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Alloy AD730TM is a recently developed Nickel base superalloy for application as turbine disk in modern gas turbines with improved thermal efficiency. Ingot casting followed by open die-forging and then heat treatments are the main manufacturing steps for the production of parts made of this alloy. Solution heat treatment operations are applied at different stages of the manufacturing in order to ease the deformation processing and/or prepare the microstructure for final heat treatment. In this research, the influence of various solution heat treatment schedules on morphology and distribution of the γ′ phase are investigated and documented. The obtained results will contribute to a better understanding of microstructure evolution of AD730TM during solution heat treatments. Differential Thermal Analysis (DTA) is used for the purposes of measurement of temperatures of phase transformations of the alloy. Based on DTA results, three solutionizing temperatures and three holding times were selected for performing and assessing the solution heat treatment process. Optical and electron microscopy were used to study the morphological evolution as well as the coarsening and dissolution of secondary phases at solvus and subsolvus temperatures. The results indicated that precipitate agglomeration and Ostwald ripening are the governing mechanisms during the initial stages and splitting and partial dissolution of γ′ precipitates takes place during subsolvus solution treatments.

Background: Traumatic dental injuries (TDIs) are one of the most common dental problems among children and adolescents, which usually occur in the anterior parts of the mouth and have great impact on the patient's physical and mental health. Therefore, dentist's knowledge and effective measures in the treatment of TDI are the most important factors in improving the prognosis of these teeth. Aims: The aim of this study was to evaluate the knowledge of general dentists working in Bojnurd and also 6th-year dental students about the treatment of such injuries. Materials and Methods: In this cross-sectional study, a questionnaire was provided to 70 general dentists and 6th-year dental students, including personal information and questions related to the knowledge of general dentists, on how to deal with various TDIs by available methods. Data were analyzed using t-test, Chi-square test, Kruskal–Wallis test, and analysis of variance, Spearman's, and Pearson's correlation coefficient. Results: Regarding general dentists' knowledge about dentoalveolar trauma: 39 (55.7%) were moderate, 28 (40%) were good, and 3 (4.3%) were excellent. The mean value knowledge of dentists and dental students was 8.18 ± 1.98. There was no significant relationship between age, gender, place of work, university of study, desire for education, and self-evaluation of dentists and level of awareness (P = 0.26, P = 0.61, P = 0.47, P = 0.93, P = 0.35, and P = 0.57, respectively). Conclusions: The results of our study indicate that majority of the participants are moderately aware of TDIs and the type of treatment, and due to the increasing prevalence of dental trauma and its high complications, especially in children, the need to make appropriate plans to update the level of knowledge of general dentists in the management and treatment of TDI increases.

The Sar Cheshmeh porphyry copper deposit is located in the Central Iranian Volcanic-Sedimentary Belt (CIVSB). The hydrothermal alteration zones are well developed within and around the porphyry stock. Given the poor soil and vegetation cover in this area, we evaluated the usefulness of multispectral remote sensing data derived from Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) and Enhanced Thematic Mapper Plus (ETM+) images and airborne magnetic-radiometric data for hydrothermal alteration mapping at a local scale. Principal component analysis (PCA), band ratios and the spectral angle mapper (SAM) technique were applied to the multispectral data sets to map hydrothermally altered rocks. PCA and band ratios were also applied to the airborne geophysical data. The overall results showed that the multispectral remote sensing data sets resulted in more accurate hydrothermal alteration mapping and lithological discrimination in the study area as compared with the airborne geophysical data. The radiometric data are also useful in enhancing areas with potassic alteration. [ABSTRACT FROM AUTHOR]

In this paper, a new entropy-based approach is developed for assessing the location of salinity monitoring stations in the Tehran Aquifer, Tehran, Iran. To find the optimal distance among stations, the measure of Transinformation in the Entropy Theory is used. Then a Transinformation-Distance (T-D) curve is developed and used in a multi-objective GA-based optimization model, which provides the best locations for monitoring stations. Because of the large area of the Tehran aquifer and significant spatial variations of the Electrical Conductivity (EC) of the groundwater in the study area, the C-means clustering method is used to classify the study area to some homogenous zones. The optimization model is applied to each zone to find the optimal location of monitoring stations. The results show the applicability and the efficiency of the model in assessing the groundwater monitoring systems. [ABSTRACT FROM AUTHOR]

While significant progress has been made in creating polymeric structures for tissue engineering, the therapeutic application of these scaffolds remains challenging owing to the intricate nature of replicating the conditions of native organs and tissues. The use of human-derived biomaterials for therapeutic purposes closely imitates the properties of natural tissue, thereby assisting in tissue regeneration. Decellularized extracellular matrix (dECM) scaffolds derived from natural tissues have become popular because of their unique biomimetic properties. These dECM scaffolds can enhance the body's ability to heal itself or be used to generate new tissues for restoration, expanding beyond traditional tissue transfers and transplants. Enhanced knowledge of how ECM scaffold materials affect the microenvironment at the injury site is expected to improve clinical outcomes. In this review, recent advancements in dECM scaffolds are explored and relevant perspectives are offered, highlighting the development and application of these scaffolds in tissue engineering for various organs, such as the skin, nerve, bone, heart, liver, lung, and kidney., (© 2024 Wiley‐VCH GmbH.)

Background: Measuring plantar pressure distribution is critical for understanding foot-ground interactions, providing valuable insights for diagnosing and managing various health conditions. Since its initial studies in 1984, this field has garnered increasing attention within healthcare and medicine due to its broad applications across clinical settings., Research Question: How does measuring plantar pressure distribution affect healthcare outcomes across different age groups and health conditions?, Methods: This review thoroughly explores the literature concerning plantar pressure distribution, focusing on studies conducted from 1984 onwards. It investigates the methodologies and clinical applications associated with plantar pressure measurement, tracing the evolution of research and practice in this field., Results: The review identifies and classifies key methods used to measure plantar pressure distribution, emphasizing their application in clinical and research contexts. It highlights the considerable influence these measurements have on the diagnosis and management of various health conditions across all age groups and demonstrates the practical benefits of plantar pressure analysis in improving diagnostic accuracy and informing more tailored treatment plans., Significance: Understanding plantar pressure distribution is crucial for advancing healthcare practices, particularly in diagnostic and therapeutic interventions. This review underscores the clinical importance of plantar pressure measurement, illustrating its value in improving patient outcomes and contributing to broader medical research. The findings aim to assist healthcare professionals, researchers, and clinicians in effectively leveraging plantar pressure data to optimize healthcare delivery and patient care., 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 © 2025 Elsevier B.V. All rights reserved.)

Developing mouse models of hemophilia A has been shown to facilitate in vivo studies to explore the probable mechanism(s) underlying the disease and to examine the efficiency of the relevant potential therapeutics. This study aimed to knockout (KO) the coagulation factor viii (fviii) gene in NMRI mice, using CRISPR/Cas9 (D10A/nickase) system, to generate a mouse model of hemophilia A. Two single guide RNAs (sgRNAs), designed from two distinct regions on NMRI mouse FVIII (mFVIII) exon 3, were designed and inserted in the pX335 vector, expressing both sgRNAs and nickase. The recombinant construct was delivered into mouse zygotes and implanted into the pseudopregnant female mice's uterus. Mutant mice were identified by genotyping, genomic sequencing, and mFVIII activity assessment. Two separate lines of hemophilia A were obtained through interbreeding the offspring of the female mice receiving potential CRISPR-Cas9-edited zygotes. Genomic DNA analysis revealed disruptions of the mfviii gene reading frame through a 22-bp deletion and a 23-bp insertion in two separate founder mice. The founder mice showed all the clinical signs of hemophilia A including; excessive bleeding after injuries, and spontaneous bleeding in joints and other organs. Coagulation test data showed that mFVIII coagulation activity was significantly diminished in the mFVIII knockout (FVIII KO ) mice compared to normal mice. The CRISPR/nickase system was successfully applied to generate mouse lines with the knockout fviii gene. The two novel FVIII KO mice demonstrated all clinical symptoms of hemophilia A, which could be successfully inherited. Therefore, both of the developed FVIII KO mouse lines are eligible for being considered as proper mouse models of hemophilia A for in vivo therapeutic studies.

X-ray sources based on the inverse Compton interaction between a laser and a relativistic electron beam are emerging as a promising compact alternative to synchrotron for the production of intense monochromatic and tunable radiation. The emission characteristics enable several innovative imaging techniques, including dual-energy K-edge subtraction (KES) imaging. The performance of these techniques is optimal in the case of perfectly monochromatic x-ray beams, and the implementation of KES was proven to be very effective with synchrotron radiation. Nonetheless, the features of inverse Compton scattering (ICS) sources make them good candidates for a more compact implementation of KES techniques. The energy and intensity distribution of the emitted radiation is related to the emission direction, which means different beam qualities in different spatial positions. In fact, as the polar angle increases, the average energy decreases, while the local energy bandwidth increases and the emission intensity decreases. The scope of this work is to describe the impact of the local energy distribution variations on KES imaging performance. By means of analytical simulations, the reconstructed signal, signal-to-noise ratio, and background contamination were evaluated as a function of the position of each detector pixel. The results show that KES imaging is possible with ICS x-ray beams, even if the image quality slightly degrades at the detector borders for a fixed collimation angle and, in general, as the beam divergence increases. Finally, an approach for the optimization of specific imaging tasks is proposed by considering the characteristics of a given source.

The human colon harbors a diverse array of microorganisms that play fundamental roles in colorectal cancer (CRC). Increasing evidence indicates that dysbiosis of the intestinal microbiome has been associated with the development of CRC. Interaction between host genetics, intestinal microbiota, and lifestyle is well-indicated in the influence, prevention, and treatment of CRC. Various microbiome compositions have reported anticancer and/or anti-inflammatory properties. The presence of our microbiota is integral to our development, but a change in its composition can often lead to adverse effects, increasing the propensity for serious diseases like cancers. Recently, molecular detection and metabolomic techniques have increased our knowledge of the role of microbiota in promoting tumorigenesis. Dietary interventions may be appropriate to regulate the growth of beneficial microbiota in the gut. Metagenomic approaches along with immunology and metabolomics will obvious a new path for the treatment of CRC. In this study, we summarized recent advances in understanding the mechanisms involved in microbiota-related colorectal carcinoma, based on evidence from immunotherapy studies., (© 2022 S. Karger AG, Basel.)

Long non-coding RNAs (lncRNAs) are an emerging group of RNAs with a crucial role in cancer pathogenesis. In gastrointestinal cancers, TP53 target 1 (TP53TG1) is an epigenetically regulated lncRNA that represents a promising therapeutic target due to its tumor suppressor properties regulating the p53-mediated DNA damage and the intracellular localization of the oncogenic YBX1 protein. However, to translate this finding into the clinic as a gene therapy, it is important to develop effective carriers able to deliver exogenous lncRNAs to the targeted cancer cells. Here, we propose the use of biocompatible sphingomyelin nanosystems comprising DOTAP (DSNs) to carry and deliver a plasmid vector encoding for TP53TG1 (pc(TP53TG1)-DSNs) to a colorectal cancer cell line (HCT-116). DSNs presented a high association capacity and convenient physicochemical properties. In addition, pc(TP53TG1)-DSNs showed anti-tumor activities in vitro, specifically a decrease in the proliferation rate, a diminished colony-forming capacity, and hampered migration and invasiveness of the treated cancer cells. Consequently, the proposed strategy displays a high potential as a therapeutic approach for colorectal cancer.

Objectives: The ongoing Coronavirus disease 2019 (COVID-19) pandemic has drastically impacted the global health and economy. Computed tomography (CT) is the prime imaging modality for diagnosis of lung infections in COVID-19 patients. Data-driven and Artificial intelligence (AI)-powered solutions for automatic processing of CT images predominantly rely on large-scale, heterogeneous datasets. Owing to privacy and data availability issues, open-access and publicly available COVID-19 CT datasets are difficult to obtain, thus limiting the development of AI-enabled automatic diagnostic solutions. To tackle this problem, large CT image datasets encompassing diverse patterns of lung infections are in high demand., Data Description: In the present study, we provide an open-source repository containing 1000+ CT images of COVID-19 lung infections established by a team of board-certified radiologists. CT images were acquired from two main general university hospitals in Mashhad, Iran from March 2020 until January 2021. COVID-19 infections were ratified with matching tests including Reverse transcription polymerase chain reaction (RT-PCR) and accompanying clinical symptoms. All data are 16-bit grayscale images composed of 512 × 512 pixels and are stored in DICOM standard. Patient privacy is preserved by removing all patient-specific information from image headers. Subsequently, all images corresponding to each patient are compressed and stored in RAR format.

Reservoir hydrodynamic and water quality modeling, in conjunction with the monitoring programs, is one of the essential tools for controlling the pollution of these types of water bodies. The complexity of the model, data scarcity, and the variable nature of natural phenomena lead to uncertainty in models, which should be considered in the calibration process of these models. Uncertainty-based automatic calibration is one of the methods that can be effective in achieving a high-reliability model. In this paper, the Sequential Uncertainty Fitting (SUFI-2) algorithm was used for the automatic calibration of the two-dimensional hydrodynamic and water quality model (CE-QUAL-W2) for the reservoir under parameter uncertainty conditions. To this end, the CE-QUAL-W2 model was developed to simulate the temperature and water surface elevation of the Karkheh Dam reservoir (western Iran). The parameters affecting temperature were regarded as uncertain parameters in the calibration process, including the coefficients of longitudinal eddy viscosity, longitudinal eddy diffusivity, Chezy coefficient or Manning, wind sheltering, solar radiation absorbed in the surface layer, extinction coefficient for pure water, and the experimental coefficients of wind speed function. The developed method demonstrated a high potential for matching the simulated temperature and water surface elevation for the reservoir with the measured data. Averagely, 69% of the simulated temperature and 90% of the simulated water surface elevation were located within the 95% confidence interval. The SUFI-2 algorithm also showed better performance in terms of the convergence rate compared with the particle swarm optimization (PSO) algorithm, which indicated a lower number of calls (80 calls compared to 2000 calls) and could reduce the total root-mean-square error by 9.6%.

In the present paper, a scenario-based many-objective optimization model is developed for the spatio-temporal optimal design of reservoir water quality monitoring systems considering uncertainties. The proposed methodology is based on the concept of nonlinear interval number programming and information theory, while handling uncertainties of temperature, reservoir inflow, and inflow constituent concentration. A reference-point-based non-dominated sorting genetic algorithm (NSGA-III) is used to deal with the many-objective optimization problem. The proposed model is developed for the Karkheh reservoir system in Iran as a real-world problem. The results show excellent performance of the optimized water quality sampling locations instead of all potential ones in providing adequate information about the reservoir water quality status. The presented uncertainty-based model leads to a 55.73% reduction in the radius of the uncertain interval caused by different scenarios. Handling uncertainties in a spatio-temporal many-objective optimization problem is the main contribution of this study, yielding a reliable and robust design of a reservoir monitoring system that is less sensitive to various scenarios., 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 Ltd. All rights reserved.)

Bone metastasis develops in multiple malignancies with a wide range of incidence. The presence of multiple bone metastases, leading to a multitude of complications and poorer prognosis. The corresponding refractory bone pain is still a challenging issue managed through multidisciplinary approaches to enhance the quality of life. Radiopharmaceuticals are mainly used in the latest courses of the disease. Bone-pain palliation with easy-to-administer radionuclides offers advantages, including simultaneous treatment of multiple metastatic foci, the repeatability and also the combination with other therapies. Several β¯- and α-emitters as well as pharmaceuticals, from the very first [ 89 Sr]strontium-dichloride to recently introduced [ 223 Ra]radium-dichloride, are investigated to identify an optimum agent. In addition, the combination of bone-seeking radiopharmaceuticals with chemotherapy or radiotherapy has been employed to enhance the outcome. Radiopharmaceuticals demonstrate an acceptable response rate in pain relief. Nevertheless, survival benefits have been documented in only a limited number of studies. In this review, we provide an overview of bone-seeking radiopharmaceuticals used for bone-pain palliation, their effectiveness and toxicity, as well as the results of the combination with other therapies. Bone-pain palliation with radiopharmaceuticals has been employed for eight decades. However, there are still new aspects yet to be established.

Colorectal carcinoma is one of the most common causes of cancer-related death, worldwide. Recently, due to the introduction of novel imaging and therapeutic techniques, five-year survival of patients has increased. However, distant metastasis is still expected in half of the patients. Colorectal cancer tends to target the abdominal cavity, liver, lungs, and bones as the common sites of metastasis. Nevertheless, rare cases of muscle metastasis have been reported. This report presents a 23-year-old male, who despite chemotherapy, demonstrated gradual progressive disease and metastases to the submandibular region, lungs, adrenal gland as well as muscles and subcutaneous tissues. He had developed multiple asymptomatic muscular metastases metachronously over two-year time period discovered on an 18 FDG-PET/CT, namely in the deltoid, external oblique abdominis, rectus abdominis, and quadriceps muscles, as well as one of the extrinsic muscles of the tongue. The presence of distant, especially extrahepatic metastasis, adversely affects the prognosis of colon carcinoma. Since limited cases of muscle metastasis have been reported in carcinoma of colon, the underlying pathophysiology, optimum treatment, and prognostic issues are yet to be substantiated.

In this study, we investigated the contributions of the MALAT1 long noncoding RNA to autoimmune neuroinflammation in central nervous system tissues from patients with multiple sclerosis (MS) and mice with experimental autoimmune encephalomyelitis (EAE). Expression of MALAT1 was decreased in the spinal cords of EAE mice as well as in stimulated splenocytes and primary macrophages. MALAT1 downregulation by specific siRNAs enhanced the polarization of macrophages towards the M1 phenotype. Interestingly, siRNA-mediated MALAT1 downregulation shifted the pattern of T-cell differentiation towards a Th1/Th17 cell profile and decreased differentiation towards a Tregs phenotype. Proliferation of T-cells was also increased following MALAT1 downregulation. These data point to a potential anti-inflammatory effect for MALAT1 in the context of autoimmune neuroinflammation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Loss of neuroprotective role of CD4 + helper T cells, regulatory T cells, and M2 microglia constitutively results in the rapid neural death in the "rapidly progressive phase" of amyotrophic lateral sclerosis (ALS)., Aim: We aimed to investigate relative count of CD4 + and regulatory T lymphocytes and expression level of IL2Ra and FOXP3 genes in peripheral blood mononuclear cells (PBMCs) from patients with ALS., Method: We performed a flow cytometric analysis on PBMC from 38 patients with ALS and 32 controls to determine the count of CD4 + and CD4 + CD25 + cells. Quantitative real-time PCR analyses were implemented to determine the level of expression of FOXP3 and IL-2Rα (CD25) genes in the peripheral blood mononucleated cells., Results: We found a significant higher proportion of CD4 + T cells (p value < 0.001), along with a significantly reduced proportion of CD4 + CD25 + Treg cells (p value = 0.001, p value = 0.02), in the peripheral blood of patient's with ALS., Conclusion: The results of our study are in line with the hypothesis that in the early phase of ALS, neuroprotective helper T cells infiltrate in the affected areas in the lumbar spinal cord. This was reflected in higher peripheral percentage of CD4 + helper T cells and higher expression of FOXP3 and IL-2Rα. The observed demise in the number of active CD4 + CD25 + regulatory T cells might indicate early signs of progression to later stages of ALS in our study group. Interestingly, disease duration was the sole independent significant determining factor that predicted CD4+CD25+ regulatory T cell counts in the peripheral blood of patients at various stages of ALS, according to a logistic regression model.

Telomerase, the enzyme responsible for cell immortality, is an important target in anti-cancer drug discovery. Boldine, an abundant aporphine alkaloid of Peumus boldus , is known to inhibit telomerase at non-toxic concentrations. Cytotoxicity of N -benzylsecoboldine hydrochloride (BSB), a synthetic derivative of boldine, was determined using the MTT method in MCF7 and MDA-MB231 cells. Aliquots of cell lysates were incubated with various concentrations of BSB in qTRAP (quantitative telomere repeat amplification protocol)-ligand experiments before substrate elongation by telomerase or amplification by hot-start Taq polymerase. The crystal structure of TERT, the catalytic subunit of telomerase from Tribolium castaneum , was used for docking and molecular dynamics analysis. The qTRAP-ligand data gave an IC 50 value of about 0.17 &plusmn; 0.1 &micro;M for BSB, roughly 400 times stronger than boldine, while the LD 50 in the cytotoxicity assays were 12.5 and 21.88 &micro;M, respectively, in cells treated for 48 h. Although both compounds interacted well with the active site, MD analysis suggests a second binding site with which BSB interacts via two hydrogen bonds, much more strongly than boldine. Theoretical analyses also evaluated the IC 50 for BSB as submicromolar. BSB, with greater hydrophobicity and flexibility than boldine, represents a promising structure to inhibit telomerase at non-toxic concentrations.

Common variable immunodeficiency (CVID) is the most common clinical primary antibody deficiency, characterized by increased susceptibility to recurrent bacterial infections. Since Toll-like receptors (TLRs) play an important role in the maturation and differentiation of B-cells, TLRs' defect can be involved in the pathogenesis of CVID. Therefore, we evaluated the expression of TLR2 and TLR4 and their signaling pathway; also their association with autoimmunity, B-cell subtypes and response to pneumovax-23 were assessed in CVID patients. Sixteen CVID patients were enrolled in the study. Flow cytometry was used for assessing the protein expression of TLR2 and TLR4, and real-time PCR was used for gene expression of myeloid differentiation primary response 88 (MyD88) and toll interacting protein (Tollip). We found a higher protein expression of TLR2 in CVID patients which was associated with lower number of end stage B-cells and hyporesponse to pneumovax-23 vaccination. We showed a lower mRNA expression of MyD88 and an almost equal Tollip mRNA expression in CVID patients compared with controls. There was a profound association between MyD88 gene expression and autoimmunity in CVID patients. According to the presence of the lower number of end stage B-cells and poor vaccine response in CVID patients and their correlation with the higher expression of TLR2, we hypothesized that there is a functional defect in this receptor and/or its downstream in the peripheral blood mononuclear cells (PBMCs) of CVID patients.

This paper introduces a Semivariance-Transinformation (S-T) based method for designing an optimum bay water nutrients monitoring network in San Francisco bay (S.F. bay), USA. Phosphorus and nitrogen are the most important nutrients that lead to eutrophic condition. The monthly phosphate and nitrate+nitrite data recorded during September 2006 to August 2015 was obtained over 14 active stations located at S.F. bay and was used in the research. Semivariance and discrete transinformation entropy have been applied to calculate the optimum range of the monitoring distance. The study indicated the ranges of 28 to 82 and 37 to 50km for the phosphate and nitrate+nitrite respectively. Useful information can be obtained from the monitoring network, if the monitoring distance is included in the mentioned intervals. The findings of the research introduce a new approach in the field of water quality monitoring networks design., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Recent studies have revealed that multiple sclerosis (MS) lesions have distinct microRNA (miRNA) expression profiles. miR-181 family members show altered expression in MS tissues although their participation in MS pathogenesis remains uncertain. Herein, we investigated the involvement of miR-181a and miR-181b in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE)., Methods: miR-181a and -b levels were measured in the central nervous system (CNS) of patients with MS and mice with EAE as well as relevant leukocyte cultures by real-time RT-PCR. To examine the role of the miRNAs in leukocyte differentiation and function, miR-181a and -b mimic sequences were transfected into cultured primary macrophages and purified CD4 + T cells which were then analyzed by RT-PCR and flow cytometry. Luciferase reporter assays were performed to investigate the interaction of miR-181a and -b with the 3'-UTR of potential target transcripts, and the expression of target genes was measured in the CNS of EAE mice, activated lymphocytes, and macrophages., Results: Expression analyses revealed a significant decrease in miR-181a and -b levels in brain white matter from MS patients as well as in spinal cords of EAE mice during the acute and chronic phases of disease. Suppression of miR-181a was observed following antigen-specific or polyclonal activation of lymphocytes as well as in macrophages following LPS treatment. Overexpression of miR-181a and -b mimic sequences reduced proinflammatory gene expression in macrophages and polarization toward M1 phenotype. miR-181a and -b mimic sequences inhibited Th1 generation in CD4 + T cells and miR-181a mimic sequences also promoted Treg differentiation. Luciferase assays revealed Suppressor of mothers against decapentaplegic 7 (Smad7), as a direct target of miR-181a and -b., Conclusion: Our data highlight the anti-inflammatory actions of miR-181a and -b in the context of autoimmune neuroinflammation. miR-181a and -b influence differentiation of T helper cell and activation of macrophages, providing potential therapeutic options for controlling inflammation in MS.

Background: MicroRNAs have emerged as an important class of modulators of gene expression. These molecules influence protein synthesis through translational repression or degradation of mRNA transcripts. Herein, we investigated the potential role of miR-142a isoforms, miR-142a-3p and miR-142a-5p, in the context of autoimmune neuroinflammation., Methods: The expression levels of two mature isoforms of miR-142 were measured in the brains of patients with multiple sclerosis (MS) and the CNS tissues from mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Expression analyses were also performed in mitogen and antigen-stimulated splenocytes, as well as macrophages and astrocytes using real-time RT-PCR. The role of the mature miRNAs was then investigated in T cell differentiation by transfection of CD4 + T cells, followed by flow cytometric analysis of intracellular cytokines. Luciferase assays using vectors containing the 3'UTR of predicted targets were performed to confirm the interaction of miRNA sequences with transcripts. Expression of targets were then analyzed in activated splenocytes and MS/EAE tissues., Results: Expression of miR-142-5p was significantly increased in the frontal white matter from MS patients compared with white matter from non-MS controls. Likewise, expression levels of miR-142a-5p and miR-142a-3p showed significant upregulation in the spinal cords of EAE mice at days 15 and 25 post disease induction. Splenocytes stimulated with myelin oligodendrocyte glycoprotein (MOG) peptide or anti-CD3/anti-CD28 antibodies showed upregulation of miR-142a-5p and miR-142a-3p isoforms, whereas stimulated bone marrow-derived macrophages and primary astrocytes did not show any significant changes in miRNA expression levels. miR-142a-5p overexpression in activated lymphocytes shifted the pattern of T cell differentiation towards Th1 cells. Luciferase assays revealed SOCS1 and TGFBR1 as direct targets of miR-142a-5p and miR-142a-3p, respectively, and overexpression of miRNA mimic sequences suppressed the expression of these target transcripts in lymphocytes. SOCS1 levels were also diminished in MS white matter and EAE spinal cords., Conclusions: Our findings suggest that increased expression of miR-142 isoforms might be involved in the pathogenesis of autoimmune neuroinflammation by influencing T cell differentiation, and this effect could be mediated by interaction of miR-142 isoforms with SOCS1 and TGFBR-1 transcripts.

Cow's milk allergy (CMA) is the most frequent food allergy in children and oral immunotherapy (OIT) is a promising approach for treatment of patients. The most challenging cases are anaphylactic with coexisting asthma and proposing safe protocols is crucial especially in high risk groups. Considering that CMA varies among patients, an individualized OIT protocol would be beneficial to achieve a safer and more efficient method of desensitization. 18 children more than 3 years of age with IgE-mediated CMA were enrolled. CMA was confirmed by positive skin prick test (SPT) and positive oral food challenge (OFC) and 60% of individuals had a convincing history of persistent asthma. SPT with milk extracts, whole fresh milk and serially diluted milk concentrations were performed.  The dilution of milk that induced 3-5 mm of wheal in each individual was selected as the starting dilution for OIT. Desensitization began by 1 drop of the defined dilution and continued increasingly. Overall, 16 out of 18 children (88.8%) achieved the daily intake of 120 mL of milk. Four out of these 16 children accomplished the protocol without any adverse allergic reactions. 12 patients experienced mild to severe reactions. Wheal and erythema in SPT (p≤0.001), and sIgE (p≤0.003) to most milk allergens were significantly decreased following desensitization. We successfully desensitized 16 of 18 children with IgE-mediated CMA by individualized desensitization protocol. Individualizing the OIT protocol would be helpful to save time and perhaps to relieve the allergic symptoms after ingesting cow's milk intake.

The efficacy of conventional anti-tumor immunotherapeutic approaches is markedly affected by the immunosuppressive microenvironment of tumor. Since adenosine is one of the main orchestra leaders in immunosuppression symphony of tumor, targeting its producing molecules such as CD73 can help to achieve a better clinical outcome following conventional cancer immunotherapeutic approaches. In the present study, we evaluated the efficacy of CD73-specific siRNA-loaded chitosan-lactate nanoparticles (ChLa NPs) in combination with tumor lysate pulsed dendritic cells (DCs) vaccine in treatment of 4T1 (murine derived) breast cancer bearing mice. Our results showed that intravenous administration of CD73-specific siRNA-loaded NPs led to reduced expression of CD73 in tumor cells which was associated with decreased tumor growth and metastasis, and improved mice survival. Furthermore, we found that the mechanism by which combination therapy inhibits tumor growth is in part related to downregulation of regulatory T (Treg), myeloid derived suppressor cells (MDSCs), and tumor associated macrophages, an augmented CTL effector function, improved proliferation status of T cells, increased production of inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17 and reduced levels of IL-10. Moreover, this treatment protocol attenuated the expression and activities of matrix metalloproteinases (MMPs) 2 and 9 which could be associated to the prevention of lung metastasis. In conclusion, our findings indicate that the use of CD73-specific siRNA-loaded NPs provides an immune potentiating function, thereby improves the efficacy of DC based cancer immunotherapy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Pest management by conventional pesticides has become progressively hindered by developing pest resistance and increase in consumers demand for safe and residue-free foodstuffs. This will create a considerable market opportunity for alternative products, including botanical pesticides. The present study was conducted to assess the combination of carvacrol and thymol, their repellent activity, and residual toxicity against Dermanyssus gallinae with the aim of designing a new strategy relying on natural compounds for the control of D. gallinae. Different ratios of carvacrol-thymol, 5:0, 4:1, 3:2, 2:3, 1:4, and 0:5 based on LD50 values, were tested for their toxicity on D. gallinae. For residual toxicity assay, mortality rate of mites recorded after being exposed to the surfaces 1, 3, 7, 14, 21, and 28 days post spraying by carvacrol-thymol preparation. In combination toxicity, carvacrol-thymol in 4:1 ratio showed the highest efficacy against D. gallinae. The highest repellent activity was observed in carvacrol-thymol 5:0 combination. Addition of thymol to carvacrol resulted in a decrease in repellent activity of carvacrol as was seen in carvacrol-thymol 3:2, 2:3, and 1:4 ratios (p < 0.05). Carvacrol-thymol in 4:1 ratio at 2 % concentration displayed good residual toxicity and was effective against D. gallinae till 14 days post spraying (p < 0.05). The present study showed that the combination of carvacrol-thymol particularly with a 4:1 ratio displayed improved acaricidal activity and good residual toxicity. However, combining the application of carvacrol and thymol did not show any synergistic effect on repellent activity. Overall, carvacrol-thymol can be suggested as an alternative strategy for the control of D. gallinae.

In this paper, a new systematic approach is designed to maximize the demand coverage and receiving waste load by river-reservoir systems while enhancing water quality criteria. The approach intends to control the reservoir eutrophication while developing a trade-off between the maximum receiving load and shortage on demand coverage. To simulate the system, a hybrid process-based and data-driven model is tailored. Initially, the two-dimensional hydrodynamics and water quality simulation model (CE-QUAL-W2) is linked with an effective single and/or multiple optimization algorithms (PSO) to evaluate the proposed scenarios. To increase the computational efficiencies, the simulation model is substituted with a surrogate model (ANN) in an adaptive-dynamically refined routine. The proposed method is illustrated by a case study in Iran, namely, Karkheh River Reservoir, for 180-monthly periods. The results showed the applicability of the methodology especially to solve high-dimensional multi-period complex water resource optimization problems. Also, the results demonstrated that eutrophication could be reduced under the optimal inflow phosphate control and reservoir operation, regulating the total phosphorous concentration in the reservoir.

Dendritic cells (DCs) are recognized as key regulators of the immune system. Active DC immunization protocols are quickly obtaining interest as an alternative therapeutic approach in acute myeloid leukemia patients. Despite apparent progress in DC-based immunotherapy, some discrepancies were reported in generating potent DCs and their source. In addition to monocytes, DCs can be differentiated from leukemic blasts of acute myeloid leukemia (AML) patients (AML-DC) possessing the ability of stimulating anti-leukemic immune response. In this study, we differentiated peripheral blood blasts of 16 out of 20 AML patients in vitro in the presence of GM-CSF and IL-4 into immature AML-DC. Then, DCs matured using different combinations of Toll-like receptor (TLR) ligands to obtain functional DCs as demonstrated by cell morphology, immunophenotype, and functional activity. Autologous cytotoxic T cell induction of matured DCs was evaluated in four patients and compared with immature counterparts. Our results showed that although the TLR3 agonist (Poly I:C) has a synergistic effect on the TLR4 agonist (lipopolysaccharide, LPS), the addition of the TLR7/8 agonist (R848) is necessary to reinforce the effect of LPS or LPS + POLY(I:C) to produce efficient DCs with the higher level of IL-12 (30 to 90 times). Such DCs activate allogeneic T cells and effectively prime autologous cytotoxic T cells in vitro. In contrast, FSL-1 as a TLR2/6 agonist has a negative effect on LPS + Poly(I:C) and LPS + R848 to produce IL-12. Thus, DCs prepared using a maturation mixture including a TLR7/8 agonist may be used as a potential tool for DC-based immunotherapy purposes in leukemic patients.

Objectives: This study was performed to evaluate the cytotoxicity of four calcium silicate-based endodontic cements at different storage times after mixing., Materials and Methods: Capillary tubes were filled with Biodentine (Septodont), Calcium Enriched Mixture (CEM cement, BioniqueDent), Tech Biosealer Endo (Tech Biosealer) and ProRoot MTA (Dentsply Tulsa Dental). Empty tubes and tubes containing Dycal were used as negative and positive control groups respectively. Filled capillary tubes were kept in 0.2 mL microtubes and incubated at 37℃. Each material was divided into 3 groups for testing at intervals of 24 hr, 7 day and 28 day after mixing. Human monocytes were isolated from peripheral blood mononuclear cells and cocultered with 24 hr, 7 day and 28 day samples of different materials for 24 and 48 hr. Cell viability was evaluated using an MTT assay., Results: In all groups, the viability of monocytes significantly improved with increasing storage time regardless of the incubation time (p < 0.001). After 24 hr of incubation, there was no significant difference between the materials regarding monocyte viability. However, at 48 hr of incubation, ProRoot MTA and Biodentine were less cytotoxic than CEM cement and Biosealer (p < 0.01)., Conclusions: Biodentine and ProRoot MTA had similar biocompatibility. Mixing ProRoot MTA with PBS in place of distilled water had no effect on its biocompatibility. Biosealer and CEM cement after 48 hr of incubation were significantly more cytotoxic to on monocyte cells compared to ProRoot MTA and Biodentine.

Background: Human breast milk, the sole source of nutrition during the early neonatal period, is rich in nutrients, hormones, growth factors, and immunoactive molecules, which influence the growth, development, and immune status of the newborn infant. It had long been thought that breast milk is an adequate source of anthracitic activity for the newborns and growing child., Objective: Human milk is a complex biologic fluid which contains nutritional and protective factors such as Osteoprotegerin (OPG), at levels 1000-fold higher than normal human serum. Since OPG and Receptor activator of nuclear factor-kappa B ligand (RANKL) system are tightly involved in bone remodeling and immune activity, the study was designated to evaluate the effect of breastfeeding on serum soluble receptor activator of nuclear factor-kappa B ligand (sRANKL) /OPG ratio in full term neonates in comparison with those of formula feeding full term neonates., Materials and Methods: In this cross-sectional study serum levels of OPG and sRANKL in 45 breastfed infants were compared to those of 44 formula-fed full term infants. The levels of serum OPG, sRANKL, and Tumor necrosis factor alpha (TNFα) were determined by standard techniques using enzyme-linked immunosorbent assay kits., Results: The serum levels of OPG were significantly higher (P < 0.001), and the concentrations of TNFα was markedly lower (P = 0.024) in breastfed infants than those of formula-fed infants. No marked differences were observed between the serum levels of sRANKL in the two study groups (P = 0.8)., Conclusions: High OPG and low TNFα levels in serum of breastfed infants are important factors involved in remodeling of bone, and immune activity may prove superiority of breastfeeding over formula feeding during infancy.

Immunosuppression in acute myeloid leukemia (AML) is an important mechanism of tumor escape. CD200, as an immunosuppressive molecule, is overexpressed in some hematological malignancies and it has also been shown to be an independent prognostic factor in AML. In the current study, simultaneous CD200 expression and Foxp3(+) regulatory T cell levels were investigated in Iranian patients with AML by flow cytometry. We also assessed the effect of CD200-CD200R blockade on Th1 and T-reg cytokine production and T cell proliferation in autologous AML- and monocyte-DC mixed lymphocyte reactions (MLRs). ELISA assay was performed to detect IL-2, IL-12, IFN-γ, IL-10, and TGF-β production in MLR supernatants. Expression of Foxp3, IL-10, and TGF-β mRNAs in MLRs were detected by real-time PCR. Our results demonstrated significant overexpression of CD200 (P = 0.001) in association with higher frequencies of Foxp3(+) T cells in AML patients (r = 0.8, P < 0.001). Blocking of CD200-CD200R interaction demonstrated a significant decrease in TGF-β and IL-10 expression in AML-DC MLRs and a significant increase in IL-12 and IFN-γ expression in monocyte-DC MLRs. Elevated T cell levels with lower Foxp3 intensity was also shown in CD200-CD200R-blocked MLRs. Expression of IL-10 mRNA declined significantly only in AML-DC MLRs where CD200-CD200R interaction was blocked and the same result was observed for TGF-β and Foxp3 mRNA in both AML- and monocyte-DC MLRs. These data present a significant role for CD200 in suppressing anti-tumor immune response through stimulation of regulatory mechanisms in AML patients and suggest that CD200 may have a prognostic value in this malignancy and its blockade may be used as a target for AML immunotherapy.

Leukemic cells from AML patients can be differentiated to dendritic cells (DCs). Such DCs have potential for immunotherapy of patients. Blasts from 15 AML patients were differentiated into DCs and matured by different TLR agonists. We could generate AML-DCs from 73% of patients mostly with M4 or M5 subtypes. The DC recoveries ranged from 28% to 50%. The results showed that concomitant use of TLR4 and TLR7/8 agonists induced proficient DCs. Therefore, a combination of TLR4 and 7/8 agonists can be considered as an appropriate maturation cocktail for AML-DC production in order to use in the immunotherapy of AML patients., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The present study describes the response of a bacterial strain, isolated from a hot spring in an area with the highest levels of natural radiation, under radium ((226)Ra) stress. The bacterium has been characterized as a novel and efficient radium biosorbent and identified as a variant of Serratia marcescens by biochemical tests and molecular recognition. In order to gain insights into key cellular events that allow this strain to survive and undergo (226)Ra adaptation and biosorption, the strain was tested under two experimental conditions of 1000 and 6000 Bq (226)Ra stress. A proteomic approach involving two-dimensional polyacrylamide gel electrophoresis and mass spectrometry was used to identify the differentially expressed proteins under (226)Ra stress. Functional assessment of identified proteins with significantly altered expression levels revealed several mechanisms thought to be involved in (226)Ra adaptation and conferring resistant phenotype to the isolate, including general stress adaptation, anti-oxidative stress, protein and nucleic acid synthesis, energy metabolism, efflux and transport proteins. It suggests that this strain through evolution is particularly well adapted to the high background radiation environment and could represent an alternative source to remove (226)Ra from such areas as well as industrial radionuclide polluted wastewaters., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Common variable immunodeficiency (CVID) is a heterogeneous group of disorders, characterized by hypogammaglobulinemia and normal or low numbers of B cells, which predispose patients to recurrent infections. Peripheral blood mononuclear cells from 19 patients with CVID, and age- and sex-matched controls, were subjected to an in vitro assay of B-cell-T-cell activation and interaction, using anti-immunoglobulin (Ig)-D conjugated to dextran (alpha-delta-dex), as a polyclonal T independent type 2 antigen mimic, with and without anti-CD3/anti-CD28, as polyclonal T-cell stimuli. Stimulation of lymphocytes with either anti-CD3 or anti-CD3 plus anti-CD28 induced T-cell activation and proliferation in CVID patients who were similar to age- and sex-matched controls, but B cells of patients were significantly less activated when peripheral blood mononuclear cells were stimulated with polyclonal T-cell agonists alone. Comparison of CD86 expression in the patients with matched controls revealed that patients had low B-cell activation in response to T-cell stimuli (bystander T-cell help). In conclusion, this sample of CVID patients exhibits a defect of T-cell "help" to B cells, and/or B-cell response to T-cell help.

Assessment and redesign of water quality monitoring networks is an important task in water quality management. This paper presents a new methodology for optimal redesign of groundwater quality monitoring networks. The measure of transinformation in discrete entropy theory and the transinformation-distance (T-D) curves are used to quantify the efficiency of sampling locations and sampling frequencies in a monitoring network. The existing uncertainties in the T-D curves are taken in to account using the fuzzy set theory. The C-means clustering method is also used to classify the study area to some homogenous zones. The fuzzy T-D curve of the zones is then used in a multi-objective hybrid genetic algorithm-based optimization model. The proposed methodology is utilized for optimal redesign of monitoring network of the Tehran aquifer in the Tehran metropolitan area, Iran.