Abstract
Objective
Multiple sclerosis (MS) is a progressing neurodegenerative disease marked by chronic central nervous system inflammation and degeneration.This study investigates gene expression ...profiles of T-box transcription factor TBX21 (T-bet), interferon-gamma (IFN-γ), and long non-coding RNA MEG3 in peripheral blood mononuclear cells (PBMCs) from treatment-naïve Relapsing-Remitting Multiple Sclerosis patients (RRMS), healthy controls, and RRMS patients on different Disease Modifying Therapies (DMTs). The aim is to understand the role of T-bet, IFN-γ, and MEG3 in MS pathogenesis and their potential as diagnostic and therapeutic targets.
Results
Elevated T-bet expression is observed in treatment-naïve RRMS patients compared to healthy individuals. RRMS patients treated with Interferon beta-1alpha (IFNβ-1a) and fingolimod exhibit downregulated T-bet and MEG3 expression levels, respectively, with more pronounced effects in females. Healthy individuals show a moderate positive correlation between T-bet and MEG3 and between IFN-γ and T-bet. In RRMS patients treated with Glatiramer Acetate (GA), a strong positive correlation is observed between MEG3 and IFN-γ. Remarkably, RRMS patients treated with Dimethyl Fumarate (DMF) exhibit a significant positive correlation between T-bet and MEG3. These findings underscore the diagnostic potential of T-bet in RRMS, warranting further exploration of MEG3, T-bet, and IFN-γ interplay in RRMS patients.
The automotive family design is known as one of the most complex engineering design problems with multiple groups of stakeholders involved from different domains of interest and contradictory ...attributes. Taking into account all stakeholders’ preferences, which are generally symmetrical, non-deterministic distributions around a mean value, and determining the right value of attributes for each alternative are two basic challenges for these types of decision-making problems. In this research, the possibility to achieve a robust-reliable decision by focusing on the two aforementioned challenges is explored. In the proposed methodology, a random simulation technique is used to elicit stakeholders’ preferences and determine the relative importance of attributes. The decision space and values of attributes are determined using the Knowledge Discovery in Databases (KDD) technique, and to achieve a robust-reliable decision, statistical and sensitivity analyses are performed. By implementing this methodology, the decision-maker is assured that the preferences of all stakeholders are taken into account and the determined values for attributes are reliable with the least degree of uncertainty. The proposed methodology aims to select benchmark platforms for the development of an automotive family. The decision space includes 546 automobiles in 11 different segments based on 34 platforms. There are 6223 unique possible states of stakeholders’ preferences. As a result, five platforms with the highest degree of desirability and robustness to diversity and uncertainty in the stakeholders’ preferences are selected. The presented methodology can be implemented in complex decision-making problems, including a large and diverse number of stakeholders and multiple attributes. In addition, this methodology is compatible with many Multi-Attribute Decision-Making (MADM) techniques, including SAW, AHP, SWARA, and TOPSIS.
•Zinc supplementation decreases NLRP3 inflammasome complex expression.•Zinc supplementation alleviates genital ulcer.•Zinc supplementation has no beneficial effect on other clinical signs of ...Behçet’s.•One of 3 Behçet’s patients benefits from zinc supplementation.
Overproduction of NLRP3 inflammasome complex is one of the causes of Behcet's disease's (BD) auto-inflammatory nature. The aim of current study was to examine the effect of zinc supplementation on NLRP3 inflammasome expression; as well as clinical manifestations of BD.
In this double-blind parallel placebo-controlled randomized clinical trial, 50 BD patients were randomly allocated into either zinc gluconate (30 mg/day elemental zinc) or placebo groups for 12 weeks. The mRNA expression of NLRP3 and caspase-1 in the leukocytes, serum level of zinc and IL-1β, anthropometric measures, and clinical manifestations of patients were collected at pre- and post-intervention phase. The Iranian Behçet's disease dynamic activity measure (IBDDAM) was scored to measure the treatment effect using the calculation of number needed to treat (NNT). Analysis of covariance was performed to obtain the corresponding effect sizes.
Zinc gluconate led to a significant improvement in genital ulcer (P = 0.019). Zinc supplementation decreased NLRP3 and caspase-1 genes expression compared with placebo group (baseline-adjusted P-value = 0.046 for NLRP3 and P-value = 0.003 for caspase-1), even after adjustment for the effect of confounding factors (baseline- and confounders-adjusted P-value = 0.032 for NLRP3 and P-value = 0.004 for caspase-1). Baseline and confounders adjusted effect size demonstrated that zinc was effective in reducing the serum level of IL-1β (P = 0.046). The NNT 95 %CI for the rate of IBDDAM improvement was 3 1.7–8.5.
Zinc gluconate supplementation (30 mg/day) for a 3-month period can be considered as an adjuvant therapy in alleviating inflammation and genital ulcer among BD patients.
Besides suppressing anti-tumoral immune responses, tumor-intrinsic inhibitory immune checkpoints have been implicated in tumor development. Herein, we aimed to investigate the significance of ...tumor-intrinsic CD73, as an inhibitory immune checkpoint, in non-small cell lung cancer (NSCLC) development and propose a novel therapeutic approach.
We investigated the cell viability, chemosensitivity, apoptosis, migration, and the cell cycle of A-549 and NCI-H1299 following treatment with cisplatin and CD73-small interfering RNA (siRNA) transfection. The 3-(4,5-dimethylthiazol-2-yl)−2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to study the viability of studied groups and chemosensitivity of tumoral cells. Flow cytometry and 4′,6-diamidino-2-phenylindole (DAPI) staining were used to investigate the apoptosis of NSCLC cells. Flow cytometry and the wound-healing assay were used to investigate the cell cycle and migration of NSCLC cells, respectively. The mRNA expression levels of c-Myc, caspase 3, ROCK, and MMP-9 were investigated to study the underlying molecular mechanism.
CD73-siRNA transfection has significantly decreased the cell viability and enhanced the chemosensitivity of A-549 and NCI-H1299 cells to cisplatin. CD73-siRNA has considerably stimulated apoptosis, arrested the cell cycle, inhibited tumor migration, downregulated the mRNA expression of c-Myc, MMP-9, and ROCK, and upregulated caspase 3 expression in NSCLC cells. Besides, combined cisplatin therapy with CD73-siRNA transfection has potentiated the aforementioned anti-tumoral effects of cisplatin on NSCLC cells.
Besides suppressing anti-tumoral immune responses, tumor-intrinsic CD73 can facilitate NSCLC development, and the combined cisplatin therapy with CD73-siRNA transfection can substantially enhance the chemosensitivity of NSCLC to cisplatin and potentiates cisplatin-induced anti-tumoral effects on NSCLC.
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Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). Dysregulated immune responses have been implicated in MS development. Growing evidence has indicated that ...inhibitory immune checkpoint molecules can substantially regulate immune responses and maintain immune tolerance. V-domain Ig suppressor of T cell activation (VISTA) is a novel inhibitory immune checkpoint molecule that can suppress immune responses; however, its expression pattern in the peripheral blood mononuclear cells (PBMCs) of relapsing-remitting multiple sclerosis (RRMS) has not thoroughly been studied. Herein, we evaluated Vsir expression in PBMCs of RRMS patients and characterized the expression pattern of the Vsir in the PBMCs of MS patients. Besides, we investigated the effect of fingolimod, IFNβ-1α, glatiramer acetate (GA), and dimethyl fumarate (DMF) on Vsir expression in PBMCs of RRMS patients. Our results have shown that Vsir expression is significantly downregulated in the PBMCs of patients with RRMS. Besides, the single-cell RNA sequencing results have demonstrated that Vsir expression is downregulated in classical monocyte, intermediate monocytes, non-classical monocytes, myeloid DCs (mDC), Plasmacytoid dendritic cells (pDCs), and naive B-cells of PBMCs of MS patients compared to the control. In addition, DMF, IFNβ-1α, and GA have significantly upregulated Vsir expression in the PBMCs of RRMS patients. Collectively, the current study has shed light on Vsir expression in the PBMCs of MS patients; however, further studies are needed to elucidate the significance of VISTA in the mentioned immune cells.
•Multiple sclerosis is an inflammatory disease of the central nervous system.•VISTA is a novel inhibitory immune checkpoint molecule that can suppress immune responses.•Single-cell RNA sequencing results demonstrated that Vsir expression is downregulated in monocytes and DCs of MS patients.•DMF, IFNβ-1α, and GA have significantly upregulated Vsir expression in the PBMCs of RRMS patients.
Immunological tolerance is mediated by CD4
CD25
regulatory T (Treg) cells. Studies have shown that thymic and peripheral generations of Treg cells depend on the CD28 signaling pathway. T helper 17 ...(Th17) cells are involved in the pathophysiology of various inflammatory diseases. Cytokines, such as interleukin (IL)-6 and TGF-β, regulate the reciprocal development of Th17 and Treg cells. In CD4
T cells, signal transducer and activator of transcription 3 (STAT3) play a critical role in the induction of Th17 cell differentiation and inhibition of Treg cell development.
In this study, we investigated the STAT3 methylation and gene expression status in patients with MS. Our study demonstrated that the level of STAT3 methylation decreased in relapsing-remitting MS patient compared to control groups, which the decreases were statistically significant. STAT3 gene expression increased in patient group relative to healthy one, and the increases were found to be statistically significant. According to our findings, it can be suggested that DNA hypermethylation of STAT3 affects the gene expression. In addition, there is a strong and significant negative correlation between the methylation status and mRNA level of STAT3.
Penetration of wind generation into power systems in recent years has greatly affected optimal power flow (OPF) because of the uncertain behavior of this new energy resource. In this research work, ...at first, a novel scenario generation approach is proposed to model wind power (WP) uncertainty. The proposed scenario generation approach includes construction of probability density function (PDF) pertaining to WP forecast error, segmentation of the PDF by an efficient clustering approach to obtain both the optimal number and the optimal arrangement of the clusters, and the generation of WP scenarios using the optimized clusters through roulette wheel mechanism. Secondly, this paper presents a new OPF framework based on DC network modeling for wind generation integrated power systems. Thirdly, a new out-of-sample analysis is presented to evaluate the long-run performance of the proposed OPF approach encountering various realizations of uncertain WPs. Finally, the performance of the proposed method for solving WP-integrated OPF problem is extensively illustrated on the IEEE 30-bus and the IEEE 118-bus test systems and compared with the performance of the deterministic method and the Weibull PDF method. These comparisons illustrate better performance of the proposed method, while it has reasonable computation times.
•A new scenario generation approach is presented.•A new wind power integrated optimal power model is proposed.•A new out-of-sample analysis is presented.•The effectiveness of the proposed model is extensively illustrated.
Security-constrained optimal power flow (SCOPF) is an important problem in power system operation. Dynamic thermal rating (DTR), as an effective method to increase transmission capacity of power ...systems, has been recently considered in some optimal power flow (OPF) and SCOPF models. Additionally, in today power systems, OPF problem involves various objectives leading to multi-objective OPF models. In this paper, a new multi-objective SCOPF model considering DTR of transmission lines is presented. In addition, a new multi-objective solution method is proposed to solve the multi-objective SCOPF problem. The proposed method is an enhanced version of goal attainment technique in which the search capability of this technique to cover borders of the Pareto frontier is enhanced. The proposed multi-objective DTR-included SCOPF model as well as the proposed multi-objective solution method are tested on the IEEE 118-bus test system and the obtained results are compared with the results of other alternatives.
•A new multi-objective DTR-included SCOPF model is presented.•A new multi-objective solution method is proposed.•Proposed method can search the beyond-utopia-hyperplane parts of Pareto frontier.•Effectiveness of the proposed model and proposed method is extensively evaluated.
This study proposes an improved normalised normal constraint (NNC) method for solving optimal power flow (OPF), which is formulated as a multi-objective problem. While NNC is an efficient solution ...method to solve multi-objective problems, it may not cover the entire Pareto frontier in the objective space when three or more objectives are present in the problem, i.e. when the Pareto frontier becomes a hyper-surface. This research work aims to solve this limitation of NNC and propose a more effective solution method, named improved NNC (INNC), for multi-objective optimisation problems with three or more objective functions. The proposed INNC is applied for solving multi-objective OPF problem with three objectives of generation cost, transmission loss and voltage regulation. The effectiveness of the proposed INNC method for solving the multi-objective OPF problem is extensively illustrated on the IEEE 30-bus and IEEE 118-bus test systems in comparison with several recently published multi-objective solution approaches.
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