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This work is an experimental study of the effects of nanoparticles with different characteristics and contents on foaming composites made of three different nanosilica particles with different geometrical and chemical surface properties in a polystyrene matrix. In addition to the general characteristics reported in our last study on the morphology of polymer–nanoparticle composites, this study shows that nanosilicas of larger sizes can result in foams of higher cell densities. Additionally, the cell densities of foams can be reduced if the nanoparticle surface becomes more affine to the polymer matrix chemically. These results show a correspondence with the effects of the characteristics of the nucleation agent on the nucleation of bubbles, which have been explored previously. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010 [ABSTRACT FROM AUTHOR]

Background: Systemic sclerosis (SSc) is a connective tissue disorder characterized by excessive fibrosis, where activated fibroblasts play a pivotal role in disease progression. This study aimed to investigate the potential of Talabostat, a small molecule inhibitor of dipeptidyl peptidases, in alleviating fibrosis and inflammation associated with SSc pathogenesis., Methods: Dermal fibroblasts were obtained from skin biopsies of ten diffuse cutaneous SSc patients and healthy controls. These fibroblasts were subjected to treatment with either TGF-β alone or in combination with Talabostat. Immunofluorescence staining was conducted to evaluate FAPα and α-SMA protein levels. The expression of activated fibroblast markers (FAPα and ACAT2), pro-fibrotic (COL1A1 and COL1A2), anti-fibrotic (MMP1, MMP2, and MMP9), and inflammatory (IL-6 and TGFβ1) related genes was measured by quantitative real-time PCR. Talabostat-treated fibroblasts were assessed for their migratory capacity using a scratch assay and for their viability through MTT assay and Annexin V staining., Results: The basal expression of COL1A1 and TGFβ1 was notably higher in healthy subjects, while MMP1 expression showed a significant increase in SSc patients. Furthermore, TGF-β stimulation led to upregulation of activated fibroblast markers, pro-fibrotic, and inflammatory-related genes in SSc-derived fibroblasts, which were attenuated upon Talabostat treatment. Interestingly, Talabostat treatment resulted in an upregulation of MMP9 expression. Moreover, Talabostat exhibited a concentration-dependent inhibition of activated fibroblast viability in both healthy and SSc fibroblasts, and suppressed fibroblast migration specifically in SSc patients., Conclusion: In summary, Talabostat modulates fibrotic genes in SSc, thereby inhibiting myofibroblast differentiation, activation, and migration. These findings suggest promising therapeutic avenues for targeting fibrosis in SSc., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

JOURNAL/nrgr/04.03/01300535-202419110-00034/figure1/v/2024-03-08T184507Z/r/image-tiff Retinitis pigmentosa is a hereditary retinal disease that affects rod and cone photoreceptors, leading to progressive photoreceptor loss. Previous research supports the beneficial effect of electrical stimulation on photoreceptor survival. This study aims to identify the most effective electrical stimulation parameters and functional advantages of transcorneal electrical stimulation (tcES) in mice affected by inherited retinal degeneration. Additionally, the study seeked to analyze the electric field that reaches the retina in both eyes in mice and post-mortem humans. In this study, we recorded waveforms and voltages directed to the retina during transcorneal electrical stimulation in C57BL/6J mice using an intraocular needle probe with rectangular, sine, and ramp waveforms. To investigate the functional effects of electrical stimulation on photoreceptors, we used human retinal explant cultures and rhodopsin knockout (Rho-/-) mice, demonstrating progressive photoreceptor degeneration with age. Human retinal explants isolated from the donors' eyes were then subjected to electrical stimulation and cultured for 48 hours to simulate the neurodegenerative environment in vitro. Photoreceptor density was evaluated by rhodopsin immunolabeling. In vivo Rho-/- mice were subjected to two 5-day series of daily transcorneal electrical stimulation using rectangular and ramp waveforms. Retinal function and visual perception of mice were evaluated by electroretinography and optomotor response (OMR), respectively. Immunolabeling was used to assess the morphological and biochemical changes of the photoreceptor and bipolar cells in mouse retinas. Oscilloscope recordings indicated effective delivery of rectangular, sine, and ramp waveforms to the retina by transcorneal electrical stimulation, of which the ramp waveform required the lowest voltage. Evaluation of the total conductive resistance of the post-mortem human compared to the mouse eyes indicated higher cornea-to-retina resistance in human eyes. The temperature recordings during and after electrical stimulation indicated no significant temperature change in vivo and only a subtle temperature increase in vitro (~0.5-1.5°C). Electrical stimulation increased photoreceptor survival in human retinal explant cultures, particularly at the ramp waveform. Transcorneal electrical stimulation (rectangular + ramp) waveforms significantly improved the survival and function of S and M-cones and enhanced visual acuity based on the optomotor response results. Histology and immunolabeling demonstrated increased photoreceptor survival, improved outer nuclear layer thickness, and increased bipolar cell sprouting in Rho-/- mice. These results indicate that transcorneal electrical stimulation effectively delivers the electrical field to the retina, improves photoreceptor survival in both human and mouse retinas, and increases visual function in Rho-/- mice. Combined rectangular and ramp waveform stimulation can promote photoreceptor survival in a minimally invasive fashion., (Copyright © 2024 Copyright: © 2024 Neural Regeneration Research.)

Background: Biomedical Relation Extraction (RE) is essential for uncovering complex relationships between biomedical entities within text. However, training RE classifiers is challenging in low-resource biomedical applications with few labeled examples., Methods: We explore the potential of Shortest Dependency Paths (SDPs) to aid biomedical RE, especially in situations with limited labeled examples. In this study, we suggest various approaches to employ SDPs when creating word and sentence representations under supervised, semi-supervised, and in-context-learning settings., Results: Through experiments on three benchmark biomedical text datasets, we find that incorporating SDP-based representations enhances the performance of RE classifiers. The improvement is especially notable when working with small amounts of labeled data., Conclusion: SDPs offer valuable insights into the complex sentence structure found in many biomedical text passages. Our study introduces several straightforward techniques that, as demonstrated experimentally, effectively enhance the accuracy of RE classifiers., (© 2024. The Author(s).)

Background: Nosocomial infections caused by multidrug-resistant Pseudomonas aeruginosa are a considerable public health threat, requiring innovative therapeutic approaches., Objectives: This study explored preconditioning mesenchymal stem cells (MSCs) with the antimicrobial peptide Nisin to enhance their antibacterial properties while maintaining regenerative capacity., Methods: Human MSCs were preconditioned with varying concentrations of Nisin (0.1-1000 IU/mL) to determine an optimal dose. MSCs preconditioned with Nisin were characterized using microscopy, flow cytometry, gene expression analysis, and functional assays. The effects of preconditioning on the viability, phenotype, differentiation capacity, antimicrobial peptide expression, and antibacterial activity of MSCs against Pseudomonas aeruginosa were tested in vitro . The therapeutic efficacy was evaluated by topically applying conditioned media from Nisin-preconditioned versus control MSCs to infected wounds in a rat model, assessing bacterial burden, healing, host response, and survival., Results: An optimal Nisin dose of 500 IU/mL was identified, which increased MSC antibacterial gene expression and secretome activity without compromising viability or stemness. Nisin-preconditioned MSCs showed upregulated expression of LL37 and hepcidin. Conditioned media from Nisin-preconditioned MSCs exhibited about 4-fold more inhibition of P. aeruginosa growth compared to non-preconditioned MSCs. In the wound infection model, the secretome of Nisin-preconditioned MSCs suppressed bacterial load, accelerated wound closure, modulated inflammation, and improved survival compared to standard MSC treatments., Conclusion: This study explores the effect of preconditioning MSCs with the antimicrobial peptide Nisin on enhancing their antibacterial properties while maintaining regenerative capacity. Secreted factors from Nisin-preconditioned MSCs have the potential to attenuate infections and promote healing in vivo . The approach holds translational promise for managing antibiotic-resistant infections and warrants further development. Preconditioned MSCs with Nisin may offer innovative, multifaceted therapies for combating nosocomial pathogens and promoting tissue regeneration., Competing Interests: The authors declared no conflicts of interest., (© 2024 The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.)

Systemic sclerosis (SSc) is an autoimmune systemic disease that is characterized by immune dysregulation, inflammation, vasculopathy, and fibrosis. Tissue fibrosis plays an important role in SSc and can affect several organs such as the dermis, lungs, and heart. Dysregulation of interferon (IFN) signaling contributes to the SSc pathogenesis and interferon regulatory factor 1 (IRF1) has been indicated as the main regulator of type I IFN. This study aimed to clarify the effect of IFN-gamma (-γ) and dexamethasone (DEX) on the IRF1, extracellular signal-regulated kinase 1/2 (ERK1/2), and the expression of alpha-smooth muscle actin (α-SMA) in myofibroblasts and genes involved in the inflammation and fibrosis processes in early diffuse cutaneous systemic sclerosis (dcSSc). A total of 10 early dcSSc patients (diffuse cutaneous form) and 10 unaffected control dermis biopsies were obtained to determine IFNγ and DEX effects on inflammation and fibrosis. Fibroblasts were treated with IFNγ and DEX at optimum time and dose. The expression level of genes and proteins involved in the fibrosis and inflammation processes have been quantified by quantitative real-time PCR (RT-qPCR) and western blot, respectively. IFNγ could up-regulate some of the inflammation-related genes (Interleukin-6; IL6) and down-regulate some of the fibrosis-related genes (COL1A1) in cultured fibroblasts of patients with early dcSSc compared to the untreated group. Besides, it has been revealed that IFNγ can induce fibroblast differentiation to the myofibroblast that expresses α-SMA. Concerning the inhibitory effect of IFNγ on some fibrotic genes and its positive effect on the inflammatory genes and myofibroblast differentiation, it seems that IFNγ may play a dual role in SSc.

Background: Bovine coronaviruses (BCoVs) are zoonotic diseases that result in substantial economic losses due to mortality, impaired growth, and increased medication expenses in large animals. These viruses pose a risk to children who live beside infected animal, as they can cause diarrhea. This study was dedicated to molecular and antigen detections and phylogenetic and immunoinformatics analysis of zoonotic coronavirus (CoV) in Iran., Materials and Methods: A total of 77 diarrheic samples were collected from Holstein dairy herds in selected provinces of Iran. Samples were tested by capture antibody enzyme-linked immunosorbent assay (ELISA) to detect CoV and reverse transcriptase-polymerase chain reaction (RT-PCR) for verification of detection and also genotyping of spike glycoprotein in CoV-positive samples. After statistical analysis, nucleotide sequence alignment, and nucleotide and protein phylogenetic tree construction, the centralized sequence for vaccine strains was obtained using computationally optimized broadly reactive antigen (COBRA)'s center-of-the-tree (COT) method., Results: Twenty-two (28.5%) and eight (10.3%) of 77 samples were positive according to RT-PCR and ELISA, respectively. (Basic Local Alignment Search Tool) BLAST and phylogenetic analysis revealed that most similar sequences to the Iranian CoV sequence were for European countries. Furthermore, there were strong correlations to other CoVs in humans and wild and domesticated animals. As CoV has variable COT, the most recent strains and COBRA vaccine strains were obtained., Conclusion: Based on the high prevalence of this viral disease in calves and its economic impact on the breeding industry, as well as the potential transmission to humans and correlation with World Health Organization (WHO) One Health approach guidelines, the study emphasizes the importance of implementing preventive strategies such as animal vaccination., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Advanced Biomedical Research.)

Drones (uncrewed aerial vehicles or UAVs) introduce new opportunities to improve vaccine distribution systems, particularly in regions with limited transportation infrastructure where maintaining the cold chain is challenging. This paper addresses the use of drones to deliver vaccines to hard-to-reach populations using a novel optimization model to strategically design a multimodal vaccine distribution network. The model is illustrated in a case study for distributing routine childhood vaccines in Vanuatu, a South Pacific island nation with limited transportation infrastructure. Our research incorporates multiple drone types, recharging of drones, a cold chain travel time limit, transshipment delays for switching transport modes, and practical limits on the vaccine paths and drone trips. The goal is to locate facilities (distribution centers, drone bases, and relay stations) and design vaccine paths to minimize transportation costs, including the fixed costs for facilities and transportation links and variable costs for transportation through the network. Results show large potential cost savings and improved service quality provided by incorporating drones in a multimodal vaccine distribution system. Results also show the impact of introducing drones on the usage of other more expensive or slower transport modes., Competing Interests: 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.

Relation Extraction (RE) is an important task in extracting structured data from free biomedical text. Obtaining labeled data needed to train RE models in specialized domains such as biomedicine can be very expensive because it requires expert knowledge. Thus, it is often the case that RE models need to be trained from relatively small labeled data sets. Despite the recent advances in Natural Language Processing (NLP) approaches for RE, training accurate RE models from small labeled data is still an open challenge. In this paper, we propose MERIT, a simple and effective approach for label augmentation that automatically increases the size of labeled data while introducing a moderate labeling noise. We performed extensive experiments on three benchmarks biomedical RE data sets. The results demonstrate the effectiveness of MERIT compared to the baseline., (©2022 AMIA - All rights reserved.)

Introduction: Inflammatory bowel disease (IBD) is an autoimmune disease involving various parts of the gastrointestinal (GI) tract, which includes Crohn's disease (CD) and ulcerative colitis (UC). Due to the contradictory results regarding the percentage of peripheral blood (PB) regulatory T cells (Tregs) in IBD patients, this meta-analysis aimed to determine the Tregs frequency in IBD patients., Method: We searched PubMed, Web of Science, SCOPUS, and Google Scholar databases for relevant observational articles that analyzed and reported the frequency of PB Tregs in IBD patients and healthy control groups. After choosing the related articles by two reviewers, the data regarding the definition of Tregs and their frequencies in different groups were recorded., Result: In 22 studies, the results showed a nonsignificant difference in the frequency of PB Tregs between IBD cases and control subjects (SMD: -0.27, 95 % CI: -0.78, 0.23). However, the frequency of CD4 + CD25 + CD127 - (SMD: -0.89, 95 % CI: -1.52, -0.26) and CD4 + CD25 + FoxP3 + (SMD: -1.32, 95 % CI: -2.37, -0.26) Tregs were significantly lower in IBD cases, compared to healthy subjects. Also, UC cases and active IBD cases showed a significantly lower frequency of Treg cells, compared to controls and remission IBD cases, respectively (SMD: -0.68, 95 % CI: -1.24, -0.11 and SMD: -0.60, 95 % CI: -0.93, -0.27)., Conclusion: Our study highlighted a probable decrease of Tregs in IBD patients, especially the patients with active states of the disease. The decrease of Treg cells might cause an imbalance in the immune system and the over-activation of auto-immune responses against the digestive tract., 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 © 2023. Published by Elsevier B.V.)

CD22 is a B-cell surface antigen which is highly expressed in cancerous B-cell lineages. Anti-CD22 antibodies are currently under focus as promising biologics against hematologic B-cell malignancies. Herein, we introduce a novel active recombinant anti-CD22 scFv.Bim fusion protein for targeting this cancerous antigen. An expression cassette encoding anti-CD22 scFv.Bim fusion protein was expressed in Pichia pastoris. The binding ability, cytotoxicity, and apoptotic activity of the purified recombinant protein against CD22 + Raji cell line were assessed by flow cytometry, microscopy, and MTT assay. Using bioinformatics, the 3D structure of the fusion protein and its interaction with CD22 were assessed. The in vitro binding analysis by immunofluorescence microscopy and flow cytometry demonstrated the specific binding of scFv.Bim to CD22 + Raji cells but not to CD22 - Jurkat cells. MTT data and Annexin V/PI flow cytometry analysis confirmed the apoptotic activity of anti-CD22 scFv.Bim against Raji cells but not Jurkat cells. In silico analysis also revealed the satisfactory stereochemical quality of the 3D model and molecular interactions toward CD22. This novel recombinant anti-CD22 scFv.Bim fusion protein could successfully deliver the pro-apoptotic peptide, BIM, to the target cells and thus nominates it as a promising molecule in treating B-cell malignancies., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To determine the effect of femtosecond laser cutting parameters on small-incision lenticule extraction (SMILE) results by evaluating cap thickness, interface light scattering, and visual and refractive outcomes., Setting: SynsLaser Clinic, Oslo, Norway., Design: Retrospective., Methods: 58 right eyes treated with SMILE using a programmed cap thickness of 130 μm were divided into 2 groups according to laser settings: Group 1: 165 nJ pulse energy and 4.5 μm spot separation (n = 36); Group 2: 125 nJ pulse energy and 4.2 μm spot separation (n = 22). The cap thickness was measured within the central 5 mm of the horizontal meridian using spectral-domain optical coherence tomography. Postoperative interface light scattering was graded based on the percentage area showing light scattering: 0: no scattering; 1: ≤25%; 2: 26% to 50%; 3: 51% to 75%; and 4: >75%., Results: At 3 months postoperatively, cap thickness was 138.9 ± 6.2 μm in Group 1 and 149.4 ± 3.5 μm in Group 2 ( P < .001). Interface scattering was 0.9 ± 1.0 in Group 1 and 0.3 ± 0.9 in Group 2 ( P < .05), with no scattering in 33.3% and 86.4% of the eyes, respectively. The postoperative spherical equivalent refraction was -0.03 ± 0.44 diopters (D) in Group 1 and -0.04 ± 0.31 D in Group 2. In Group 1, 83.3% of the eyes were within ± 0.5 D of the desired outcome, and 69.4% achieved an uncorrected distance visual acuity of 20/20 or better. In Group 2, these values were 95.5% and 86.4%, respectively., Conclusions: Lower pulse energy with tighter spots seems to reduce interface light scattering and improve refractive outcomes while also significantly increasing cap thickness., (Copyright © 2022 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Objective: Congenital hyperinsulinism (CHI) is the most frequent cause of severe and persistent hypoglycaemia from birth. Understanding the pathophysiology and genetic defects behind hyperinsulinism and its complications provides clues to timely diagnosis and management. The aim of this study was to evaluate the underlying genetic aetiology of a specific Iranian pediatric cohort with CHI., Methods: A total of 44 unrelated children, 20 girls and 24 boys, with an initial diagnosis or history of CHI from all regions of Iran were recruited between 2016 and 2019. Targeted next generation sequencing (tNGS) was performed for the genes found in about half of CHI patients., Results: Mutations were identified in 24 cases (55%). Patients with a confirmed genetic cause were mainly diagnosed below age of one year old (p=0.01), had fewer other syndromic features, excluding seizure, (p=0.03), were less diazoxide responsive (p=0.04) and were more diazoxide unresponsive leading to pancreatectomy (p=0.007) compared to those with no identified mutations. Among 24 patients with identified genetic mutations, 17 (71%) had a mutation in ABCC8 , 3 (12%) in KCNJ11 , 3 (12%) in HADH , and 1 patient had a mutation in KMT2D . These included five novel mutations in ABCC8, KCNJ11 , and KMT2D ., Conclusion: This is the biggest genetic study of CHI in Iran. A high frequency of recessive forms of CHI, especially HADH mutations, in our study could be due to a high rate of consanguineous marriage. We recommend tNGS to screen for all the CHI genes.

Superficial fungal infections are prevalent worldwide, with dermatophytes as the most common cause. Various antifungal agents including azoles and allylamines are commonly used to treat dermatophytosis. However, their overuse has yielded drug-resistant strains, calling for the development of novel antimycotic compounds. Olorofim is a newly developed antifungal compound that targets pyrimidine biosynthesis in molds. The purpose of this study was to determine the in vitro and in vivo antifungal effects of olorofim against common dermatophytes. The in vitro activity of olorofim against dermatophytes was assessed by microtiter broth dilution method. Bioinformatic analysis of olorofim binding to dihydroorotate dehydrogenase (DHODH) of dermatophytes was also performed, using Aspergillus fumigatus DHODH as a template. The in vivo efficacy of the drug was investigated, using a guinea pig model, experimentally infected with Microsporum gypseum. Microtiter assays confirmed the high in vitro sensitivity of dermatophytes to olorofim (MIC = 0.015-0.06 mg/liter). Amino acid sequence analysis indicated that DHODH is highly conserved among dermatophytes. The critical residues, in dermatophytes, involved in olorofim binding were similar to their counterparts in A. fumigatus DHODH, which explains their susceptibility to olorofim. Typical skin lesions of dermatophyte infection were observed in the guinea pig model at 7 days postinoculation. Following 1 week of daily topical administration of olorofim, similar to the clotrimazole group, the skin lesions were resolved and normal hair growth patterns appeared. In light of the in vitro and in vivo activity of olorofim against dermatophytes, this novel agent may be considered as a treatment of choice against dermatophytosis.

Competing Interests: None

Background: The methylotrophic yeast Pichia pastoris is an appealing production host for a variety of recombinant proteins, including biologics. In this sense, various genetic- and non-genetic-based techniques have been implemented to improve the production efficiency of this expression platform. Loss of supression (Los1) encodes a non-essential nuclear tRNA exporter in Saccharomyces cerevisiae, which its deletion extends replicative lifespan. Herein, a los1-deficient strain of P. pastoris was generated and characterized., Methods: A gene disruption cassette was prepared and transformed into an anti-CD22-expressing strain of P. pastoris. A δ los1 mutant was isolated and confirmed. The drug sensitivity of the mutant was also assessed. The growth pattern and the level of anti-CD22 single-chain variable fragment (scFv) expression were compared between the parent and mutant strains., Resuults: The los1 homologue was found to be a non-essential gene in P. pastoris. Furthermore, the susceptibility of los1 deletion strain to protein synthesis inhibitors was altered. This strain showed an approximately 1.85-fold increase in the extracellular level of anti-CD22 scFv (p < 0.05). The maximum concentrations of total proteins secreted by δ los1 and parent strains were 125 mg/L and 68 mg/L, respectively., Conclusion: The presented data suggest that the targeted disruption of los1 homologue in P. pastoris can result in a higher expression level of our target protein. Findings of this study may improve the current strategies used in optimizing the productivity of recombinant P. pastoris strains.

Background: Cervical cancer is a growing health concern, especially in resource-limited settings., Objective: The objective of this study was to assess the burden of cervical cancer mortality and disability-adjusted life years (DALYs) in the Eastern Mediterranean Region (EMR) and globally between the years 2000 and 2017 by using a pooled data analysis approach., Methods: We used an ecological approach at the country level. This included extracting data from publicly available databases and linking them together in the following 3 steps: (1) extraction of data from the Global Burden of Disease (GBD) study in the years 2000 and 2017, (2) categorization of EMR countries according to the World Bank gross domestic product per capita, and (3) linking age-specific population data from the Population Statistics Division of the United Nations (20-29 years, 30-49 years, and >50 years) and GBD's data with gross national income per capita and globally extracted data, including cervical cancer mortality and DALY numbers and rates per country. The cervical cancer mortality rate was provided by the GBD study using the following formula: number of cervical cancer deaths × 100,000/female population in the respective age group., Results: The absolute number of deaths due to cervical cancer increased from the year 2000 (n=6326) to the year 2017 (n=8537) in the EMR; however, the mortality rate due to this disease decreased from the year 2000 (2.7 per 100,000) to the year 2017 (2.5 per 100,000). According to age-specific data, the age group ≥50 years showed the highest mortality rate in both EMR countries and globally, and the age group of 20-29 years showed the lowest mortality rate both globally and in the EMR countries. Further, the rates of cervical cancer DALYs in the EMR were lower compared to the global rates (2.7 vs 6.8 in 2000 and 2.5 vs 6.8 in 2017 for mortality rate per 100,000; 95.8 vs 222.2 in 2000 and 86.3 vs 211.8 in 2017 for DALY rate per 100,000; respectively). However, the relative difference in the number of DALYs due to cervical cancer between the year 2000 and year 2017 in the EMR was higher than that reported globally (34.9 vs 24.0 for the number of deaths and 23.5 vs 18.1 for the number of DALYs, respectively)., Conclusions: We found an increase in the burden of cervical cancer in the EMR as per the data on the absolute number of deaths and DALYs. Further, we found that the health care system has an increased number of cases to deal with, despite the decrease in the absolute number of deaths and DALYs. Cervical cancer is preventable if human papilloma vaccination is taken and early screening is performed. Therefore, we recommend identifying effective vaccination programs and interventions to reduce the burden of this disease., (©Fereshteh Safaeian, Shidrokh Ghaemimood, Ziad El-Khatib, Sahba Enayati, Roksana Mirkazemi, Bruce Reeder. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 12.05.2021.)

Background and Aims: In-stent restenosis (ISR) remains the most daunting challenge of current treatments of coronary artery disease (CAD). MicroRNAs (miRNAs) are prominent regulators of key pathological processes leading to restenosis and used as diagnostic tools in different studies. miR-152 and miR-148a are implicated to contribute in the putative intracellular mechanisms of ISR. The aim of present study is to investigate the potential early-stage diagnostic role of miR-152 and miR-148a expression levels for ISR in peripheral blood mononuclear cells (PBMCs) of patients who underwent stent implantation., Methods and Results: The miRNAs that are supposed to be involved in the ISR were nominated by bioinformatics approach mainly using miRWalk3. Then by quantitative real-time PCR, we determined the relative expression of miR-152 and miR-148a of PBMCs from ISR patients with their age/sex-matched controls., Results: The presence of ISR significantly coincided with a decrease in the relative expression of miR-152. The area under the curve (AUC) for miR-152 receiver operating characteristic (ROC) curve was 0.717 (95% CI; 0.60-0.83) with a sensitivity of 70% and a specificity of 67%, suggesting that the miRNA expression level might be employed to identify patients at risk of ISR., Conclusions: To the best of our knowledge, this is the first work to show that the miR-152 expression level can possibly be applied to predict CAD patients at risk of ISR. The results suggest that the expression levels of miR-152 in PBMCs may serve as a biomarker for ISR. Our finding suggests the importance of miRNA levels in PBMCs as a novel biological tool to detect diseases in their early clinical stages., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Tumor segmentation in brain MRI images is a noted process that can make the tumor easier to diagnose and lead to effective radiotherapy planning. Providing and building intelligent medical systems can be considered as an aid for physicians. In many cases, the presented methods' reliability is at a high level, and such systems are used directly. In recent decades, several methods of segmentation of various images, such as MRI, CT, and PET, have been proposed for brain tumors. Advanced brain tumor segmentation has been a challenging issue in the scientific community. The reason for this is the existence of various tumor dimensions with disproportionate boundaries in medical imaging. This research provides an optimized MRI segmentation method to diagnose tumors. It first offers a preprocessing approach to reduce noise with a new method called Quantum Matched-Filter Technique (QMFT). Then, the deep spiking neural network (DSNN) is implemented for segmentation using the conditional random field structure. However, a new algorithm called the Quantum Artificial Immune System (QAIS) is used in its SoftMax layer due to its slowness and nonsegmentation and the identification of suitable features for selection and extraction. The proposed approach, called QAIS-DSNN, has a high ability to segment and distinguish brain tumors from MRI images. The simulation results using the BraTS2018 dataset show that the accuracy of the proposed approach is 98.21%, average error-squared rate is 0.006, signal-to-noise ratio is 97.79 dB, and lesion structure criteria including the tumor nucleus are 80.15%. The improved tumor is 74.50%, and the entire tumor is 91.92%, which shows a functional advantage over similar previous methods. Also, the execution time of this method is 2.58 seconds., Competing Interests: We declare no conflict of interest., (Copyright © 2021 Mohsen Ahmadi et al.)

Multifunctional matrix protein (M) of rabies virus (RABV) plays essential roles in the pathogenesis of rabies infection. Identification of M protein interacting partners in target hosts could help to elucidate the biological pathways and molecular mechanisms involved in the pathogenesis of this virus. In this study, two-dimensional Far-western blotting (2D-Far-WB) technique was applied to find possible matrix protein partners in the rat brainstem. Recombinant RABV M was expressed in Pichia pastoris and was partially purified. Subsequently, 2D-Far-WB-determined six rat brainstem proteins interacted with recombinant M proteins that were identified by mass spectrometry. Functional annotation by gene ontology analysis determined these proteins were involved in the regulation of synaptic transmission processes, metabolic process and cell morphogenesis-cytoskeleton organization. The interaction of viral M protein with selected host proteins in mouse Neuro-2a cells infected with RABV was verified by super-resolution confocal microscopy. Molecular docking simulations also demonstrated the formation of RABV M complexes. However, further confirmation with co-immunoprecipitation was only successful for M-actin cytoplasmic 1 interaction. Our study revealed actin cytoplasmic 1 as a binding partner of M protein, which might have important role(s) in rabies pathogenesis., (© The Author(s) 2020. Published by Oxford University Press on behalf of FEMS.)

Purpose: Neurons carry electrical signals and communicate via electrical activities. The therapeutic potential of electrical stimulation (ES) for the nervous system, including the retina, through improvement of cell survival and function has been noted. Here we investigated the neuroprotective and regenerative potential of ES in a mouse model of inherited retinal degeneration., Methods: Rhodopsin-deficient (Rho-/-) mice received one or two sessions of transpalpebral ES or sham treatments for 7 consecutive days. Intraperitoneal injection of 5-ethynyl-2'-deoxyuridine was used to label proliferating cells. Weekly electroretinograms were performed to monitor retinal function. Retinal morphology, photoreceptor survival, and regeneration were evaluated in vivo using immunohistochemistry and genetic fate-mapping techniques. Müller cell (MC) cultures were employed to further define the optimal conditions of ES application., Results: Noninvasive transpalpebral ES in Rho-/- mice improved photoreceptor survival and electroretinography function in vivo. ES also triggered residential retinal progenitor-like cells such as MCs to reenter the cell cycle, possibly producing new photoreceptors, as shown by immunohistochemistry and genetic fate-mapping techniques. ES directly stimulated cell proliferation and the expression of progenitor cell markers in MC cultures, at least partially through bFGF signaling., Conclusions: Our study showed that transpalpebral ES improved photoreceptor survival and retinal function and induced the proliferation, probably photoreceptor regeneration, of MCs; this occurs via stimulation of the bFGF pathways. These results suggest the exciting possibility of applying noninvasive ES as a versatile tool for preventing photoreceptor loss and mobilizing endogenous progenitors for reversing vision loss in patients with photoreceptor degeneration.

Non-invasive electrical stimulation (ES) is increasingly applied to improve vision in untreatable eye conditions, such as retinitis pigmentosa and age-related macular degeneration. Our previous study suggested that ES promoted retinal function and the proliferation of progenitor-like glial cells in mice with inherited photoreceptor degeneration; however, the underlying mechanism remains obscure. Müller cells (MCs) are thought to be dormant residential progenitor cells that possess a high potential for retinal neuron repair and functional plasticity. Here, we showed that ES with a ramp waveform of 20 Hz and 300 µA of current was effective at inducing mouse MC proliferation and enhancing their expression of progenitor cell markers, such as Crx (cone-rod homeobox) and Wnt7 , as well as their production of trophic factors, including ciliary neurotrophic factor. RNA sequencing revealed that calcium signaling pathway activation was a key event, with a false discovery rate of 5.33 × 10 -8 ( p = 1.78 × 10 -10 ) in ES-mediated gene profiling changes. Moreover, the calcium channel blocker, nifedipine, abolished the observed effects of ES on MC proliferation and progenitor cell gene induction, supporting a central role of ES-induced Ca 2+ signaling in the MC changes. Our results suggest that low-current ES may present a convenient tool for manipulating MC behavior toward neuroregeneration and repair.

The aim of this study was to determine the effects of caffeine and chlorogenic acid supplementation on gut microbiota, and metabolic disturbances in patients with NAFLD and diabetes. In this randomized, placebo-controlled, clinical trial, 26 patients with diabetes and NAFLD were randomly assigned to four groups to receive either 200 mg caffeine plus 200 mg chlorogenic acid (CFCA), or 200 mg caffeine plus 200 mg placebo (starch) (CFPL), or 200 mg chlorogenic acid plus 200 mg placebo (CAPL), or 200 mg placebo plus 200 mg placebo (PLPL) for 12 weeks. After 3 months of supplementation, patients in the intervention groups showed a significant decrease in body weight (CFCA group =-3.69 kg; CFPL group=-0.7kg; CAPL group=-0.43kg; PLPL group=0.26 kg) (p=0.004). Weight reduced significantly more in CFCA group compared to all other three groups (p=0.005 for PLPL; p=0.023 for CAPL; and p=0.031 for CFPL). Although the number of gut Bifidobacteria increased in CFCA group, there were no statistically significant differences within and between the groups in any of bacteria numbers. In conclusion, our study showed that 12 weeks consumption of 200 mg/day caffeine plus 200 mg/day chlorogenic acid is effective in reduction of weight in patients with NAFLD and diabetes which might be at least partially through the rise in gut Bifidobacteria. This pilot study shed a light on the pathway of future clinical trials assessing the effects of coffee consumption in these patients. This trial has been registered at clinicaltrial.gov with registration number of NCT02929901., (Copyright © 2020 Mansour et al.)

In Saccharomyces cerevisiae, los1 encodes a nuclear tRNA exporter. Despite the non-essentiality, the deletion of los1 has been shown to extend replicative life span in yeast. Here, we characterized AfuXpot, the los1 homologue in human pathogen Aspergillus fumigatus and found that it is continuously expressed during fungal growth. Microscopic examination of an AfuXpot-GFP-expressing transformant confirmed the nuclear localization of the fusion protein. The targeted gene deletion affirmed the non-essential role of AfuXpot in hyphal growth and sporulation. However, the growth of the deletion mutant was affected by amino acid, but not glucose, deprivation. The susceptibility of the deletant strain to protein and DNA/RNA synthesis inhibitors was also altered. Using bioinformatics tools, some transcription factor binding sites were predicted in AfuXpot promoter. Expression analyses of potential AfuXpot-interacting genes showed a marked down-regulation of sfp1 and mtr10 homologues in ΔAfuXpot strain. Our data demonstrates some conserved aspects of AfuXpot as a tRNA exporter in A. fumigatus.

Aim: To examine the extent to which discriminatory testing using antibodies and Type 1 diabetes genetic risk score, validated in European populations, is applicable in a non-European population., Methods: We recruited 127 unrelated children with diabetes diagnosed between 9 months and 5 years from two centres in Iran. All children underwent targeted next-generation sequencing of 35 monogenic diabetes genes. We measured three islet autoantibodies (islet antigen 2, glutamic acid decarboxylase and zinc transporter 8) and generated a Type 1 diabetes genetic risk score in all children., Results: We identified six children with monogenic diabetes, including four novel mutations: homozygous mutations in WFS1 (n=3), SLC19A2 and SLC29A3, and a heterozygous mutation in GCK. All clinical features were similar in children with monogenic diabetes (n=6) and in the rest of the cohort (n=121). The Type 1 diabetes genetic risk score discriminated children with monogenic from Type 1 diabetes [area under the receiver-operating characteristic curve 0.90 (95% CI 0.83-0.97)]. All children with monogenic diabetes were autoantibody-negative. In children with no mutation, 59 were positive to glutamic acid decarboxylase, 39 to islet antigen 2 and 31 to zinc transporter 8. Measuring zinc transporter 8 increased the number of autoantibody-positive individuals by eight., Conclusions: The present study provides the first evidence that Type 1 diabetes genetic risk score can be used to distinguish monogenic from Type 1 diabetes in an Iranian population with a large number of consanguineous unions. This test can be used to identify children with a higher probability of having monogenic diabetes who could then undergo genetic testing. Identification of these individuals would reduce the cost of treatment and improve the management of their clinical course., (© 2019 Diabetes UK.)

Nephropathy is a common diabetes complication. ERRFI1 gene which participates in various cellular pathways has been proposed as a candidate gene in diabetic nephropathy. This study aimed to investigate the role of +808T/G polymorphism (rs377349) in ERRFI1 gene in diabetic nephropathy. In this case-control study, patients including diabetes with nephropathy (DN=104), type 2 diabetes without nephropathy (DM=100), and healthy controls (HC=106) were included. DNA was extracted from blood, and genotyping of the +808T/G polymorphism was carried out using PCR-RFLP technique. The differences for genotype and allele frequencies for +808T/G polymorphism in ERRFI1 gene between DN vs. HC and DN+DM vs. HC were significant (P<0.05) while no significant difference between DN and DM was observed. The allele frequencies were significantly different in DN vs. HC and DN+DM vs. HC in males but not in females. G allele of +808T/G polymorphism in ERRFI1 gene has no significant role in development and progression of diabetic nephropathy in diabetes patients while it is a risk allele for developing diabetes in Iranian population.

Pathogenic variants in COL9A1 are primarily associated with autosomal recessive Stickler syndrome. Patients with COL9A1-associated Stickler syndrome (STL) present hearing loss (HL), ophthalmic manifestations and skeletal abnormalities. However, the clinical spectrum of patients with COL9A1 variants can also include multiple epiphyseal dysplasia, as well as non-syndromic HL that was observed in one previously reported proband. Exome sequencing was performed on the genomic DNA of an Iranian patient and his affected brother who both report non-syndromic HL. A 44.6 kb homozygous in-frame deletion spanning exons 6 to 33 of COL9A1 was detected via exome-based copy number variation analysis. The deleted exons were confirmed by PCR in the patient and his affected brother, who both have non-syndromic HL. Segregation analysis via qPCR confirmed the parents as heterozygous deletion carriers. Breakpoint analysis mapped the homozygous deletion spanning introns 5 to 33 (g.70,948,188&#95;70,997,277del, NM&#95;001851.4(COL9A1):c.697-3754&#95;2112+769del, p.(Phe233&#95;Ser704del), with an additional 67 bp of inserted intronic sequence that may have originated due to a fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR) mechanism. This mechanism has not been previously implicated in HL or STL. This is also the first reported copy number variation in COL9A1 that was identified through an exome data set in an Iranian family with apparent non-syndromic HL. The present study emphasizes the importance of exome-wide copy number variation analysis in molecular diagnosis and provides supporting evidence to associate COL9A1 with autosomal recessive non-syndromic HL., (Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Mutations of the autoimmune regulator gene (AIRE), located on chromosome 21q22.3, are recognized as the cause of a rare monogenic organ-specific autoimmune disorder called autoimmune polyglandular syndrome type 1 (APS-1). Three major components of this syndrome include chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenocortical failure., Case Presentation: We report a 19-year-old girl, who was born in an Iranian Muslim family with a clinical diagnosis of APS-1. To identify the causative mutation, a direct sequencing of the entire AIRE gene sequence was performed by Sanger sequencing method. Three distinct variants were discovered, including c.1095 + 2 T > A, c.1197 T > C (rs1800521) and c.1578 T > C (rs1133779), in intron 9, exons 10 and 14 of the AIRE gene, respectively., Conclusions: To the best of our knowledge, this is the first report of an Iranian Muslim APS-1 patient with combination of these variations. In addition, the effect of c.1095 + 2 T > A mutation on AIRE mRNA expression was reported for the first time. This study expands the diversity of variants that could cause APS-1. More genetic studies are required to determine the exact frequency of these variants and their diagnostic significance.

Background: Type 2 diabetes mellitus (T2DM) is a continuous metabolic disease linked with increased rate of mortality and morbidity. High levels of glucose can damage organs including kidneys, eyes, and the nervous system. Individuals with T2DM have a high prevalence of major depression. One possible question we aimed to address was the extent of co-occurrence of diabetes and depression resulting from correlated genetic risk factors., Objectives: The current study aimed to investigate the possible associations between the macrophage migration inhibitory factor (MIF) functional variant and the risk of developing depression in T2DM patients., Patients and Methods: The study groups consisted of 120 patients with T2DM and comorbid depression and 120 patients with T2DM, without depression, who were recruited from the same region. Genotyping of the MIF -173 G > C (rs755622) variant was performed using Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP). In addition, the level of MIF expression was comparatively evaluated in both groups by quantitative real-time PCR., Result: The data showed that the presence of C allele (GC + CC vs. GG) might predispose females to depression in patients with T2DM. In addition, patients with T2DM carrying at least one C allele showed significantly elevated levels of MIF RNA expression in comparison to individuals with GG genotype., Conclusion: MIF variant could be considered as a factor making female patients with T2DM vulnerable to depression. So, this might be an important result for precise diagnosis and/or earlier treatment., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background and Purpose: Immunological pathways play a crucial role in developing and precipitating neuropsychiatric disorders. Although the exact pathogenesis of schizophrenia is unknown, the possible role of genetic and biomarker involvement of the immune system is gaining attention. Here we quantified the mRNA expression of cytokines as a key role player of the immune system from the peripheral blood mononuclear cells of patients with schizophrenia and healthy controls to identify the differentially expressed genes., Methods: Sixteen medication-free schizophrenia patients and 16 healthy subjects were enrolled in the current study. To investigate the desired expression level of mRNAs including TGF-β1, IL-1β, IL-23, TNF-α, NF-κB, and BDNF, quantitative real-time PCR was performed using specific oligonucleotide primers and the Applied Bio systems StepOne™ real time PCR system. DNA methylation was also analyzed through methylation-specific polymerase chain reaction (MSP)., Results: TGF-β1 was significantly up-regulated in peripheral blood mononuclear cells of patients vs. healthy individuals (P value = 0.03). In addition, we found a significant correlation between the positive symptom scale and TGF-β1 gene overexpression (r = 0.536, P = 0.039). However, we did not observe any statistically significant differences for the methylation status of CpG Islands 1 and 2 between the patients and normal group. No statistical significance was found either for gene expression of IL-1β (P = 0.32), IL-23 (P = 0.12), TNF-α (P = 0.87), NF-κB (P = 0.07), and BDNF (P = 0.33)., Conclusions: Although the number of medication-free schizophrenia patients is extremely limited, our data highlighted the potential role of TGF-β1 as a regulatory cytokine in complex inflammatory mechanism involved in medication-free schizophrenia. In addition, we observed that increased level of TGF-β1 mRNA in this disease might not be under methylation as an epigenetic control element at the genomic level., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Increases in overweight and obesity among youths have resulted in the diagnosis of Type 2 diabetes mellitus (T2DM) at earlier ages. The impact of lifestyle-related factors has been implicated; however, its relation to morbidity and mortality and sex differences remain unclear. We aimed to document the changes in risk factors and sex differences associated with T2DM-related morbidity and mortality during 1995-2015., Method: We used mortality rates and morbidity estimates from the Global Burden of Diseases Study 2016 using Disability-Adjusted Life Years (DALY). Multiple linear regression analyses were used to determine associations between T2DM-related mortality and related risk factors. DALYs were grouped by country income level, and were stratified by sex., Results: Increases in mortality were observed for both sexes, and females tended to have higher mortality rates per 100,000 persons. Body mass index (BMI) continued to be the leading risk factor for T2DM-related mortality, and increases in BMI were more common in low- and middle-income countries (LIC and MIC). Low physical activity was strongly associated with mortality rates, followed by dietary risks and smoking (2.4; 1.4; 0.8 per 100,000 persons, respectively). Similar patterns were observed after adjustments for income level, sex, and age. DALYs continued to show increasing trends across all income levels during 1995-2015 (high-income (HIC):16%; MIC: 36%; LIC: 12%). Stratification by sex showed similar results; males had fewer T2DM DALYs than females, though a greater increase was observed among males., Conclusion: Overall, T2DM related mortality was higher among females. Compared to in HIC, there appeared to be a considerable increase in the burden of T2DM in MIC and LIC, where BMI is the leading risk factor for T2DM-related mortality. Prevention programs should emphasize related risk factors according to the existing standard of care.

Background: Despite assessing the expression of CD11c gene in macrophages in adipose tissues and suggesting association between the gene expressions and predisposing to obesity, the relationship of the changes in CD11c gene and its variants with obesity has not been exclusively evaluated. The present study aimed to assess the relationship between rs2230424 gene polymorphism leading a single amino acid Arginine 48 to Tryptophan interchange in CD11c gene protein chain and obesity in a sample of Iranian population., Methods: This case-control association study was performed on 247 subjects including obese individuals and a sex- and age-matched healthy non-obese individuals. After DNA extraction, the DNA sequence containing the relevant polymorphic site was amplified by polymerase chain reaction (PCR). Determining different genotypic patterns of the SNP was carried out by restriction fragment length polymorphism (RFLP) analysis. To final draft the suspected genotypes of the SNP, DNA sequencing was performed., Results: The frequency of wild genotype (TT) of Trp48Arg polymorphism of the CD11c gene in obese and non-obese groups was 97.9% and 94.6% and the frequency of heterozygous genotype (TC) was 2.1% and 5.4%, respectively with no significant difference ( p  = 0.230,). None of the participants had mutant genotypic pattern of the polymorphism. There was no association of the genotypic pattern of Trp48Arg polymorphism with different underlying risk factors as well as mean laboratory parameters., Conclusion: The presence of Trp48Arg polymorphism of the CD11c gene is not associated with increased risk for obesity among Iranian population.

Congenital Leptin receptor (LEPR) deficiency is a rare genetic cause of early-onset morbid obesity characterised by severe early onset obesity, major hyperphagia, hypogonadotropic hypogonadism and immune and neuroendocrine/metabolic dysfunction. We identified a homozygous loss-of-function mutation, NM&#95;002303.5:c.464 T > G; p.(Tyr155*), in the LEPR in an extended consanguineous family with multiple individuals affected by early-onset severe obesity and hyperphagia. Interestingly, the LEPR-deficient adult females have extremely high body mass index (BMI) with hypogonadal infertility, the BMI of the affected males began to decline around the onset of puberty (13-15 years) with fertility being preserved. These findings lead to the speculation that LEPR deficiency may have a gender-specific effect on the regulation of body weight. In order to elucidate gender-specific effects of LEPR deficiency on reproduction further investigations are needed. The limitations of this study are that our conclusion is based on observations of two males and two females. Further LEPR deficient males and females are required for comparison in order to support this finding more confidently., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Objective: Wolcott-Rallison syndrome (WRS) is an extremely rare autosomal recessive condition, characterized by permanent neonatal diabetes mellitus (PNDM) associated with skeletal dysplasia, growth retardation and liver dysfunction. WRS is caused by biallelic mutations in the gene encoding eukaryotic translation initiation factor 2alpha kinase 3 (EIF2AK3)., Methods: As part of a comprehensive study on clinical and genetic investigation of neonatal diabetes in an Iranian population, 60 unrelated Iranian subjects referred with PNDM were analyzed. All the probands were screened for KCNJ11, INS, ABCC8 and EIF2AK3 using a polymerase chain reaction-based sequencing approach., Results: We identified 9 different variants in EIF2AK3 in 11 unrelated Iranian probands, of which 5 variants were shown to be novel and not reported previously. The diagnosis of WRS was made by molecular genetic testing and confirmed by clinical re-evaluation of the subjects. Clinical follow up of the affected individuals shows that in at least some of them, PNDM was associated with short stature, failure to thrive, neurodevelopmental delay, epilepsy and hepatic and renal dysfunction. There was a strong family history of neonatal diabetes in the families of the probands with a high mortality rate., Conclusion: WRS is a common cause of PNDM in children of consanguineous parents. Furthermore, clinical diagnosis of WRS would have been delayed or possibly missed without genetic testing because this study shows that the associated features of WRS might be obscured by a diagnosis of PNDM. Therefore EIF2AK3 should be considered for any infant and young child with PNDM, particularly if the parents are related., (Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.)

Background: Design of experiments is a rapid and cost-effective approach for optimization of recombinant protein production process. In our previous study, we generated a potent dual-acting fusion protein, anti-CD22 scFv-apoptin, to target B-cell malignant cell lines. In the present investigation, we report the effect of different variables on the expression levels of this fusion protein., Methods: Four variables (cell optical density at induction, IPTG concentration, induction temperature, and induction time) were tested using experimental design., Results: Our findings demonstrated that among the examined variables, only the induction time had a significant positive effect on the protein expression yield., Conclusion: Experimental design was successfully applied in this study. The optimized condition obtained in the current study can be applied in future commercial production of this novel fusion protein.