Automatic Autism Spectrum Disorder Detection Using Artificial Intelligence Methods with MRI Neuroimaging: A Review

Autism spectrum disorder (ASD) is a brain condition characterized by diverse signs and symptoms that appear in early childhood. ASD is also associated with communication deficits and repetitive behavior in affected individuals. Various ASD detection methods have been developed, including neuroimaging modalities and psychological tests. Among these methods, magnetic resonance imaging (MRI) imaging modalities are of paramount importance to physicians. Clinicians rely on MRI modalities to diagnose ASD accurately. The MRI modalities are non-invasive methods that include functional (fMRI) and structural (sMRI) neuroimaging methods. However, the process of diagnosing ASD with fMRI and sMRI for specialists is often laborious and time-consuming; therefore, several computer-aided design systems (CADS) based on artificial intelligence (AI) have been developed to assist the specialist physicians. Conventional machine learning (ML) and deep learning (DL) are the most popular schemes of AI used for diagnosing ASD. This study aims to review the automated detection of ASD using AI. We review several CADS that have been developed using ML techniques for the automated diagnosis of ASD using MRI modalities. There has been very limited work on the use of DL techniques to develop automated diagnostic models for ASD. A summary of the studies developed using DL is provided in the appendix. Then, the challenges encountered during the automated diagnosis of ASD using MRI and AI techniques are described in detail. Additionally, a graphical comparison of studies using ML and DL to diagnose ASD automatically is discussed. We conclude by suggesting future approaches to detecting ASDs using AI techniques and MRI neuroimaging

Identification of potential transcription factors that enhance human iPSC generation

Although many factors have been identified and used to enhance the iPSC reprogramming process, its efficiency remains quite low. In addition, reprogramming efficacy has been evidenced to be affected by disease mutations that are present in patient samples. In this study, using RNA-seq platform we have identified and validated the differential gene expression of five transcription factors (TFs) (GBX2, NANOGP8, SP8, PEG3, and ZIC1) that were associated with a remarkable increase in the number of iPSC colonies generated from a patient with Parkinson's disease. We have applied different bioinformatics tools (Gene ontology, protein–protein interaction, and signaling pathways analyses) to investigate the possible roles of these TFs in pluripotency and developmental process. Interestingly, GBX2, NANOGP8, SP8, PEG3, and ZIC1 were found to play a role in maintaining pluripotency, regulating self-renewal stages, and interacting with other factors that are involved in pluripotency regulation including OCT4, SOX2, NANOG, and KLF4. Therefore, the TFs identified in this study could be used as additional transcription factors that enhance reprogramming efficiency to boost iPSC generation technology.This study was supported by QBRI internal grant (QB16) and the Qatar University Student grant (QUST-2-CMED-2019-1)

Hyperosmotic Stress Induces a Specific Pattern for Stress Granule Formation in Human-Induced Pluripotent Stem Cells

Stress granules (SGs) are assemblies of selective messenger RNAs (mRNAs), translation factors, and RNA-binding proteins in small untranslated messenger ribonucleoprotein (mRNP) complexes in the cytoplasm. Evidence indicates that different types of cells have shown different mechanisms to respond to stress and the formation of SGs. In the present work, we investigated how human-induced pluripotent stem cells (hiPSCs/IMR90-1) overcome hyperosmotic stress compared to a cell line that does not harbor pluripotent characteristics (SH-SY5Y cell line). Gradient concentrations of NaCl showed a different pattern of SG formation between hiPSCs/IMR90-1 and the nonpluripotent cell line SH-SY5Y. Other pluripotent stem cell lines (hiPSCs/CRTD5 and hESCs/H9 (human embryonic stem cell line)) as well as nonpluripotent cell lines (BHK-21 and MCF-7) were used to confirm this phenomenon. Moreover, the formation of hyperosmotic SGs in hiPSCs/IMR90-1 was independent of eIF2α phosphorylation and was associated with low apoptosis levels. In addition, a comprehensive proteomics analysis was performed to identify proteins involved in regulating this specific pattern of hyperosmotic SG formation in hiPSCs/IMR90-1. We found possible implications of microtubule organization on the response to hyperosmotic stress in hiPSCs/IMR90-1. We have also unveiled a reduced expression of tubulin that may protect cells against hyperosmolarity stress while inhibiting SG formation without affecting stem cell self-renewal and pluripotency. Our observations may provide a possible cellular mechanism to better understand SG dynamics in pluripotent stem cells

Regulation of coagulation factors by microRNAs : role in interindividual variability and implications for hemostatic disorders= Regulación de los factores de la coagulación a través de microRNA: papel en la variabilidad interindividual y su implicación en trastornos hemostáticos

En esta tesis, se estudiaron tres aspectos relacionados con el campo de la hemostasia y se presentan en tres capítulos independientes con un nexo común; el papel de los miRNA como nuevos reguladores del sistema hemostático. Objetivos: 1) Evaluar la regulación de FXI por miRNA en hígado humano. 2) Identificar SNP en el 3'UTR de factores de coagulación que desestabilicen la unión de miRNA con consecuencias en los niveles plasmáticos y riesgo de sufrir trombosis. 3) Estudiar el papel indirecto de miRNA sobre la regulación de las proteínas hemostáticas a través de HNF4α. Métodos: Se realizaron microarrays y búsquedas in silico de miRNAs. Líneas celulares humanas, cultivo primario de hepatocitos murinos se emplearon para transfecciones y ensayos de luciferasa. Correlaciones entre los niveles de expresión de miRNAs y mRNAs se realizaron en muestras de hígados. Se incluyeron sujetos de los estudios MEGA y LETS. Para la identificación de variantes en el 3'UTR, se seleccionaron los sujetos con niveles extremos para su secuenciación y genotipado. Resultados: 1. MiR-181a-5p regula la expresión de FXI Predicciones in silico identifican cuatro miRNA como potenciales candidatos a regular la expresión de FXI. Sólo miR-181a-5p redujo los niveles de mRNA y proteína de FXI, y el anti-miR-181-5p aumentó los niveles de mRNA y proteína de FXI en células hepáticas. Los ensayos de luciferasa demostraron una interacción directa entre miR-181-5p y el 3’UTR de F11. En hígados humanos sanos se mostró una correlación inversa y significativa entre los niveles de mRNA de F11 y de miR-181a-5p. 2. Identificación de una variante en el 3’UTR del F11 potencialmente regulada por miRNA En dos estudios caso-control, se secuenciaron los 3'UTR de 9 genes hemostáticos en sujetos con niveles plasmáticos extremos. Se identificaron 26 variantes, 4 de ellas con diferencias significativas entre los grupos de los extremos [F2: rs1799963 (previamente descrita) y F11: rs4253429, rs4253430 y rs1062547]. Los SNP de F11 mostraron un alto desequilibrio de ligamiento con las variantes funcionales descritas rs2289252 y rs2036914. El análisis en controles con el alelo silvestre para estas variantes conocidas de F11 mostró que rs1062547 y rs4253430 se asociaban con un aumento significativo de la actividad FXI. Se evaluaron aquellos SNP que pudieran perturbar la unión de miRNA in silico e in vitro. La predicción in silico reveló que la presencia de estos SNP podrían interferir en la unión de 2 miRNA (rs1062547 con miR-513a-5p y rs4253430 con miR-544). Los ensayos de luciferasa mostraron que sólo miR-544 disminuía significativamente su actividad. Dicha inhibición no se observó cuando se utilizó un vector mutado con rs4253430. 3. MiR-24 y miR-34a regulan la expresión de proteínas hemostáticas a través de HNF4α Se encontraron correlaciones positivas y muy significativas entre los niveles de expresión de HNF4A y dianas hepáticas de la coagulación. Los hígados con niveles extremos de miRNA mostraron asociaciones inversas con los niveles de expresión de factores de coagulación. Estos resultados sugieren que las diferencias en la expresión de mRNA de HNF4A pueden explicar, en parte, las variaciones individuales observadas en la expresión de factores de coagulación en el hígado humano. MiR-24 y miR-34a se unen a varios sitios en HNF4A humano. MiR-24 y miR-34a redujo los niveles diferentes proteínas hemostaticas en HepG2. En tejido hepático sano se observaron correlaciones negativas entre los niveles de HNF4A, miR-24 y miR-34a. Además, miR-24 y miR-34a redujeron los niveles del HNF4α y los niveles de expresión de diferentes proteínas hemostáticas en hepatocitos murinos. Conclusiones: Aproximaciones in silico, in vitro y ex vivo, han mostrado que ciertos miRNA funcionan como reguladores de la expresión de diversos factores hemostáticos. Las consecuencias patológicas de estas regulaciones quedan por ser exploradas. In the present Thesis, I have addressed three points of investigation in the thrombosis field that have been reported as independent Chapters with a common nexus, the role of miRNAs as new regulators of the hemostatic system. Aims: 1) To investigate the potential relevance of miRNAs as new elements that may modulate FXI in human liver. 2) To identify 3’UTR variants in coagulation genes that influence coagulation factor levels and deep vein thrombosis risk through miRNA modulation. 3) To gain a deeper insight into the physiological modulator role of miRNAs in the expression of coagulation factors regulated by HNF4α. Methods: Microarray and in silico search of miRNAs were performed. Human cell lines and Murine hepatocyte primary culture were used for transfections (in vitro validation). Luciferase assays were used. Ex vivo correlations between miRNAs and mRNAs expression levels were performed in liver samples. Study subjects from MEGA and LETS studies were included. For the identification of 3’UTR variants, we selected subjects with extreme levels. Sequencing and genotyping were performed in 3’UTR of hemostatic factors genes. Results: 1. MiR-181a-5p regulates FXI expression in human liver In silico predictions suggest that 4 miRNAs may bind to F11 mRNA. However, only miR-181a-5p inhibits FXI by decreasing levels of both F11 mRNA and protein expression, anti-miR-181-5p increased both mRNA and protein levels of FXI in human. The expression of F11 mRNA in human liver is inversely correlated with the expression of miR-181a-5p, demonstrating for the first time that F11 expression may be regulated by miRNAs. This new regulatory mechanism of F11 expression could partially explain the interindividual variability of plasma FXI found in population. 2. Identification of a variant in the F11 3'UTR potentially regulated by miRNA In two case-control studies, 3’ UTRs of selected coagulation factor genes were sequenced. Four (in F2 and F11) of the 28 variants identified, were clearly more prevalent in low than high levels. F11 SNPs were in partial, inverse linkage (0.4 ≤r2<0.5) with functional variants rs2289252 & rs2036914 previously described. In wildtype carriers of the known variants, rs1062547 and rs4253430 were associated with plasma F11 activity, but none of the variants were associated with venous thrombosis risk. In silico prediction revealed that certain SNPs might disturb the binding sites of miRNAs. In vitro data, confirmed that only miR-544 showed a significant decrease of the luciferase activity in comparison with a scrambled control. This inhibition was not observed when using a mutated vector with rs4253430. 3. MiR-24 and miR-34a regulate several hemostatic proteins expression through HNF4α modulation In human healthy livers we observed significant and positive correlations between expression levels of both HNF4A and several hemostatic proteins. In samples with extreme levels of miR-24 and miR34a, we observed that HNF4A and hemostatic factors transcript levels were inversely correlated. Variations in the expression of these miRNAs could partly explain differences of HNF4A expression levels and therefore levels of several hemostatic factors in healthy subjects. MiR-24 and miR-34a bind to several sites on human HNF4A. In HepG2 cells, miR-24 transfections reduced expression levels of F10, F12, PROC, and PROS1, these latter were also reduced with miR-34a as well asSERPINC1 and PROZ transcript levels. HNF4A transcripts levels were negatively correlated with miR-24 and miR-34a levels in human healthy livers. In murine hepatocytes, miR-24 and miR-34a transfections reduced HNF4α levels and the expression levels of various hemostatic proteins. Conclusions: The present thesis identifies diverse mechanisms implicating miRNAs in the control of hemostasis. Further studies will help in linking these gene-silencing processes with pathologic processes as well as translating them into practical application

The Potential Role of COVID-19 in the Pathogenesis of Multiple Sclerosis—A Preliminary Report

Coronavirus 2019 (COVID-19) is an infectious respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that mainly affects the lungs. COVID-19 symptoms include the presence of fevers, dry coughs, fatigue, sore throat, headaches, diarrhea, and a loss of taste or smell. However, it is understood that SARS-CoV-2 is neurotoxic and neuro-invasive and could enter the central nervous system (CNS) via the hematogenous route or via the peripheral nerve route and causes encephalitis, encephalopathy, and acute disseminated encephalomyelitis (ADEM) in COVID-19 patients. This review discusses the possibility of SARS-CoV-2-mediated Multiple Sclerosis (MS) development in the future, comparable to the surge in Parkinson’s disease cases following the Spanish Flu in 1918. Moreover, the SARS-CoV-2 infection is associated with a cytokine storm. This review highlights the impact of these modulated cytokines on glial cell interactions within the CNS and their role in potentially prompting MS development as a secondary disease by SARS-CoV-2. SARS-CoV-2 is neurotropic and could interfere with various functions of neurons leading to MS development. The influence of neuroinflammation, microglia phagocytotic capabilities, as well as hypoxia-mediated mitochondrial dysfunction and neurodegeneration, are mechanisms that may ultimately trigger MS development

Circulating Non-Coding RNAs as a Signature of Autism Spectrum Disorder Symptomatology

Autism spectrum disorder (ASD) is a multifaced neurodevelopmental disorder that becomes apparent during early childhood development. The complexity of ASD makes clinically diagnosing the condition difficult. Consequently, by identifying the biomarkers associated with ASD severity and combining them with clinical diagnosis, one may better factionalize within the spectrum and devise more targeted therapeutic strategies. Currently, there are no reliable biomarkers that can be used for precise ASD diagnosis. Consequently, our pilot experimental cohort was subdivided into three groups: healthy controls, individuals those that express severe symptoms of ASD, and individuals that exhibit mild symptoms of ASD. Using next-generation sequencing, we were able to identify several circulating non-coding RNAs (cir-ncRNAs) in plasma. To the best of our knowledge, this study is the first to show that miRNAs, piRNAs, snoRNAs, Y-RNAs, tRNAs, and lncRNAs are stably expressed in plasma. Our data identify cir-ncRNAs that are specific to ASD. Furthermore, several of the identified cir-ncRNAs were explicitly associated with either the severe or mild groups. Hence, our findings suggest that cir-ncRNAs have the potential to be utilized as objective diagnostic biomarkers and clinical targets

The immediate and late effects of thyroid hormone (triiodothyronine) on murine coagulation gene transcription

Thyroid dysfunction is associated with changes in coagulation. The aim of our study was to gain more insight into the role of thyroid hormone in coagulation control. C57Black/6J mice received a low-iodine diet and drinking water supplemented with perchlorate to suppress endogenous triiodothyronine (T3) and thyroxine (T4) production. Under these conditions, the impact of exogenous T3 on plasma coagulation, and hepatic and vessel-wall-associated coagulation gene transcription was studied in a short- (4 hours) and long-term (14 days) setting. Comparing euthyroid conditions (normal mice), with hypothyroidism (conditions of a shortage of thyroid hormone) and those with replacement by incremental doses of T3, dosages of 0 and 0.5 μg T3/mouse/day were selected to study the impact of T3 on coagulation gene transcription. Under these conditions, a single injection of T3 injection increased strongly hepatic transcript levels of the well-characterized T3-responsive genes deiodinase type 1 (Dio1) and Spot14 within 4 hours. This coincided with significantly reduced mRNA levels of Fgg, Serpinc1, Proc, Proz, and Serpin10, and the reduction of the latter three persisted upon daily treatment with T3 for 14 days. Prolonged T3 treatment induced a significant down-regulation in factor (F) 2, F9 and F10 transcript levels, while F11 and F12 levels increased. Activity levels in plasma largely paralleled these mRNA changes. Thbd transcript levels in the lung (vessel-wall-associated coagulation) were significantly up-regulated after a single T3 injection, and persisted upon prolonged T3 exposure. Two-week T3 administration also resulted in increased Vwf and Tfpi mRNA levels, whereas Tf levels decreased. These data showed that T3 has specific effects on coagulation, with Fgg, Serpinc1, Proc, Proz, Serpin10 and Thbd responding rapidly, making these likely direct thyroid hormone receptor targets. F2, F9, F10, F11, F12, Vwf, Tf and Tfpi are late responding genes and probably indirectly modulated by T

Combined Noncoding RNA-mRNA Regulomics Signature in Reprogramming and Pluripotency in iPSCs

Somatic cells are reprogrammed with reprogramming factors to generate induced pluripotent stem cells (iPSCs), offering a promising future for disease modeling and treatment by overcoming the limitations of embryonic stem cells. However, this process remains inefficient since only a small percentage of transfected cells can undergo full reprogramming. Introducing miRNAs, such as miR-294 and miR302/3667, with reprogramming factors, has shown to increase iPSC colony formation. Previously, we identified five transcription factors, GBX2, NANOGP8, SP8, PEG3, and ZIC1, which may boost iPSC generation. In this study, we performed quantitative miRNAome and small RNA-seq sequencing and applied our previously identified transcriptome to identify the potential miRNA&ndash;mRNA regulomics and regulatory network of other ncRNAs. From each fibroblast (N = 4), three iPSC clones were examined (N = 12). iPSCs and original fibroblasts expressed miRNA clusters differently and miRNA clusters were compared to mRNA hits. Moreover, miRNA, piRNA, and snoRNAs expression profiles in iPSCs and original fibroblasts were assessed to identify the potential role of ncRNAs in enhancing iPSC generation, pluripotency, and differentiation. Decreased levels of let-7a-5p showed an increase of SP8 as described previously. Remarkably, the targets of identifier miRNAs were grouped into pluripotency canonical pathways, on stemness, cellular development, growth and proliferation, cellular assembly, and organization of iPSCs

Hepatic transcript levels and plasma levels of procoagulant coagulation factors.

<p>Hepatic transcript levels (A and C) and plasma levels (B) of procoagulant coagulation factors in mice treated with 0 μg T₃ (white bars) or 0.5 μg T₃ (black bars). Panel A shows the T₃-induced changes in hepatic transcript levels 4 hours after a single T₃ injection. Panels B and C show plasma levels and T₃-induced changes in hepatic transcripts for 14 days, respectively. Data are presented as mean with the error bar representing the calculated maximum expression level (panels A and C) or mean±SEM (standard error of the mean) (panel B) of n = 12 mice per group, with the vehicle-treated group set as a reference. Relative expression levels (A and C) were compared using the comparative threshold cycle method with ß-actin as internal control. *p<0.05, **p<0.01, and ***p<0.001 as compared to vehicle-treated mice. Fg-γ: Fibrinogen-γ plasma levels.</p