CD44 Suppression Improved the Chemosensitivity of HT-29 Colorectal Cancer Cells to 5-Fluorouracil and Inhibited Cell Migration

Purpose: CD44 plays a pivotal role through tumorigenesis by regulating cancer cell metastasis, stemness, and chemosensitivity and is considered a promising therapeutic target for human cancers, including colorectal cancer (CRC). Therefore, the present research aimed to examine the simultaneous therapeutic effect of CD44 silencing and 5-fluorouracil (5-FU) on in vitro tumorigenesis of CRC cells. Methods: CD44 expression was initially evaluated in TCGA datasets and CRC tissues. Furthermore, functional analysis was performed on HT-29 CRC cells overexpressing CD44. The cells were transfected with CD44 siRNA and then treated with 5-FU. Consequently, to explore the combination therapy effect on cell viability, migration, apoptosis, and chromatin fragmentation, we performed MTT assay, scratch assay, Annexin V/PI staining and DAPI staining assays, respectively. The spheroid and colony formation assays were further employed to investigate stemness features. The gene expression at protein and mRNA levels were explored using western blotting and qPCR. Results: Our findings illustrated that CD44 was significantly overexpressed in CRC tissues compared to normal samples. The suppression of CD44 considerably promoted the chemosensitivity of HT-29 cells to 5-FU by apoptosis induction. Also, the combination therapy led to overexpression of apoptotic genes, including P53, caspase-3, and caspase-9, as well as downregulation of AKT1 expression. Furthermore, CD44 suppression, separately or combined with 5-FU, hindered stemness properties in HT-29 cells via downregulation of Sox2 and Nanog expression. Besides, the combination therapy remarkably downregulated MMPs and suppressed CRC cell migration. Conclusion: Considering its involvement in chemosensitivity to 5-FU, CD44 could be suggested as a potential target for improving the efficiency of CRC chemotherapy

Prune-1 drives polarization of tumor-associated macrophages (TAMs) within the lung metastatic niche in triple-negative breast cancer

M2-tumor-associated macrophages (M2-TAMs) in the tumor microenvironment represent a prognostic indicator for poor outcome in triple-negative breast cancer (TNBC). Here we show that Prune-1 overexpression in human TNBC patients has positive correlation to lung metastasis and infiltrating M2-TAMs. Thus, we demonstrate that Prune-1 promotes lung metastasis in a genetically engineered mouse model of metastatic TNBC augmenting M2-polarization of TAMs within the tumor microenvironment. Thus, this occurs through TGF-β enhancement, IL-17F secretion, and extracellular vesicle protein content modulation. We also find murine inactivating gene variants in human TNBC patient cohorts that are involved in activation of the innate immune response, cell adhesion, apoptotic pathways, and DNA repair. Altogether, we indicate that the overexpression of Prune-1, IL-10, COL4A1, ILR1, and PDGFB, together with inactivating mutations of PDE9A, CD244, Sirpb1b, SV140, Iqca1, and PIP5K1B genes, might represent a route of metastatic lung dissemination that need future prognostic validations

A posteriori error estimates for a coupled wave system with a local damping

We study a finite element method applied to a system of coupled wave equations in a bounded smooth domain in Rd, d = 1, 2, 3, associated with a locally distributed damping function. We start with a spatially continuous finite element formulation allowing jump discontinuities in time. This approach yields, L2(L2) and L∞(L2), a posteriori error estimates in terms of weighted residuals of the system. The proof of the a posteriori error estimates is based on the strong stability estimates for the corresponding adjoint equations. Optimal convergence rates are derived upon the maximal available regularity of the exact solution and justified through numerical examples

A posteriori error estimates for a coupled wave system with a local damping

We study a finite element method applied to a system of coupled wave equations in abounded smooth domain in Rd, d = 1, 2, 3, associated with a locally distributed dampingfunction. We start with a spatially continuous finite element formulation allowing jumpdiscontinuities in time. This approach yields, L2(L2) and L∞(L2), a posteriori errorestimates in terms of weighted residuals of the system. The proof of the a posteriorierror estimates is based on the strong stability estimates for the corresponding adjointequations. Optimal convergence rates are derived upon the maximal available regularityof the exact solution and justified through numerical examples

Molecular Docking Studies of Some Hydroxy Nitrodiphenyl Ether Analogues as Tyrosinase Inhibitors

Background & Objective: Tyrosinase is a key enzyme in pigment synthesis.Overproduction of melanin in parts of the skin results in hyperpigmentation diseases. Thus, its inhibitors are highly important in the medical, cosmetic and agricultural fields. The aim of this research is the bioinformatical study of tyrosinase inhibition by a number of hydroxy nitrodiphenyl ether derivatives. Material & Methods: This is a descriptive-analytic study. In order to investigate the mode of interaction of the compounds with tyrosinase active site, the chemical structures of all compounds were designed using ChemDraw program, then transferred into Hyperchem software for energy minimization. Docking study was performed by AutoDock 4.2 program and the resulting docking poses were analyzed in AutoDockTools, DS Visualizer 3.5 and Ligplot software. Results: Among the all studied compounds, the best docking results were related to 4-Hydroxy- 2'-nitrodiphenyl etherdisplayed. In fact, this compound had the most negative ΔGbind (-12.79 Kcal/mol) that indicated favorable interactions with the key amino acid residues at active site of tyrosinase. Docking results for this compound are in accordance with those of co-crystallized ligand (tropolone). In this compound, the oxygen of nitro group has an efficient metal-ligand interaction with the Cu2+ ions in the active site. Conclusion: Finally, in respect to  high effectiveness and docking results, we can conclude that the compound 4-Hydroxy- 2'-nitrodiphenyl ether may be regarded as an effective anti-tyrosinase inhibitor

Designing Multi‐Epitope Subunit Vaccine Candidate for Zika Virus Utilizing In silico Tools

Background: The arboviruses Zika virus (ZIKV) is a pathogen that threatens human health. Scientists have warned that a single mutation in the mosquito-borne ZIKV could spark another major outbreak of the disease in humans. Therefore, designing a suitable vaccine for this virus seems necessary. This study aimed to predict the protective epitopes of envelope protein from the Zika virus with bioinformatics methods for multi-epitope vaccine development. Materials and Methods: Computational studies including the identification of potential B-cell and T-cell epitopes were used. For generating a multi-epitopic vaccine construct (MEVC), selected epitopes are connected by suitable linkers. To enhance protein immunogenicity, Maltosebound protein was added to the MEVC after the prediction and refinement of the 3D structure of the designed vaccine. The binding mode of the MEVC with toll-like receptor was investigated by molecular docking technique. Finally, molecular dynamics and in silico cloning were performed for the designed vaccine. Results: This study showed that this recombinant vaccine is nontoxic, nonallergenic, and thermostable and elicits immune responses against the Zika virus. Conclusion: The computational data suggest that the MEVC has appropriate characteristics and a high-quality structure

Path analysis of the components of production jump, reproductive barriers - support in empowering rural cooperatives

Context and purpose.The main purpose of the research is to explain a model of the application of production jump components, removing obstacles in the empowerment of rural cooperatives in Kohgiluyeh and Boyerahmad province.Methodology/approach.The current research is of the hybrid-alignment type. In the qualitative part, 10 experts of the cooperatives were selected using the targeted sampling method. In the quantitative part of the research method, it is a survey and 249 members of the cooperatives were selected by simple random sampling.Findings and conclusions. The results of the theme analysis identified 6 main components of the production jump-removal of obstacles: social, economic, political-legal, managerial, educational, infrastructural indicators. The results of the structural equations showed that managerial-organizational indicators with a standard coefficient of 0.220 have the greatest impact; And legal-political indicators with a standard coefficient of 0.125 have the least impact on the empowerment of rural cooperatives. Therefore, it is possible to improve the performance of this sector by creating obstacles and paying attention to production indicators in the cooperative sector.Originality. In previous researches, factors affecting the success and performance of cooperatives were repeatedly discussed. In this research, while taking into account the indicators identified in previous researches, specifically, the indicators of production jump-obstacles in the light of the statements of the supreme leader of the revolution and the second step of the extraction revolution and their role in empowering rural cooperatives have been studied. The method and results of this research are innovative

Docking Study on salicylaldehyde Derivatives as Anti-melanogenesis Agents

Background & Objective: Abnormal production of melanin pigment which causes melasma, freckles, ephelides, and age spots, are esthetic problems. Polyphenol oxidase (PPO), a copper-containing enzyme, is involved in melanin biosynthesis and the abnormal accumulation of melanin pigments. Thus, its inhibitors are of great importance in the medical and cosmetic fields. The aim of this study was to investigate some salicylaldehyde Analogues as Polyphenol oxidase inhibitors. Material & Methods: In the present study, thirty five derivatives of salicylaldehyde scaffold were subjected to molecular docking studies to investigate the mode of interaction of the compounds with tyrosinase active site. Docking study was performed by AutoDock 4.2 program and the resulting docking poses were analyzed in AutoDockTools, DS Visualizer 3.5 and Ligplot softwares. Results: Among the all studied compounds, Ligand 4-isopropylsalicylaldehyde displayed good docking results. In fact, this compound had the most negative ΔGbind (-4.01 Kcal/mol) that indicated favorable interactions with the key amino acid residues at active site of Polyphenol oxidase. Docking results for this compound are in accordance with the docking results of Co-crystallized ligand (tropolone). In this compound, the oxygen of a carbonyl group has an efficient metal-ligand interaction with the Cu2+ ion in the active site. Conclusion: The presence of non-polar moiety in salicylaldehyde Analogues increases the inhibitory property

Comparison of alternative soil particle-size distribution models and their correlation with soil physical attributes

Complete descriptions of the particle-size distribution (PSD) curve should provide more information about various soil properties as opposed to only the textural composition (sand, silt and clay (SSC) fractions). We evaluated the performance of 19 models describing PSD data of soils using a range of efficiency criteria. While different criteria produced different rankings of the models, six of the 19 models consistently performed the best. Mean errors of the six models were found to depend on the particle diameter, with larger error percentages occurring in the smaller size range. Neither SSC nor the geometric mean diameter and its standard deviation correlated significantly with the saturated hydraulic conductivity (Kfs); however, the parameters of several PSD models showed significant correlation with Kfs. Porosity, mean weight diameter of the aggregates, and bulk density also showed significant correlations with PSD model parameters. Results of this study are promising for developing more accurate pedotransfer functions

Comparison of alternative soil particle-size distribution models and their correlation with soil physical attributes

Complete descriptions of the particle-size distribution (PSD) curve should provide more information about various soil properties as opposed to only the textural composition (sand, silt and clay (SSC) fractions). We evaluated the performance of 19 models describing PSD data of soils using a range of efficiency criteria. While different criteria produced different rankings of the models, six of the 19 models consistently performed the best. Mean errors of the six models were found to depend on the particle diameter, with larger error percentages occurring in the smaller size range. Neither SSC nor the geometric mean diameter and its standard deviation correlated significantly with the saturated hydraulic conductivity (Kfs); however, the parameters of several PSD models showed significant correlation with Kfs. Porosity, mean weight diameter of the aggregates, and bulk density also showed significant correlations with PSD model parameters. Results of this study are promising for developing more accurate pedotransfer functions