes of CYP1A1/GSTM1/GSTT1/AhR exploitation low-risk genotype as a reference., Conclusion: This study indicated that the single-gene contribution and the combined effect of xenobiotic-metabolizing gene polymorphisms (AhR, CYP1A1-MspI, GSTM1, and GSTT1) may have a considerable association with increased cervical cancer risk., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: In the last years, mesenchymal stem cells (MSCs) have been considered as a useful strategy to treat many diseases such as traumatic brain injury (TBI). The production of inflammatory agents by TBI elicits an inflammatory response directed to other systems of body, such as the heart and the kidneys. In this study, the efficacy of oral mucosal mesenchymal stem cells (OMSCs) prescription after TBI in inflammation and oxidative stress of the heart and kidneys was evaluated., Methods: Twenty-four male rats were located in groups as follows: sham, TBI, vehicle (Veh), and stem cell (SC). OMSCs were injected intravenously 1 and 24 hours after TBI. Inflammatory, oxidative stress, and histopathological outcomes of the heart and kidney tissues were investigated 48 hours after TBI., Results: TBI caused an increase in the level of interleukin-1 β (IL-1 β ), interleukin-6 (IL-6), malondialdehyde (MDA), and carbonyl protein (PC) of the heart and kidney compared to the sham group. Superoxide dismutase (SOD), total antioxidant capacity (TAC), catalase (CAT), and interleukin-10 (IL-10) of the heart and kidney decreased after TBI. The use of OMSCs after TBI reduced the changes of these factors in both the heart and the kidney., Conclusion: Application of OMSCs after TBI can decrease inflammation and oxidative stress of the heart and kidney tissues leading to the reduction of damage. Therefore, this method can be evaluated in the TBI patients in future studies., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Maryam Radavi-Asgar et al.)

Platinum resistance is one of the major concerns in ovarian cancer treatment. Recent evidence shows the critical role of epithelial-mesenchymal transition (EMT) in this resistance. Epithelial-like ovarian cancer cells show decreased sensitivity to cisplatin after cisplatin treatment. Our study prospected the association between epithelial phenotype and response to cisplatin in ovarian cancer. Microarray dataset GSE47856 was acquired from the GEO database. After identifying differentially expressed genes (DEGs) between epithelial-like and mesenchymal-like cells, the module identification analysis was performed using weighted gene co-expression network analysis (WGCNA). The gene ontology (GO) and pathway analyses of the most considerable modules were performed. The protein-protein interaction network was also constructed. The hub genes were specified using Cytoscape plugins MCODE and cytoHubba, followed by the survival analysis and data validation. Finally, the co-expression of miRNA-lncRNA-TF with the hub genes was reconstructed. The co-expression network analysis suggests 20 modules relating to the Epithelial phenotype. The antiquewhite4, brown and darkmagenta modules are the most significant non-preserved modules in the Epithelial phenotype and contain the most differentially expressed genes. GO, and KEGG pathway enrichment analyses on these modules divulge that these genes were primarily enriched in the focal adhesion, DNA replication pathways and stress response processes. ROC curve and overall survival rate analysis show that the co-expression pattern of the brown module's hub genes could be a potential prognostic biomarker for ovarian cancer cisplatin resistance., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Johne's disease caused by Mycobacterium avium subsp. paratuberculosis (MAP) is a major concern in dairy industry. Since, the pathogenesis of the disease is not clearly known, it is necessary to develop an approach to discover molecular mechanisms behind this disease with high confidence. Biological studies often suffer from issues with reproducibility. Lack of a method to find stable modules in co-expression networks from different datasets related to Johne's disease motivated us to present a computational pipeline to identify non-preserved consensus modules. Two RNA-Seq datasets related to MAP infection were analyzed, and consensus modules were detected and were subjected to the preservation analysis. The non-preserved consensus modules in both datasets were determined as they are modules whose connectivity and density are affected by the disease. Long non-coding RNAs (lncRNAs) and TF genes in the non-preserved consensus modules were identified to construct integrated networks of lncRNA-mRNA-TF. These networks were confirmed by protein-protein interactions (PPIs) networks. Also, the overlapped hub genes between two datasets were considered hub genes of the consensus modules. Out of 66 consensus modules, 21 modules were non-preserved consensus modules, which were common in both datasets and 619 hub genes were members of these modules. Moreover, 34 lncRNA and 152 TF genes were identified in 12 and 19 non-preserved consensus modules, respectively. The predicted PPIs in 17 non-preserved consensus modules were significant, and 283 hub genes were commonly identified in both co-expression and PPIs networks. Functional enrichment analysis revealed that eight out of 21 modules were significantly enriched for biological processes associated with Johne's disease including "inflammatory response," "interleukin-1-mediated signaling pathway", "type I interferon signaling pathway," "cytokine-mediated signaling pathway," "regulation of interferon-beta production," and "response to interferon-gamma." Moreover, some genes (hub mRNA, TF, and lncRNA) were introduced as potential candidates for Johne's disease pathogenesis such as TLR2, NFKB1, IRF1, ATF3, TREM1, CDH26, HMGB1, STAT1, ISG15, CASP3 . This study expanded our knowledge of molecular mechanisms involved in Johne's disease, and the presented pipeline enabled us to achieve more valid results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Heidari, Pakdel, Bakhtiarizadeh and Dehghanian.)

The ever-growing stream of waste production has become a critical issue for many metropolitan areas. An effective strategy to address this problem has been the concept of reverse logistics (RL). This paper seeks to develop an appropriate product recovery approach for electronic waste generated in an urban area. Consequently, we have proposed an integrated fuzzy RL model with buyback (BB) offers based on the condition of used-products (UPs) at the time of return. However, this strategy contains a significant challenge, which derives from unpredictability surrounding the return rate of UPs due to its dependency on multiple external factors. Hence, a novel fuzzy probability function is developed to approximate UPs' chance of return. Besides that, the mathematical RL network's inherent uncertainty prompted us to employ the fuzzy credibility-based method in the model. Afterward, the model's objectives are locating and allocating collection centres to customer zones, determining flow between facilities and finding the optimal amount of gathered UPs and BB offers. Finally, we applied the model to a case study concerning product recovery in Mashhad city, Iran, and the results have proven its validity and utility.

Background: Neuroprotective effects of stem cells have been shown in some neurologic diseases. In this study, the effect of oral mucosal mesenchymal stem cells (OMSCs) on traumatic brain injury (TBI) was evaluated in long term., Materials and Methods: TBI was induced by Marmarou's method. The number of 2 × 10 6 OMSCs was intravenously injected 1 and 24 h after the injury. Brain edema and pathological outcome were assessed at 24 h and 21 days after the injury. Besides, long-term neurological, motor, and cognitive outcomes were evaluated at days 3, 7, 14, and 21 after the injury., Results: OMSCs administration could significantly inhibit microglia proliferation, and reduce brain edema and neuronal damage, at 24 h and 21 days after the injury. Neurological function improvement was observed in the times evaluated in OMSCs group. Cognitive and motor function dysfunction and anxiety-like behavior were prevented especially at 14 and 21 days after the injury in the treatment group., Conclusion: According to the results of this study, OMSCs administration after TBI reduced brain edema and neuronal damage, improved neurologic outcome, and prevented memory and motor impairments and anxiety-like behavior in long term., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Fatemeh Dehghanian et al.)

Type 2 diabetes is known as a risk factor for pancreatic cancer (PC). Various genetic and environmental factors cause both these global chronic diseases. The mechanisms that define their relationships are complex and poorly understood. Recent studies have implicated that metabolic abnormalities, including hyperglycemia and hyperinsulinemia, could lead to cell damage responses, cell transformation, and increased cancer risk. Hence, these kinds of abnormalities following molecular events could be essential to develop our understanding of this complicated link. Among different molecular events, focusing on shared signaling pathways including metabolic (PI3K/Akt/mTOR) and mitogenic (MAPK) pathways in addition to regulatory mechanisms of gene expression such as those involved in non-coding RNAs (miRNAs, circRNAs, and lncRNAs) could be considered as powerful tools to describe this association. A better understanding of the molecular mechanisms involved in the development of type 2 diabetes and pancreatic cancer would help us to find a new research area for developing therapeutic and preventive strategies. For this purpose, in this review, we focused on the shared molecular events resulting in type 2 diabetes and pancreatic cancer. First, a comprehensive literature review was performed to determine similar molecular pathways and non-coding RNAs; then, the final results were discussed in more detail., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

The development of dopaminergic (DA) neurons is a very complex process, and a combination of extrinsic and intrinsic factors involves their differentiation. Transcription factor, Nurr1 plays an essential role in the differentiation and maintenance of midbrain DA neurons. Nurr1-based therapies may restore DA function in Parkinson's disease (PD) by replacing damaged cells with differentiated cells derived from stem cells. Providing tissue-specific microenvironments such as brain extract can effectively induce dopaminergic gene expression in stem cells. The present study aimed to investigate the combined effects of Nurr1 gene overexpression and a neonatal rat brain extract (NRBE) induction on dopaminergic differentiation of P19 stem cells. In order to neural differentiation induction, stably Nurr1-transfected cells were treated with 100 μg/ml of NRBE. The differentiation potential of the cells was then evaluated during a period of 1-3 weeks via various methods. The initial evaluation of the cells by direct observation under a light microscope and cresyl violet specific staining, confirmed neuron-like morphology in the differentiated cells. In addition, different molecular and cellular techniques, including real-time PCR, immunofluorescence, and flow cytometry, demonstrated that the treated cells expressed pan-neuronal and dopaminergic markers. In all experimental groups, neuronal phenotype with dopaminergic neuron-like cells characteristics mainly appeared in the second week of the differentiation protocol. Overall, the results of the present study revealed for the first time the synergistic effects of Nurr1 gene overexpression and possible soluble factors that existed in NRBE on the differentiation of P19 stem cells into dopaminergic neuron-like cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Beiki, Khaghani, Esmaeili and Dehghanian.)

Background: Gabriele-de Vries syndrome is a rare autosomal dominant genetic disease caused by de novo pathogenic variants in YY1. In this study, we report a 10-year-old boy with a de novo novel pathogenic variant in YY1, the first Iranian patient with Gabriele-de Vries Syndrome., Methods: The novel de novo pathogenic variant detected in this study (NM_003403:c.690delA, p.Glu231Ilefs*25) was identified by whole-exome sequencing and confirmed by Sanger sequencing., Results: The proband presented with delayed motor and speech development, ataxia, abnormal gait, autistic behavior, brain atrophy, and severe learning disability. Finally, we provide a case-based review of the clinical features associated with Gabriele-de Vries Syndrome. Thus far, merely 13 Gabriele-de Vries Syndrome patients have been reported in the literature., Conclusion: The investigations for a suspected case of Gabriele-de Vries Syndrome must involve molecular diagnosis of the disease and its underlying genetic defect because the clinical investigations are generally variable and nonspecific., (© 2021 John Wiley & Sons Ltd/University College London.)

Multiple sclerosis (MS) is a chronic inflammatory and autoimmune disorder of the central nervous system characterized by myelin loss and axonal dysfunction. Increased production of inflammatory factors such as cytokines has been implicated in axon destruction. In the present study, we compared the expression level of IL7R, NFATc2, and RNF213 genes in the peripheral blood of 72 MS patients (37 familial MS, 35 sporadic MS) and 74 healthy controls (34 individuals with a family history of the disease, 40 healthy controls without a family history) via Real-time PCR. Our results showed that the expression level of IL7R was decreased in the sporadic patients in comparison with other groups. Additionally, there was an increased NFATc2 expression level in MS patients versus healthy controls. Increased expression of NFATc2 in sporadic and familial groups compared to the controls, and familial group versus FDR was also seen. Our results also represented an increased expression level of RNF213 in familial patients as compared to the control group. The similar RNF213 expression between sporadic and control group, as well as FDR and familial group was also seen. Diagnostic evaluation was performed by receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) calculation. The correlation of clinical parameters including onset age and Expanded Disability Status Scale (EDSS) with our gene expression levels were also assessed. Overall, decreased expression level of IL7R in the sporadic cases and increased expression level of NFATc2 may be associated with the pathogenesis of MS disease. Confirmation of the effects of differential expression of RNF213 gene requires further studies in the wider statistical populations., (© 2021. The Author(s).)

In recent years, many strategies have been used to overcome the fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors (TKIs) resistance caused by different mutations. LY2874455 (or 6LF) is a pan-FGFR inhibitor which is identified as the most efficient TKI for all resistant mutations in FGFRs. Here, we perform a comparative dynamics study of wild type (WT) and the FGFR4 V550L mutant for better understanding of the 6LF inhibition mechanism. Our results confirm that the pan-FGFR inhibitor 6LF can bind efficiently to both WT and V550L FGFR4. Moreover, the communication network analysis indicates that in apo-WT FGFR4, αD-αE loop behaves like a switch between open and close states of the substrate-binding pocket in searching of its ligand. In contrast, V550L mutation induces the active conformation of the FGFR4 substrate-binding pocket through disruption of αD-αE loop and αG helix anti-correlation. Interestingly, 6LF binding causes the rigidity of hinge and αD helix regions, which results in overcoming V550L induced resistance. Collectively, the results of this study would be informative for designing more efficient TKIs for more effective targeting of the FGFR signaling pathway., (© 2021. The Author(s).)

GM3 synthase deficiency is associated with salt and pepper developmental regression syndrome (SPDRS), a rare genetic disorder. Herein, we report the first Iranian patient with SPDRS. We detected a novel pathogenic variant of ST3GAL5 (NM_003896.4: c.1030_1031del, p.Ile344Cysfs*11). The proband had intellectual disability (ID), failure to thrive, cerebral atrophy, microcephaly, and atonic seizures. The main future challenge proceeding from the results of this study is the prenatal detection of the newly discovered variant; the next step would involve further studies to elucidate the phenotypic spectrum of SPDRS and detect new variants that could cause symptoms ranging from mild to severe., (© 2021. The Author(s).)

Johne's disease is a chronic infection of ruminants that burdens dairy herds with a significant economic loss. The pathogenesis of the disease has not been revealed clearly due to its complex nature. In order to achieve deeper biological insights into molecular mechanisms involved in MAP infection resulting in Johne's disease, a system biology approach was used. As far as is known, this is the first study that considers lncRNAs, TFs, and mRNAs, simultaneously, to construct an integrated gene regulatory network involved in MAP infection. Weighted gene coexpression network analysis (WGCNA) and functional enrichment analysis were conducted to explore coexpression modules from which nonpreserved modules had altered connectivity patterns. After identification of hub and hub-hub genes as well as TFs and lncRNAs in the nonpreserved modules, integrated networks of lncRNA-mRNA-TF were constructed, and cis and trans targets of lncRNAs were identified. Both cis and trans targets of lncRNAs were found in eight nonpreserved modules. Twenty-one of 47 nonpreserved modules showed significant biological processes related to the immune system and MAP infection. Some of the MAP infection's related pathways in the most important nonpreserved modules comprise "positive regulation of cytokine-mediated signaling pathway," "negative regulation of leukocyte migration," "T-cell differentiation," "neutrophil activation," and "defense response." Furthermore, several genes were identified in these modules, including SLC11A1, MAPK8IP1, HMGCR, IFNGR1, CMPK2, CORO1A, IRF1, LDLR, BOLA-DMB, and BOLA-DMA, which are potentially associated with MAP pathogenesis. This study not only enhanced our knowledge of molecular mechanisms behind MAP infection but also highlighted several promising hub and hub-hub genes involved in macrophage-pathogen interaction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Heidari, Pakdel, Bakhtiarizadeh and Dehghanian.)

Quercetin (QC) is a dietary bioflavonoid that can be conjugated with nanoparticles to facilitate its brain bioavailability. We previously showed that quercetin-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) reduced the level of blood glucose in diabetic rats. Glucose transporters (GLUTs), insulin-like growth factor-1 (IGF-1), and microRNA-29 (miR-29) play a critical role in brain glucose homeostasis. In the current study, we examined the effects of QCSPION on the expression of glucose metabolism-related genes, and the miR-29 family as a candidate regulator of glucose handling in the hippocampus of diabetic rats. Our in silico analyses introduce the miR-29 family as potential regulators of glucose transporters and IGF-1 genes. The expression level of the miR-29 family, IGF-1, GLUT1, GLUT2, GLUT3, and GLUT4 were measured by qPCR. Our results indicate that diabetes significantly results in upregulation of the miR-29 family and downregulation of the GLUT1, 2, 3, 4, and IGF-1 genes. Interestingly, QCSPIONs reduced miR-29 family expression and subsequently enhanced GLUT1, 2, 3, 4, and IGF-1expression. In conclusion, our findings suggest that QCSPION could regulate the expression of the miR-29 family, which in turn increases the expression of glucose transporters and IGF-1, thereby reducing diabetic complications.

Alterations in the regulatory mechanisms that control the process of myelination in the nervous system, may lead to the impaired myelination in the Multiple sclerosis. The Hippo pathway is an important mediator of myelination in the nervous system and might contribute to the pathophysiology of MS. This study examined via qPCR the RNA expression of YAP1, TAZ, and CRB3 as the key effectors of the Hippo pathway and also, VDR in the peripheral blood of 35 sporadic, 37 familial MS patients; and also 34 healthy first-degree relatives of the familial MS patients (HFR) and 40 healthy individuals without a family history of the disease (control). The results showed the increased expression of VDR in the sporadic group, as compared to other groups. There was also an increased expression of TAZ in the familial and HFR groups, as compared to the control group. The familial and sporadic patients displayed a significantly lower level of expression of YAP1 in comparison to the HFR group. The increased expression level in the sporadic patients and control group, as compared to the HFR group, was seen in CRB3. We also assessed different clinical parameters and MRI characteristics of the patients. Overall, these findings suggest that Hippo pathway effectors and also VDR gene may play a potential role in the pathophysiology of the sporadic and familial forms of MS. Confirmation of different gene expression patterns in sporadic and familial MS groups may have obvious implications for the personalization of therapies in the disease.

Quercetin-conjugated superparamagnetic iron oxide nanoparticles (QCSPIONs) have an ameliorative effect on diabetes-induced memory impairment. The current study aimed to compare the effect of quercetin (QC) and QCSPIONs on inflammation-related microRNAs and NF-κB signaling pathways in the hippocampus of diabetic rats. The expression levels of miR-146a, miR-9, NF-κB, and NF-κB-related downstream genes, including TNF-α, BACE1, AβPP, Bax, and Bcl-2 were measured using quantitative real-time PCR. To determine the NF-κB activity, immunohistochemical expression of NF-κB/p65 phosphorylation was employed. Computer simulated docking analysis also performed to find the QC target proteins involved in the NF-κB pathway. Results indicate that diabetes significantly upregulated the expression levels of miR-146a, miR-9, TNF-α, NF-κB, and subsequently AβPP, BACE1, and Bax. Expression analysis shows that QCSPIONs are more effective than pure QC in reducing the expression of miR-9. Interestingly, QCSPIONs reduce the pathological activity of NF-κB and subsequently normalize BACE1, AβPP, and the ratio of Bax/Bcl-2 expression better than pure QC. Comparative docking analyses also show the stronger binding affinity of QC to IKK and BACE1 proteins compared to specific inhibitors of each protein. In conclusion, our study suggests the potent efficacy of QCSPIONs as a promising drug delivery system in memory improvement through targeting the NF-κB pathway.

Blood supply managers in the blood supply chain have always sought to create enough reserves to increase access to different blood products and reduce the mortality rate resulting from expired blood. Managers' adequate and timely response to their customers is considered vital due to blood perishability, uncertainty of blood demand, and the direct relationship between the availability/lack of blood supply and human life. Further to this, hospitals' awareness of the optimal amount of requests from suppliers is vital to reducing blood return and blood loss, since the loss of blood products surely leads to high expenses. This paper aims to design an optimal management model of blood transfusion network by a synthesis of reusable simulation technique (applicable to all bases) and deep neural network (the latest neural network technique) with multiple recursive layers in the blood supply chain so that the costs of blood waste, return, and shortage can be reduced. The model was implemented on and developed for the blood transfusion network of Khorasan Razavi, which has 6 main bases active from October 2015 to October 2017. In order to validate the data, the data results of the variables examined with the real data were compared with those of the simulation, and the insignificant difference between them was investigated by t test. The solution of the model facilitated a better prediction of the amount of hospital demand, the optimal amount of safety reserves in the bases, the optimal number of hospital orders, and the optimal amount of hospital delivery. This prediction helps significantly reduce the return of blood units to bases, increase availability of inventories, and reduce costs.

We investigated the physiological and proteomic changes in the leaves of three Lolium perenne genotypes, one Iranian putative self-pollinating genotype named S10 and two commercial genotypes of Vigor and Speedy, subjected to drought stress conditions. The results of this study indeed showed higher RWC (relative water content), SDW (shoot dry weight), proline, ABA (abscisic acid), nitrogen and amino acid contents, and antioxidant enzymes activities of S10 under drought stress in comparison with the two other genotypes. A total of 915 proteins were identified using liquid chromatography-mass spectrometry (LC/MS) analysis, and the number of differentially abundant proteins between normal and stress conditions was 467, 456, and 99 in Vigor, Speedy, and S10, respectively. Proteins involved in carbon and energy metabolism, photosynthesis, TCA cycle, redox, and transport categories were up-regulated in the two commercial genotypes. We also found that some protein inductions, including those involved in amino acid and ABA metabolisms, aquaporin, HSPs, photorespiration, and increases in the abundance of antioxidant enzymes, are essential responses of the two commercial genotypes to drought stress. In contrast, we observed only slight changes in the protein profile of the S10 genotype under drought stress. Higher homozygosity due to self-pollination in the genetic background of the S10 genotype may have led to a lower variation in response to drought stress conditions., Competing Interests: The authors have declared that no competing interests exist.

Traumatic brain injury (TBI), a leading cause of morbidity and mortality throughout the world, will probably become the third cause of death in the world by the year 2020. Lack of effective treatments approved for TBI is a major health problem. TBI is a heterogeneous disease due to the different mechanisms of injury. Therefore, it requires combination therapies or multipotential therapy that can affect multiple targets. In recent years, mesenchymal stem cells (MSCs) transplantation has considered one of the most promising therapeutic strategies to repair of brain injuries including TBI. In these studies, it has been shown that MSCs can migrate to the site of injury and differentiate into the cells secreting growth factors and anti-inflammatory cytokines. The reduction in brain edema, neuroinflammation, microglia accumulation, apoptosis, ischemia, the improvement of motor and cognitive function, and the enhancement in neurogenesis, angiogenesis, and neural stem cells survival, proliferation, and differentiation have been indicated in these studies. However, translation of MSCs research in TBI into a clinical setting will require additional preclinical trials.

Deoxyribozymes or DNAzyme are identified as catalytic DNA sequences which catalyze different chemical reactions. Ligating deoxyribozymes catalyze the formation of branched and linear products. Due to the lack of efficient read-out systems, there is no report on in vivo application of ligating deoxyribozymes. To expand the biological application of branched-RNA forming deoxyribozymes, we performed our study in order to suggest a practical toolkit for measurement of in vivo real-time activity of ligating deoxyribozymes. Further in vitro studies were designed to analyze the effects of the location of branch site on reverse transcriptase (RT) interference. With this toolkit even the activity of RT was measured precisely. Our results indicate that the activity of RT enzyme significantly affected by a 17 nt branched adaptor synthesized by 10DM24 ligating deoxyribozyme. The RT stalls at or near the RNA branch point during both initiation and elongation phases. The DNA synthesis is decreased 4.3 and 2.7 fold during initiation and elongation phases respectively. In conclusion, we introduce a general and practical toolkit called "DMLR" which is based on Real-time PCR method. The use of DMLR precisely determines RT behavior when encountered with any backbone modification with the ability of stopping the enzyme activity., Competing Interests: Declaration of competing interest We have no conflict of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Rett syndrome (RTT) is an X-linked severe neurological disorder. Mutations in Methyl-CpG-Binding Protein2 (MECP2) gene are the main cause of RTT disease. In this study, we report the results of screening the MECP2 gene for mutations in 7 Iranian patients with RTT syndrome. MECP2 sequencing identified two novel mutations in the heterozygous state, a splice mutation, c.354G>T, p.Gly119Gly, resulting in a premature splice-donor site and a 20-bp deletion, c.1167-1186del20 (p.P390Rfs), leading to modifying the c-terminal parts of the protein and it also changes the reading frames of all coding sequence downstream of the mutation. Multiple sequence alignment showed that amino acid changes occurred in the well conserved protein regions across species. Based on the results of this study and literature reviews, about 70% of mutations are found in exon 3 and 4 of the MECP2 gene, and mutations in exon 4 are more common than other exons. Therefore, it is recommended that exon 4 to be a priority for screening the genetic analysis of RTT patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The Hippo signaling pathway is identified as a potential regulatory pathway which plays critical roles in differentiation and stem cell self-renewal. Yap1 is a primary transcriptional effector of this pathway. The importance of Yap1 in embryonic stem cells (ESCs) and differentiation procedure remains a challenging question, since two different observations have been reported. To answer this question we used co-expression network and differential co-expression analyses followed by experimental validations. Our results indicate that Yap1 is highly co-expressed with stem cell markers in ESCs but not in differentiated cells (DCs). The significant Yap1 down-regulation and also translocation of Yap1 into the cytoplasm during P19 differentiation was also detected. Moreover, our results suggest the E2f7, Lin28a and Dppa4 genes as possible regulatory nuclear factors of Hippo pathway in stem cells. The present findings are actively consistent with studies that suggested Yap1 as an essential factor for stem cell self-renewal., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A large number of studies have focused on the generation of dopaminergic neurons from pluripotent cells. Differentiation of stem cells into distinct cell types is influenced by tissue-specific microenvironment. Since, central nervous system undergoes further development during postnatal life, in the present study neonatal rat brain tissue extract (NRBE) was applied to direct the differentiation of embryonal carcinoma stem cell line, P19 into dopaminergic (DA) phenotypes. Additionally, a neuroprotective drug, deprenyl was used alone or in combination with the extract. Results from morphological, immunofluorescence, and qPCR analyses showed that during a period of one to three weeks, a large percentage of stem cells were differentiated into neural cells. The results also indicated the greater effect of NRBE on the differentiation of the cells into tyrosine hydroxylase-expressing cells. MS analysis of NRBE showed the enrichment of gene ontology terms related to cell differentiation and neurogenesis. Network analysis of the studied genes and some DA markers resulted in the suggestion of potential regulatory candidates such as AVP, ACHE, LHFPL5, and DLK1 genes. In conclusion, NRBE as a natural native inducer was apparently able to simulate the brain microenvironment and support neural differentiation of P19 cells., (© 2019 Wiley Periodicals, Inc.)

Background: Type 1 diabetes (T1D) is a multifactorial disease identified by a deficiency in the production of insulin. MicroRNAs (miRNAs) are identified as important epigenetic regulators in T1D. Many studies highlight the differential expression of these small non-coding molecules in the pathogenesis of T1D., Aim of the Study: In the present study, the expression pattern of miR-21, miR-155 and miR-338 were analyzed in the peripheral blood mononuclear cells (PBMCs) of T1D patients compared to healthy controls., Methods: The expression levels of miR-21, miR-155 and miR-338 were measured in the PBMCs of 30 T1D patients and 11 healthy controls by real time PCR method. The final results were statistically analyzed and ROC curves were created for miRNAs with significant differential expression., Results: Both miR-155 (p value: 0.021) and miR-21 (p value: 0.05) were upregulated in the PBMCs of T1D patients compared to healthy controls. There was no significant difference in the expression level of miR-338 between patients and controls. Furthermore, ROC curve analysis was performed for miR-21 (AUC: 0.65) and miR-155 (AUC: 0.73) which suggests the potential role of miR-155 as a biomarker in T1D patients. Using integrative computational analysis, a number of dysregulated miR155-mRNA and miR21-mRNA interactions were also suggested., Conclusion: Our findings suggest the significant association between the expression levels of miR-21 and miR-155 with T1D. In addition, miR-155 (AUC: 0.73) could be considered as a possible biomarker to track disease in T1D patients., (Copyright © 2019 IMSS. Published by Elsevier Inc. All rights reserved.)

Type 1 diabetes (T1D) is an autoimmune disorder which is characterized by autoimmune attack on β cells of pancreas and lack of insulin. The involvement of microRNAs (miRNAs) in the development of immune system and their differential expression in various autoimmune diseases including T1D have been well established. In this study, the association between expression levels of miR-20a, miR-326 and T1D were evaluated. The expression levels of miR-20a and miR-326 were measured in the PBMCs of 21 T1D patients and 16 healthy controls using qPCR method. In silico analysis was also performed on targetome of miR-20a and miR-326. Both miR-20a (p value: 0.015) and miR-326 (p value: 0.005) were upregulated in the PBMCs of T1D patients compared to healthy controls. Furthermore, different dysregulated miR326-mRNA and miR20a-mRNA interactions were also suggested using integrative computational analysis. The expression level of miR-20a and miR-326 indicates significant association with T1D which suggests the possible regulatory effects of these non-coding RNAs in T1D.

Heterogeneous astrocyte populations are defined by diversity in cellular environment, progenitor identity or function. Yet, little is known about the extent of the heterogeneity and how this diversity is acquired during development. To investigate the impact of TGF (transforming growth factor) β-signaling on astrocyte development in the telencephalon we deleted the TGFBR2 (transforming growth factor beta receptor 2) in early neural progenitor cells in mice using a FOXG1 (forkhead box G1)-driven CRE-recombinase. We used quantitative proteomics to characterize TGFBR2-deficient cells derived from the mouse telencephalon and identified differential protein expression of the astrocyte proteins GFAP (glial fibrillary acidic protein) and MFGE8 (milk fat globule-EGF factor 8). Biochemical and histological investigations revealed distinct populations of astrocytes in the dorsal and ventral telencephalon marked by GFAP or MFGE8 protein expression. The two subtypes differed in their response to TGFβ-signaling. Impaired TGFβ-signaling affected numbers of GFAP astrocytes in the ventral telencephalon. In contrast, TGFβ reduced MFGE8-expression in astrocytes deriving from both regions. Additionally, lineage tracing revealed that both GFAP and MFGE8 astrocyte subtypes derived partly from FOXG1-expressing neural precursor cells.

The Hippo signaling pathway (HSP) has been identified as an essential and complex signaling pathway for tumor suppression that coordinates proliferation, differentiation, cell death, cell growth and stemness. In the present study, we conducted a genome-scale co-expression analysis to reconstruct the HSP in colorectal cancer (CRC). Five key modules were detected through network clustering, and a detailed discussion of two modules containing respectively 18 and 13 over and down-regulated members of HSP was provided. Our results suggest new potential regulatory factors in the HSP. The detected modules also suggest novel genes contributing to CRC. Moreover, differential expression analysis confirmed the differential expression pattern of HSP members and new suggested regulatory factors between tumor and normal samples. These findings can further reveal the importance of HSP in CRC., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

G M2 gangliosides are a group of lysosomal lipid storage disorders that are due to mutations in HEXA , HEXB and GM2A . In our study, 10 patients with these diseases were enrolled, and Sanger sequencing was performed for the HEXA and HEXB genes. The results revealed one known splice site mutation (c.346+1G>A, IVS2+1G>A) and three novel mutations (a large deletion involving exons 6-10; one nucleotide deletion, c.622delG [p.D208Ifsx15]; and a missense mutation, c.919G>A [p.E307K]) in HEXA . In HEXB , one known mutation (c.1597C>T [p.R533C]) and one variant of uncertain significance (c.619A>G [p.I207V]) were identified. Five patients had c.1597C>T in HEXB , indicating a common mutation in south Iran. In this study, a unique large deletion in HEXA was identified as a homozygous state. To predict the cause of the large deletion in HEXA , RepeatMasker was used to investigate the Alu elements. In addition, to identify the breakpoint of this deletion, PCR was performed around these elements. Using Repeat masker, different Alu elements were identified across HEXA , mainly in intron 5 and intron 10 adjacent to the deleted exons. PCR around the Alu elements and Sanger sequencing revealed the start point of a large deletion in Alu Sz6 in the intron 6 and the end of its breakpoint 73 nucleotides downstream of Alu Jo in intron 10. Our study showed that HEXA is an Alu -rich gene that predisposes individuals to disease-associated large deletions due to these elements., Competing Interests: The authors declare no conflict of interest.

Competing Interests: Authors' Disclosures of Potential Conflicts of Interest: No potential conflicts of interest relevant to this article were reported.

Crizotinib is an anticancer tyrosine kinase inhibitor that is approved for use as a first-line treatment for some non-small-cell lung cancers. L1196M is the most frequently observed mutation in NSCLC patients. This mutation, known as the gatekeeper mutation in the ALK kinase domain, confers resistance to crizotinib by sterically blocking the binding of the drug. However, the molecular mechanism of crizotinib resistance caused by the L1196M mutation is still unclear. Molecular dynamics simulation was therefore utilized in this study to investigate the mechanism by which the L1196M mutation may affect crizotinib resistance. Our results suggest that larger fluctuations in some important regions of the mutant complex compared to the wild-type complex may contribute to the resistance of the mutant complex to crizotinib. Also, mutation-induced alterations to the secondary structure of the complex as well as unstable hydrogen-bonding patterns in the A-loop and P-loop regions decrease the total binding energy of the complex. This study therefore provides a molecular explanation for the resistance to crizotinib caused by the L1196M mutation, which could aid the design of more efficient and selective drugs.

Neuronal activity is altered in several neurological and psychiatric diseases. Upon depolarization not only neurotransmitters are released but also cytokines and other activators of signaling cascades. Unraveling their complex implication in transcriptional control in receiving cells will contribute to understand specific central nervous system (CNS) pathologies and will be of therapeutically interest. In this study we depolarized mature hippocampal neurons in vitro using KCl and revealed increased release not only of brain-derived neurotrophic factor (BDNF) but also of transforming growth factor beta (TGFB). Neuronal activity together with BDNF and TGFB controls transcription of DNA modifying enzymes specifically members of the DNA-damage-inducible (Gadd) family, Gadd45a, Gadd45b, and Gadd45g. MeDIP followed by massive parallel sequencing and transcriptome analyses revealed less DNA methylation upon KCl treatment. Psychiatric disorder-related genes, namely Tshz1, Foxn3, Jarid2, Per1, Map3k5, and Arc are transcriptionally activated and demethylated upon neuronal activation. To analyze whether misexpression of Gadd45 family members are associated with psychiatric diseases, we applied unpredictable chronic mild stress (UCMS) as established model for depression to mice. UCMS led to reduced expression of Gadd45 family members. Taken together, our data demonstrate that Gadd45 family members are new putative targets for UCMS treatments., (© The Author 2017. Published by Oxford University Press.)

Crizotinib is an efficient antineoplastic drug for treatment of non-small cell lung carcinoma (NSCLC), which is identified as an anaplastic lymphoma kinase (ALK) inhibitor. F1174V is a recently identified acquired point mutation relating to the Crizotinib resistance in NSCLC patients. The mechanism of Crizotinib resistance relating to F1174V mutation as a non-active site mutation remains unclear. In this study, the molecular dynamic simulation was used to investigate the possible mechanisms by which F1174V mutation may affect the structure and activity of ALK kinase domain. The results suggested that F1174V mutation could cause two important secondary structure alterations, which led to the local conformational change in ALK kinase domain. This causes more positive free energy in the mutant complex in comparison with the wild-type one. In addition, our structural analyses illustrated that F1174V mutation could result in some important interactions, which represent the key characteristics of the ALK active conformation. This study provided a molecular mechanism for ALK Crizotinib resistance caused by F1174V mutation,which could facilitate designing more efficient drugs., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder among the elderly. Because the existing treatments for Alzheimer's disease only offer limited symptomatic alleviation, more efficient therapeutic agents are urgently needed. Date seed is a hepatoprotective and neuroprotective agent. Date seed extract (DSE) has bioactive components like phenolics, flavonoids, and vitamins. In view of the ameliorative effects of DSE against an oxidative injury, the current study was designed to reveal whether DSE has a neuroprotective resource in the rat model of Alzheimer's disease. In the current study, 24 adult male Sprague-Dawely rats were divided into three groups (n=8) of: Sham (Distilled Water, 3μl intracerebroventricular (ICV) injection), β-Amyloid (β-amyloid, 3μl ICV injection), and DSE-treated groups (80mg/kg, Intraperitoneal (IP) injection), for 12days. Twelve days after Alzheimer induction, behavioral analysis, the Morris Water Maze (MWM), as well as western blot and histological studies were performed to reveal the neuroprotective potential of DSE in rats. Administration of DSE significantly restored memory and learning impairments induced by Aβ in the MWM test. DSE significantly decreased the caspase-3 expression level in the treated group. In addition, DSE reduced the number of degenerated neurons in the hippocampal CA1 subfield of the DSE treated rats. These results demonstrate that DSE may have beneficial effects in the prevention of Aβ-induced Alzheimer in a rat model. Date seed extract may have advantageous effects in preventing Alzheimer's disease in male rats., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Deficiency of phenylalanine hydroxylase (PAH) enzyme and elevation of phenylalanine in body fluids cause phenylketonuria (PKU). The gold standard for confirming PKU and PAH deficiency is detecting causal mutations by direct sequencing of the coding exons and splicing involved sequences of the PAH gene. Furthermore, haplotype analysis could be considered as an auxiliary approach for detecting PKU causative mutations before direct sequencing of the PAH gene by making comparisons between prior detected mutation linked-haplotypes and new PKU case haplotypes with undetermined mutations., Methods: In this study, 13 unrelated classical PKU patients took part in the study detecting causative mutations. Mutations were identified by polymerase chain reaction (PCR) and direct sequencing in all patients. After that, haplotype analysis was performed by studying VNTR and PAHSTR markers (linked genetic markers of the PAH gene) through application of PCR and capillary electrophoresis (CE)., Results: Mutation analysis was performed successfully and the detected mutations were as follows: c.782G>A, c.754C>T, c.842C>G, c.113-115delTCT, c.688G>A, and c.696A>G. Additionally, PAHSTR/VNTR haplotypes were detected to discover haplotypes linked to each mutation., Conclusions: Mutation detection is the best approach for confirming PAH enzyme deficiency in PKU patients. Due to the relatively large size of the PAH gene and high cost of the direct sequencing in developing countries, haplotype analysis could be used before DNA sequencing and mutation detection for a faster and cheaper way via identifying probable mutated exons.

Background: Some dynamic changes occurs during spermatogenesis such as histone removal and its replacement with transition nuclear protein and protamine. These proteins are required for packing and condensation of sperm chromatin. JHDM2A is a histone demethylase that directly binds to promoter regions of Tnp1 and Prm1 genes and controls their expression by removing H3K9 at their promoters., Objective: The association between polymorphisms of exon 12 and exon 24 in JHDM2A gene and male infertility were evaluated for the first time., Materials and Methods: In this experimental study, 400 infertile men (oligospermia and azoospermia) and normal healthy fathers were evaluated (n=200). Single Strand Conformation Polymorphism (SSCP-PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods were used for screening any polymorphisms that are exist in exon 12 and exon 24., Results: Exon 24 PCR products were analyzed by RFLP but no polymorphism was found in this exon at the restriction site of EcoRV enzyme. Our monitoring along the whole nucleotides of exon 12 and exon 24 were continued using SSCP method, but we found no change along these exons., Conclusion: Generally, this study evaluated the association between polymorphisms in exon 12 and exon 24 of JHDM2A gene and male infertility which suggests that polymorphisms of these exons may not be associated with the risk of male infertility.

Azo dyes are one of the most important class of dyes, which have been widely used in industries. Because of the environmental pollution of azo dyes, many studies have been performed to study their biodegradation using bacterial systems. In present work, the AzrC of mesophilic gram-positive Bacillus sp. B29 has been considered to study its interaction with five common azo dyes (orange G, acid red 88, Sudan I, orange I, and methyl red). The molecular dynamics simulations have been employed to study the interaction between AzrC and azo dyes. The trajectory was confirmed using root mean square deviation and the root mean square fluctuation analyses. Then, the hydrogen bond and alanine scanning analyses were performed to reveal active site residues. Phe105 (A), Phe125 (B), Phe172 (B), and Pro132 (B) have been found as the most important hydrophobic residues whereas Asn104 (A), Tyr127 (B), and Asn187 (A) have key role in making hydrogen bond. The results of molecular mechanics Poisson-Boltzmann surface area and molecular mechanics generalized Born surface area calculations proved that the hydrophobic azo dyes like Acid red 88 binds more tightly to the AzrC protein. The calculated data suggested MR A 121 (B) I as a potential candidate for improving the AzrC-MR interactions.

Background: The risk of developing female infertility has been associated with gene polymorphisms that decrease the activity of enzymes involved in systemic Oxidative Stress (OS). In this study, PON1 L55M polymorphism for association with susceptibility to infertility was investigated among Iranian female population., Methods: Samples from 120 Iranian females [20 endometriosis; 30 Polycystic Ovary Syndrome (PCO); 70 controls] were analyzed and PCR-RFLP assay was used to determine the PON1 rs854560 (L55M) frequencies. The paraoxonase (PONase) and arilesterase (AREase) activities of PON1 enzyme were also assessed in order to investigate the association between serum PON1 activities, female infertility, and PON1 L55M polymorphism., Results: The women with a MM genotype (p=0.021; OR=2.55) showed more possibilities of experiencing infertility than those with a LM genotype (p=0.039; OR=1.91). According to LSD test, endometriosis subjects had significantly lower paraoxonase enzyme activity compared to control group (p=0.0024; CI=95%). No significant difference was found in women with PCOS for both PONase and AREase activity in comparison with control group (p=0.469; CI=95%). Furthermore, PON1 activities were the highest in LL genotype followed by LM and then MM genotype (MM

Azo dyes are broadly used in different industries through their chemical stability and ease of synthesis. These dyes are usually identified as critical environmental pollutants and many attentions were performed to degradation of azo dyes using biological systems. In this study, the interactions of an azoreductase from mesophilic gram-positive Bacillus sp. B29, AzrC, with four common azo dyes (orange I, orange II, orange G and acid red 88) were investigated. Fifteen points, double, triple and quadruple mutant forms of AzrC were made using Molegro Virtual Docker 6.0 in order to improve the binding affinity of azo dyes to AzrC. The impact of 15 different mutations on azo dye affinity potency of AzrC was computationally analyzed using AzrC-azo dye molecular docking, and each interaction was scored based on AutoDock 4.2 free binding energy. Our results have indicated that Asn 104 (A), Asn 187 (B), and Tyr 151 (A) make stable hydrogen bond between AzrC and azo dyes. The hydrophobic amino acids like Phe105 (A), Phe 125 (B), and Phe 172 (B) in wild type form make hydrophobic interactions. In addition, the presence of more hydrophobic residues F60 (B), I119 (B), I121 (B) and F132 (B) in mutant forms made more powerful hydrophobic pocket in the active site. In conclusion, recombinant AzrC with quadruple mutations was suggested in order to increase the biodegradation capacity of AzrC through improving its affinity to four studied azo dyes. This study would be promising for future experimental analyses in order to produce recombinant form of AzrC., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Infertility is a health problem which affects about 10-20% of married couples. Male factor infertility is involved approximately 50% of infertile couples. Most of male infertility is regarding to deletions in the male-specific region of the Y chromosome., Objective: In this study, the occurrence of deletions in the AZF region and association between infertility and paternal age were investigated in Iranian men population., Materials and Methods: To assess the occurrence of Y chromosomal microdeletions and partial deletions of the AZF region, 100 infertile men and 100 controls with normal spermatogenesis were analyzed. AZFa, AZFb, AZFc and partial deletions within the AZFc region were analyzed using multiplex PCR method. Finally, the association between paternal age and male infertility was evaluated., Results: No AZFa, AZFb or AZFc deletions were found in the control group. Seven infertile men had deletions as the following: one AZFb, five AZFc, and one AZFab. Partial deletions of AZFc (gr/gr) in 9 of the 100 infertile men (9/100, 9%) and 1 partial AZFc deletions (gr/gr) in the control group (1/100, 1%) were observed. In addition, five b2/b3 deletions in five azoospermic subjects (5/100, 5%) and 2 partial AZFc deletions (b2/b3) in the control group (2/100, 2%) were identified. Moreover, the risk of male infertility was influenced by the paternal age., Conclusion: The results of this study suggested that the frequency of Y chromosome AZF microdeletions increased in subjects with severe spermatogenic failure and gr/gr deletion associated with spermatogenic failure.

Among all VEGF-A isoforms, VEGF-111 is particularly important in molecular biology research owing to its potent angiogenic properties and its remarkable resistance to proteolysis. These features make it a potential candidate for therapeutic use in ischemic diseases. VEGF-111 is not expressed in normal cells, but expression is induced by UV-B irradiation and exposure to genotoxic agents. Here, to increase expression at the transcriptional and translational levels, we synthesized and cloned recombinant VEGF-111 cDNA. Two fragments encoding exons 1-4 and intron 4/5 plus exon 8a were amplified and cloned into the pBud.CE4.1 vector using a class IIs restriction enzyme-based method. The expression of VEGF-111 in CHO-dhfr - and HEK 293 cell lines was evaluated with real-time PCR, dot blotting, and ELISA. VEGF expression was increased about 10- and 18-fold in transfected CHO-dhfr - and HEK 293 cells, respectively. Dot blotting and ELISA confirmed successful production of VEGF-111 in both cell lines.

VEGF-A is a critical growth factor in tumor growth and progression. Two families of VEGF-A isoforms are produced through alternative splicing including VEGFxxx pro-angiogenic and VEGFxxxb anti-angiogenic isoforms. VEGF111b is a new member of the VEGFxxxb family that is induced by mitomycin C and doesn't express in normal conditions. The potent anti-angiogenic properties of VEGF-111b and its remarkable resistance to proteolysis make it an interesting alternative candidate for therapeutic use in all types of cancers. Here, the recombinant VEGF-111b cDNA with insertion of intronic sequence was constructed by using a class IIs restriction enzyme-based method. The recombinant pBud-VEGF111b was transfected into CHO dhfr(-) and HEK 293 cell lines which are currently the standard hosts for the production of candidate therapeutic proteins. Then, the VEGF-111b expression was evaluated in two cell lines using the Real-time PCR. The production of VEGF-111b protein was also investigated here by dot blotting. The VEGF expression was increased about 109 and 185-folds in transfected CHO-dhfr(-) and HEK 293 cells, respectively, in comparison with the un-transfected cells. Dot blotting approach confirmed that both cell lines have successfully produced the VEGF-111b protein., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Vascular endothelial growth factor (VEGF-A) is one of the most important regulatory factors in pathological and physiological angiogenesis. Alternative splicing is a complicated molecular process in VEGF-A gene expression which adds complexity to VEGF-A biology. Among all VEGF-A exons, alternative splicing of exon 8 is the key determinant of isoform switching from pro-angio-genic VEGF-xxx to anti-angiogenic VEGF-xxxb. This is known as a key molecular switching in many pathological situations. In fact, the balance between VEGF-xxx and VEGF-xxxb isoforms is a critical controlling switch in both conditions of health and disease. Here, the properties of VEGF-xxx and VEGF-xxxb isoforms were discussed and their regulatory mechanism and their roles in certain pathological processes were evaluated. In summary, it was suggested that C-terminal VEGF-A alternative splicing can provide a new treatment opportunity in angiogenic diseases.

Objective: People are usually susceptible to carcinogenic aromatic amines, present in cigarrette smoke and polluted environment, which can cause DNA damage. Therefore, maintenance of genomic DNA integrity is a direct result of proper function of DNA repair enzymes. Polymorphic diversity could affect the function of repair enzymes and thus augment the risk of different cancers. Xeroderma pigmentosum group D (XPD) gene encodes one of the most prominent repair enzymes and the polymorphisms of this gene are thought to be of importance in lung cancer risk. This gene encodes the helicase, which is a component of transcription factor IIH and an important part of the nucleotide excision repair system. Studies reveal that individuals with Lys751Gln polymorphism of XPD gene have a low repairing capacity to delete the damages of ultraviolet light among other XPD polymorphisms., Materials and Methods: In this case-control study, first Lys751Gln polymorphism was genotyped, then its association with lung cancer risk was analyzed. Genomic DNA was extracted from the whole blood sample of 640 individuals from Iran (352 healthy individuals and 288 patients). Allele frequencies and heterozygosity of Lys751Gln polymorphism were determined using polymerase chain reaction-restriction fragment length polymorphism method., Results: According to statistical analyses, lung cancer risk in individuals with Lys751Gln polymorphism (Odd Ratio=1.8, 95% Confidence Interval 0.848-3.819) is approximately twice as high as that of Lys/Lys genotype, however 751Gln/Gln genotype did not relate to lung cancer risk (Odd Ratio=0.7, 95% Confidence Interval 0/307-1/595)., Conclusion: This study suggests that heterozygous polymorphism (Lys/Gln) increases the sensitivity of lung cancer risk, while homozygous polymorphism (Lys/Lys) probably decreases its risk and C allele frequency shows no remarkable increase in the patients.

Multiple sclerosis (MS) is one of the most important autoimmune diseases recognized by demyelination and axonal lesion. It is the most common cause of disability in the young population. Various immunomodulatory and immunosuppressive therapies, including different formulations of interferon beta (IFNβ), glatiramer acetate (GA), mitoxantrone, and natalizumab are available for this disease. However, interferon has been the best prescribed. Although the precise mechanism of IFNβ is unclear, many studies indicate some potential mechanism including blocking T cells activation, controlling pro- and anti-inflammatory cytokine secretion, preventing activated immune cell migration through BBB, and inducing repair activity of damaged nerve cells by differentiating neural stem cells into oligodendrocytes. These molecular mechanisms have significant roles in IFNβ therapy. More researches are required in order for us to comprehend the mechanism of action of IFNβ, and improve and develop drugs for more efficient MS treatment.

Anti-inflammatory and anti-oxidant agents can alleviate ischemic cerebral injury. The immunomodulary drug Setarud, which is composed of herbal extracts including Rosa canina, Urtica dioica and Tanacetum vulgare, supplemented with selenium exhibits anti-inflammatory and anti-oxidant properties. Therefore, we hypothesized that Setarud will have a neuroprotective effect against ischemic cerebral injury. To validate this hypothesis, rats were intraperitoneally administered with 0.66 mL/kg Setarud for 30 minutes after middle cerebral artery occlusion. Triphenyltetrazolium chloride staining showed that Setarud could reduce cerebral infarct volume of rats subjected to cerebral ischemia. Transmission electron microscopy and hematoxylin-eosin staining results showed that Setarud could alleviate the degenerative changes in cortical neurons of rats with cerebral ischemia. The inclined plate test and prehensile test showed that Setarud could significantly improve the motor function of rats with cerebral ischemia. These findings suggest that Setarud shows neuroprotective effects against ischemic brain injury.