Extending the solid step fixed-charge transportation problem to consider two-stage networks and multi-item shipments

This paper develops a new mathematical model for a capacitated solid step fixed-charge transportation problem. The problem is formulated as a two-stage transportation network and considers the option of shipping multiple items from the plants to the distribution centers (DC) and afterwards from DCs to customers. In order to tackle such an NP-hard problem, we propose two meta-heuristic algorithms; namely, Simulated Annealing (SA) and Imperialist Competitive Algorithm (ICA). Contrary to the previous studies, new neighborhood strategies maintaining the feasibility of the problem are developed. Additionally, the Taguchi method is used to tune the parameters of the algorithms. In order to validate and evaluate the performances of the model and algorithms, the results of the proposed SA and ICA are compared. The computational results show that the proposed algorithms provide relatively good solutions in a reasonable amount of time. Furthermore, the related comparison reveals that the ICA generates superior solutions compared to the ones obtained by the SA algorithm

The Founder Effect? -FXIII Deficiency in Southeast Iran: A Molecular Study Report

Background: Congenital factor XIII (FXIII) deficiency is an extremely rare bleeding disorder (RBD) with different clinical coagulation disorders and great impacts on the perioperative patient outcome. Its prevalence in Southeast Iran is approximately 4,000 times higher than the worldwide prevalence, with Trp187Arg (c.559T> C as the only causative mutation of FXIIID there. We investigated the founder effect of rs1742924, rs4960181, rs3778360 and rs4142290 using haplotype analysis to define the genetic phenomenon in this geographic region. Materials and Methods: In a case-control study, 10 patients with FXIIID and 10 healthy individuals were assessed. Initially, Trp187Arg (c.559T> C) mutation was assessed in all study populations using a PCR-RFLP technique, then haplotype analysis was performed by assessing rs1742924, rs4960181, rs3778360 and rs4142290 polymorphisms. Data were analyzed using a two-proportion z-test. Results: All patients were homozygote for Trp187Arg (c.559T>C), and this mutation was not observed in any form of homozygote or heterozygote in the control group. Polymorphisms in rs1742924, rs4960181, and rs377836 were homozygote (TT, GG, GG, respectively) and T, G, and G alleles distribution in cases and controls with significant difference (P<0.001, P<0.001, and P=0.01 respectively). Rs4142290 polymorphism showed no significant difference between patients and controls (P=0.3). Two types of haplotypes were observed in the case group, and haplotype number 1* was observed among 90% of them, while not observed in the control group. Conclusion: It seems that founder effectors of haplotype number *1 have more antiquity versus other haplotypes, and probably founder effect is responsible for this high prevalence of FXIIID in the southeast of Iran

Remote controlling of CAR-T cells and toxicity management: Molecular switches and next generation CARs

Cell-based immunotherapies have been selected for the front-line cancer treatment approaches. Among them, CAR-T cells have shown extraordinary effects in hematologic diseases including chemotherapy-resistant acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL). In this approach, autologous T cells isolated from the patient's body genetically engineered to express a tumor specific synthetic receptor against a tumor antigen, then these cells expanded ex vivo and re-infusion back to the patient body. Recently, significant clinical response and high rates of complete remission of CAR T cell therapy in B-cell malignancies led to the approval of Kymriah and Yescarta (CD19-directed CAR-T cells) were by FDA for treatment of acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Despite promising therapeutic outcomes, CAR T cells also can elicit the immune-pathologic effects, such as Cytokine Release Syndrome (CRS), Tumor Lysis Syndrome (TLS), and on-target off-tumor toxicity, that hampered its application. Ineffective control of these highly potent synthetic cells causes discussed potentially life-threatening toxicities, so researchers have developed several mechanisms to remote control CAR T cells. In this paper, we briefly review the introduced toxicities of CAR-T cells, then describe currently existing control approaches and review their procedure, pros, and cons. © 2021 The Author

Mutation characterization and heterodimer analysis of patients with leukocyte adhesion deficiency: Including one novel mutation

Abstract Background and aim Leukocyte adhesion deficiency type 1 (LAD-I) is a rare, autosomal recessive disorder of neutrophil migration, characterized by severe, recurrent bacterial infections, inadequate pus formation and impaired wound healing. The ITGB2 gene encodes the β2 integrin subunit (CD18) of the leukocyte adhesion cell molecules, and mutations in this gene cause LAD-I. The aim of the current study was to investigate the mutations in patients diagnosed with LAD-I and functional studies of the impact of two previously reported and a novel mutation on the expression of the CD18/CD11a heterodimer. Materials and methods Blood samples were taken from three patients who had signed the consent form. Genomic DNA was extracted and ITGB2 exons and flanking intronic regions were amplified by polymerase chain reaction. Mutation screening was performed after Sanger sequencing of PCR products. For functional studies, COS-7 cells were co-transfected with an expression vector containing cDNA encoding mutant CD18 proteins and normal CD11a. Flow cytometry analysis of CD18/CD11a expression was assessed by dimer-specific IB4 monoclonal antibody. Results Two previously reported mutations and one novel mutation,p. Cys562Tyr, were found. All mutations reduced CD18/CD11 heterodimer expression. Conclusion Our strategy recognized the p.Cys562Tyr mutation as a pathogenic alteration that does not support CD18 heterodimer formation. Therefore, it can be put into a panel of carrier and prenatal diagnosis programs. Keywords Leukocyte adhesion deficiency type I Immunodeficiency Mutation Genetic testing CD1

Therapeutic applications of CRISPR/Cas9 system in gene therapy

Gene therapy is based on the principle of the genetic manipulation of DNA or RNA for treating and preventing human diseases. The clustered regularly interspaced short palindromic repeats/CRISPR associated nuclease9 (CRISPR/Cas9) system, derived from the acquired immune system in bacteria and archaea, has provided a new tool for accurate manipulation of genomic sequence to attain a therapeutic result. The advantage of CRISPR which made it an easy and flexible tool for diverse genome editing purposes is that a single protein (Cas9) complex with 2 short RNA sequences, function as a site-specific endonuclease. Recently, application of CRISPR/Cas9 system has become popular for therapeutic aims such as gene therapy. In this article, we review the fundamental mechanisms of CRISPR-Cas9 function and summarize preclinical CRISPR-mediated gene therapy reports on a wide variety of disorders. © 2018, Springer Science+Business Media B.V., part of Springer Nature

Therapeutic applications of CRISPR/Cas9 system in gene therapy

Gene therapy is based on the principle of the genetic manipulation of DNA or RNA for treating and preventing human diseases. The clustered regularly interspaced short palindromic repeats/CRISPR associated nuclease9 (CRISPR/Cas9) system, derived from the acquired immune system in bacteria and archaea, has provided a new tool for accurate manipulation of genomic sequence to attain a therapeutic result. The advantage of CRISPR which made it an easy and flexible tool for diverse genome editing purposes is that a single protein (Cas9) complex with 2 short RNA sequences, function as a site-specific endonuclease. Recently, application of CRISPR/Cas9 system has become popular for therapeutic aims such as gene therapy. In this article, we review the fundamental mechanisms of CRISPR-Cas9 function and summarize preclinical CRISPR-mediated gene therapy reports on a wide variety of disorders. © 2018, Springer Science+Business Media B.V., part of Springer Nature

MiR-330-3p and miR-485-5p as biomarkers for glioblastoma: An integrated bioinformatics and experimental study

Glioblastoma Multiforme (GBM) is the most common, invasive, and malignant primary brain tumor with a poor prognosis and a median survival of 12�15 months. This study tried to identify the most significant miRNA biomarkers in both tissue and serum samples of GBM. GSE25632 was employed from gene expression omnibus and using WGCNA package, association of miRNA networks and clinical data was explored and brown and green modules identified as the most relevant modules. Independently, Limma package was utilized to identify differentially expressed miRNAs (DEMs) in GSE25632 by cutoff logFC > 2 and P.value < 0.05. By merging the results of Limma and WGCNA, the miRNAs that were in brown and green modules and had mentioned cutoff were selected as hub miRNAs. Performing enrichment analysis, Pathways in cancer, Prostate cancer, Glioma, p53 signaling pathway, and Focal adhesion were identified as the most important signaling pathways. Based on miRNA- target genes, has-mir-330�3p and has-mir-485�5p were identified as core miRNAs. The expression level of core miRNAs was validated by GSE90604, GSE42657, and GSE93850. We evaluated the expression level of common target genes of two detected core genes based on GSE77043, GSE42656, GSE22891, GSE15824, and GSE122498. The ability of detected miRNAs to discriminate GBM from healthy controls was assessed by area under the curve (AUC) using the ROC curve analysis. Based on TCGA database, we tested the prognostic significance of miRNAs using overall survival analysis. We evaluated the expression level of the miRNAs in tissue of 83 GBM patients and also non-tumoral adjacent (as control) tissues. We used serum samples of 34 GBM patients to evaluate the expression levels of the hub miRNAs compare to the controls. Our results showed that has-mir-330�3p and has-mir-485�5p could be potential biomarkers in GBM. © 2021 Elsevier Lt

A novel human T17N-phospholamban variation in idiopathic dilated cardiomyopathy

Background: In humans mutations in the PLN gene, a crucial Ca2+ cycling protein, have been associated with idiopathic dilated cardiomyopathy with prevalence depending on the population. In Iran, the prevalence of PLN mutations in dilated cardiomyopathy patients is unknown. Our purpose was to identify PLN mutations in Iranian patients suffering from dilated cardiomyopathy. Methods: We studied 300 unrelated subjects with idiopathic dilated cardiomyopathy and 170 healthy controls for disease-causing PLN mutations by Sanger sequencing. Results: We identified one novel heterozygous variant in the PLN gene c.50C &gt; A (p.Thr17Asn). Identified variation probably results in loss of phosphorylation site of CaMK2 and Akt and is in HAX1 binding region. Bioinformatics analysis tools predicted the identified variation is likely pathogenic. Conclusions: In Iran, similar to most populations, PLN mutations are rarely cause of dilated cardiomyopathy. The confirmation of the pathogenicity of observed variation requires experimental validation. © 201

Screening the underlying molecular mechanisms involved in the development of heart failure

Heart failure (HF) causes a great socioeconomic and medical burden in our societies. We aimed to screen the molecular mechanisms related to the development of HF that may lead to new therapeutic targets. We incorporated four expression datasets (GSE5406, GSE1869, GSE29819, and GSE42955) of dilated cardiomyopathy (DCM) from GEO repository to identify differentially expressed genes (DEGs) between 33 controls and 111 patients. WGCNA package, MetaQC, MetaDE, and Metapath packages of Meta-omics, affy, and limma R packages have been used in the bioinformatics analysis for the assessment of quality control, differentially expressed genes and enrichment of detected genes. Search Tool for the Retrieval Interacting Genes (STRING) was used as well for the analysis of protein-protein interaction (PPI) network. Using the false discovery rate (FDR) cut-off of 0.0001, 508 genes (229 up-regulated and 279 down-regulated), were differentially expressed by the Fisher's method. The most enrichment Gene Ontology (GO) terms contain genes involved in oxidative phosphorylation (OXPHOS), proteasome complex, and protein folding related pathways. Finally, to increase the significance of our study, the identified DEGs by meta-analysis cross-checked by the results of the DEGs analysis of patients with right ventricular dysfunction (GSE29819, that contains 6 controls and 7 patients samples). Overall, our bioinformatic-based study provided a preliminary molecular profile which is worth to be further investigated as possible new therapeutic targets. © 2020 Elsevier B.V

How to assess founder effect in patients with congenital factor XIII deficiency

Congenital factor XIII (FXIII) deficiency is an extremely rare bleeding disorder (RBD) with estimated prevalence of one per 2 million in the general population. The disorder causes different clinical manifestations such as intracranial hemorrhage (ICH), recurrent miscarriage, umbilical cord bleeding, etc. High incidence of the disorder might be due to founder effect. To assess founder effect, haplotype analysis is an important step. For this purpose, suitable and reliable genetic markers such as microsatellites (Hum FXIIIA01 and HumFXIIIA02) and single nucleotide polymorphisms (SNP) are suggested. In the present study we tried to describe evaluation of founder effect in patients with congenital FXIII deficiency via haplotype analysis using suitable genetic markers. © 2020, Tehran University of Medical Sciences (TUMS). All rights reserved