Evaluation of circulating levels of miR-135a and miR-193 in patients with sepsis.

BACKGROUND: Sepsis is a life-threatening condition where early diagnosis and prognostic awareness provide guidance for selecting the appropriate treatment strategies. A wide variety of biomarker-based studies in clinical medicine provide new insights into personalized medicine for sepsis patients. MiRNAs are endogenous non-coding RNA molecules that have been acting as great potential diagnostic, prognostic and therapeutic biomarkers in various diseases. METHODS AND RESULTS: In the present study, the expression levels of two selected miRNAs, including miR-135a and miR-193, were evaluated for their prognostic potential in patients with sepsis. The circulating levels of miRNAs were quantified by quantitative PCR (qPCR) in patients with sepsis (n = 100) and age- and sex-matched healthy controls (n = 100). Statistical findings confirmed the valuable prognostic potential of miR-135a in patients with sepsis, while no significant difference was found between the miR-193 expression level in the patients with sepsis and the controls. CONCLUSIONS: Circulating levels of miRNA-135a can serve a the prognostic biomarker for patients with sepsis. These findings highlight the importance of miRNAs as signatures in the personalized managements of sepsis.

Prognostic potential of circulating cell free mitochondrial DNA levels in COVID-19 patients.

BACKGROUND: In viral infections, mitochondria act as one of the main hubs of the pathogenesis. Recent findings present new insights into the potential role of circulating cell-free mitochondrial DNA (ccf-mtDNA) in COVID-19 pathogenesis by the induction of immune response and aggressive cytokine storm in SARS-CoV-2 infection. METHODS AND RESULTS: The levels of ccf-mtDNA were investigated in 102 hospitalized patients with COVID-19 using the quantitative PCR (q-PCR) method. Statistical analysis confirmed a strong association between the levels of ccf-mtDNA and and mortality, ICU admission, and intubation. Also, our findings highlighted the pivotal role of comorbidities as a risk factor for COVID-19 mortality and severity. CONCLUSION: Higher levels of ccf-mtDNA can serve as a potential early indicator for progress and poor prognosis of COVID-19.

Association between leukocyte telomere length and COVID-19 severity.

Background: Inter-individual variations in the clinical manifestations of SARS-CoV-2 infection are among the challenging features of COVID-19. The known role of telomeres in cell proliferation and immune competency highlights their possible function in infectious diseases. Variability in telomere length is an invaluable parameter in the heterogeneity of the clinical presentation of diseases. Result: In this study, our aim was to investigate the possible association between leukocyte telomere length (LTL) and COVID-19 severity. LTL was measured in 100 patients with moderate and severe forms of COVID-19 using the quantitative PCR (q-PCR) method. Statistical analysis confirmed a strong inverse correlation between relative LTL and COVID-19 severity. Conclusions: These findings suggest that LTL can be a useful parameter for predicting disease severity in patients, as individuals with short telomeres may have a higher risk of developing severe COVID-19. Supplementary Information: The online version contains supplementary material available at 10.1186/s43042-023-00415-z.

A novel mutation in the ALS2 gene in an iranian kurdish family with juvenile amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rare disorder that affects both upper and lower motor neurons. Mutations in Alsin Rho Guanine Nucleotide Exchange Factor (ALS2) correlates with three similar but distinctive syndromes, including the juvenile form of ALS. An Iranian Kurdish family was involved in this study and all members were evaluated with relevant clinical guidelines. Whole exome sequencing and sanger sequencing were applied to all family members to undermine the possible genetic factors. A substitution c. 2110 C>T (p. Arg704X) identified in the ALS2 gene. Bioinformatics analysis indicated the mutation is located in the well-conserved and functional domain of the protein. This study recognized a novel mutation in the ALS2 gene in a proband with the juvenile form of ALS. To our knowledge, this is the first identified ALS2 mutation among the Iranian population.

Roles of mitochondrial DNA in dynamics of the immune response to COVID-19.

Mitochondria dynamics have a pivotal role in many aspects of immune function. Viral infections affect mitochondrial dynamics and trigger the release of mitochondrial DNA (mtDNA) in host cells. Released mtDNA guides the immune response towards an inflammatory response against pathogens. In addition, circulating cell-free mtDNA (ccf-mtDNA) is considered an invaluable indicator for the prognosis and severity of infectious diseases. This study provides an overview of the role of mtDNA in the dynamics of the immune response to COVID-19. We focused on the possible roles of mtDNA in inducing the signaling pathways, and the inflammasome activation and regulation in SARS-CoV-2. Targeting mtDNA-related pathways can provide critical insights into therapeutic strategies for COVID-19.

Exhaled breath condensate efficacy to identify mutations in patients with lung cancer: A pilot study.

Exhaled breath condensate (EBC) is used to investigate the efficacy of EBC to detect the genetic mutations in patients with lung cancer. Samples of 5 patients and 5 healthy volunteers were collected. DNA was extracted and used for amplification of hotspot regions of TP53 and KRAS genes by using PCR. We performed the mutation analysis by direct sequencing in all subjects. Detected mutations in EBC samples were compared with those of corresponding tumor tissues and there was complete agreement within the detected mutations in EBC and tumorous tissue. EBC can be used as an efficient and noninvasive source for the assessment of gene mutations in patients with lung cancer.

Understanding the role of telomere attrition and epigenetic signatures in COVID-19 severity.

Within the past several decades, the emergence and spread of infectious diseases with pandemic potential have endangered human lives. Coronavirus disease 2019 (COVID-19) outbreak represents an unprecedented threat for all health systems worldwide. The clinical spectrum of COVID-19 is highly heterogeneous, ranging from asymptomatic and mild upper respiratory tract illness to severe interstitial pneumonia with respiratory failure and even death. Highly age-dependent patterns of immune response potentially explain the higher rates of the severe forms of COVID-19 in elderly patients. However, genetic and epigenetic architecture can influence multiple biological processes during the lifespan, therefore as far as our knowledge shows, vulnerability to viral infection concerning telomere length and epigenetic signature is not a new idea. This review aims is to summarize the current understanding of the role of telomere length and epigenetic mechanisms on the severity of COVID-19. The current knowledge highlights the significant association between the shorter telomere length and the higher risk of developing severe COVID-19. Differential DNA methylation patterns and miRNA expression profiles imply that these hallmarks can play a pivotal role in COVID- 19 pathogenesis. Understanding the causes of inter-individual variations in COVID-19 outcomes could provide clues to the development of the personalized therapeutic intervention.

An updated overview and classification of bioinformatics tools for MicroRNA analysis, which one to choose?

The term 'MicroRNA' (miRNA) refers to a class of small endogenous non-coding RNAs (ncRNAs) regenerated from hairpin transcripts. Recent studies reveal miRNAs' regulatory involvement in essential biological processes through translational repression or mRNA degradation. Recently, there is a growing body of literature focusing on the importance of miRNAs and their functions. In this respect, several databases have been developed to manage the dispersed data produced. Therefore, it is necessary to know the parameters and characteristics of each database to benefit their data. Besides, selecting the correct database is of great importance to scientists who do not have enough experience in this field. A comprehensive classification along with an explanation of the information contained in each database leads to facilitating access to these resources. In this regard, we have classified relevant databases into several categories, including miRNA sequencing and annotation, validated/predicted miRNA targets, disease-related miRNA, SNP in miRNA sequence or target site, miRNA-related pathways, or gene ontology, and mRNA-miRNA interactions. Hence, this review introduces available miRNA databases and presents a convenient overview to inform researchers of different backgrounds to find suitable miRNA-related bioinformatics web tools and relevant information rapidly.

Migraine: A Review on Its History, Global Epidemiology, Risk Factors, and Comorbidities.

Migraine affects more than one billion individuals each year across the world, and is one of the most common neurologic disorders, with a high prevalence and morbidity, especially among young adults and females. Migraine is associated with a wide range of comorbidities, which range from stress and sleep disturbances to suicide. The complex and largely unclear mechanisms of migraine development have resulted in the proposal of various social and biological risk factors, such as hormonal imbalances, genetic and epigenetic influences, as well as cardiovascular, neurological, and autoimmune diseases. This review presents a comprehensive review of the most up-to-date literature on the epidemiology, and risk factors, as well as highlighting the gaps in our knowledge.

A novel splice site mutation in the SDCCAG8 gene in an Iranian family with Bardet-Biedl syndrome.

PURPOSE: Bardet-Biedl syndrome (BBS: OMIM 209,900) is a rare ciliopathic human genetic disorder that affects many parts of the body systems. BBS is a genetically heterogeneous disorder with a wide spectrum of clinical manifestations which makes its diagnosis and management more challenging. RetNet reports 18 genes that cause BBS and each of genes has had several known mutations. Genetic studies suggesting that serologically defined colon cancer antigen 8 (SDCCAG8) gene mutations are a major cause of BBS. MATERIALS AND METHODS: In this section, we investigated the consanguineous Iranian family members with BBS. Whole-exome sequencing and Sanger sequencing, were performed to screen and confirm the suspicious pathogenic mutations. The identified mutation was investigated using bioinformatics tools to predict the effect of the mutation on protein structure. RESULTS: Sequential analysis identified a novel splice site mutation c.1221 + 2 T > A in the SDCCAG8 gene in BBS patients. Structure-based approaches have predicted significant structural alterations in SDCCAG8 protein. CONCLUSIONS: This study was conducted to show the aberrant alternative splicing as one of the single splicing mutations identified can cause BBS by affecting the function of SDCCAG8 protein.

LRP8 (rs5177) and CEP85L (rs11756438) are contributed to schizophrenia susceptibility in Iranian population.

Introduction Schizophrenia is recognized as one of the most important mental illnesses of the last century. Many genetic and environmental factors are involved in this condition. Recently, the genome-wide association study identified two significant genes LRP8 and CEP85L associated with psychiatric disorders. LRP8 (low-density lipoprotein receptor-related protein 8) acts as a cytoplasmic receptor for Reelin. Many studies have revealed that LRP8 was significantly related to schizophrenia and bipolar disorder in Chinese population. CEP85L standing for 'centrosomal protein 85 kDa-like' is another gene, which has been reportedly associated with BPD. Methods We performed a case-control study to analyze the association between rs5177 single-nucleotide polymorphism in the LRP8 gene plus the single-nucleotide polymorphism rs11756438 in the CEP85L gene and schizophrenia in the Iranian population. The genotype for rs5177 was determined by ARMS PCR method, while for rs11756438 genotype, it was determined by PCR-RFLP method after which statistical analysis was performed for each polymorphism. In rs5177, the CC genotype was susceptible to the disease while G allele was associated with disease protection. Results and Conclusion In rs11756438, the AA genotype was associated with disease susceptibility, while allele A did not have a significant association with the disease.

Macromolecular biomarkers of chronic obstructive pulmonary disease in exhaled breath condensate.

Biomarkers provide important diagnostic and prognostic information on heterogeneous diseases such as chronic obstructive pulmonary disease (COPD). However, finding a suitable specimen for clinical analysis of biomarkers for COPD is challenging. Exhaled breath condensate (EBC) sampling is noninvasive, rapid, cost-effective and easily repeatable. EBC sampling has also provided recent progress in the identification of biological macromolecules, such as lipids, proteins and DNA in EBC samples, which has increased its utility for clinical scientists. In this article, we review applications involving EBC sampling for the analysis of COPD biomarkers and discuss its future potential.

Tips for improving the quality and quantity of the extracted DNA from exhaled breath condensate samples.

There is a growing interest in the tracking of genetic and epigenetic alterations in exhaled breath condensate (EBC) samples. The effects of different procedures on the quality and quantity of DNA in EBC were studied. The results demonstrated that sodium acetate precipitation and oligo (dT) improved the quality of the extracted DNA significantly (p < 0.01). Also, sodium acetate precipitation, using oligo (dT), incubation at 70 °C and SDS treatment increased the quantity of DNA significantly (p < 0.01). These results showed the advantages of the chemical and physical manipulations for improving the quality and quantity of the extracted DNA from EBC samples.

CNKSR1 gene defect can cause syndromic autosomal recessive intellectual disability.

The advent of high-throughput sequencing technologies has led to an exponential increase in the identification of novel disease-causing genes in highly heterogeneous diseases. A novel frameshift mutation in CNKSR1 gene was detected by Next-Generation Sequencing (NGS) in an Iranian family with syndromic autosomal recessive intellectual disability (ARID). CNKSR1 encodes a connector enhancer of kinase suppressor of Ras 1, which acts as a scaffold component for receptor tyrosine kinase in mitogen-activated protein kinase (MAPK) cascades. CNKSR1 interacts with proteins which have already been shown to be associated with intellectual disability (ID) in the MAPK signaling pathway and promotes cell migration through RhoA-mediated c-Jun N-terminal kinase (JNK) activation. Lack of CNKSR1 transcripts and protein was observed in lymphoblastoid cells derived from affected patients using qRT-PCR and western blot analysis, respectively. Furthermore, RNAi-mediated knockdown of cnk, the CNKSR1 orthologue in Drosophila melanogaster brain, led to defects in eye and mushroom body (MB) structures. In conclusion, our findings support the possible role of CNKSR1 in brain development which can lead to cognitive impairment.

Biallelic missense variants in ZBTB11 can cause intellectual disability in humans.

Exploring genes and pathways underlying intellectual disability (ID) provides insight into brain development and function, clarifying the complex puzzle of how cognition develops. As part of ongoing systematic studies to identify candidate ID genes, linkage analysis and next-generation sequencing revealed Zinc Finger and BTB Domain Containing 11 (ZBTB11) as a novel candidate ID gene. ZBTB11 encodes a little-studied transcription regulator, and the two identified missense variants in this study are predicted to disrupt canonical Zn2+-binding residues of its C2H2 zinc finger domain, leading to possible altered DNA binding. Using HEK293T cells transfected with wild-type and mutant GFP-ZBTB11 constructs, we found the ZBTB11 mutants being excluded from the nucleolus, where the wild-type recombinant protein is predominantly localized. Pathway analysis applied to ChIP-seq data deposited in the ENCODE database supports the localization of ZBTB11 in nucleoli, highlighting associated pathways such as ribosomal RNA synthesis, ribosomal assembly, RNA modification and stress sensing, and provides a direct link between subcellular ZBTB11 location and its function. Furthermore, given the report of prominent brain and spinal cord degeneration in a zebrafish Zbtb11 mutant, we investigated ZBTB11-ortholog knockdown in Drosophila melanogaster brain by targeting RNAi using the UAS/Gal4 system. The observed approximate reduction to a third of the mushroom body size-possibly through neuronal reduction or degeneration-may affect neuronal circuits in the brain that are required for adaptive behavior, specifying the role of this gene in the nervous system. In conclusion, we report two ID families segregating ZBTB11 biallelic mutations disrupting Zn2+-binding motifs and provide functional evidence linking ZBTB11 dysfunction to this phenotype.

Intellectual Disability and Ataxia: Genetic Collisions.

Intellectual disability (ID) is a common and highly heterogeneous neurodevelopmental disorder. The prevalence of ID is around 1%-3% in the general population. ID is associated with a wide range of additional neurological disabilities and the results of various studies have disclosed the co-morbidity of ID and ataxia. The aim of this review is elucidation of the common molecular and cellular pathways in the etiology of ID and ataxia. Categorization of these genes with various cellular functions indicates several genetic collisions in the co-occurrence of ID and ataxia.

The human RIT2 core promoter short tandem repeat predominant allele is species-specific in length: a selective advantage for human evolution?

Evolutionary analyses of the critical core promoter interval support a selective advantage for expanding the length of certain short tandem repeats (STRs) in humans. We recently reported genome-wide data on human core promoter STRs that are "exceptionally long" (≥6-repeats). Near the top of the list, the neuron-specific gene, RIT2, contains one of the longest GA-STRs at 11-repeats. In the present study, we analyzed the evolutionary implications of this STR across species. We also studied this STR in a sample of 2,143 Iranian human subjects that encompassed a number of neuropsychiatric disorders and controls. We report that this GA repeat is functional and different lengths of the repeat result in significant alteration in gene expression activity. The 11-repeat allele was human specific and the sole allele detected in 110 unrelated Iranian individuals randomly selected and sequenced from our control pool. Remarkably, homozygosity for a 5-repeat allele was detected in a consanguineous, hospitalized case of schizophrenia, which significantly decreased gene expression activity (p < 5 × 10-6). The frequency of the 5-repeat allele in the Iranian population was calculated at <0.0001, putting this allele in the deleterious mutations category based on allele frequency. The 5-repeat allele is annotated in the Ensembl database in the heterozygous status (5/11) in one of four indigenous hunter-gatherer men sequenced from southern Africa (BUSHMAN KB1: rs113265205). The present findings indicate for the first time, selective advantage for a human-specific allele at an STR locus, and a phenomenon in which genotypes and alleles at the extreme length of STRs occur with disease only. This is a pilot study that warrants large-scale sequencing of the RIT2 core promoter STR in diseases and characteristics that are linked to the brain function.

Core promoter short tandem repeats as evolutionary switch codes for primate speciation.

Alteration in gene expression levels underlies many of the phenotypic differences across species. Because of their highly mutable nature, proximity to the +1 transcription start site (TSS), and the emerging evidence of functional impact on gene expression, core promoter short tandem repeats (STRs) may be considered an ideal source of variation across species. In a genome-scale analysis of the entire Homo sapiens protein-coding genes, we have previously identified core promoters with at least one STR of ≥ 6-repeats, with possible selective advantage in this species. In the current study, we performed reverse analysis of the entire Homo sapiens orthologous genes in mouse in the Ensembl database, in order to identify conserved STRs that have shrunk as an evolutionary advantage to humans. Two protocols were used to minimize ascertainment bias. Firstly, two species sharing a more recent ancestor with Homo sapiens (i.e. Pan troglodytes and Gorilla gorilla gorilla) were also included in the study. Secondly, four non-primate species encompassing the major orders across Mammals, including Scandentia, Laurasiatheria, Afrotheria, and Xenarthra were analyzed as out-groups. We introduce STR evolutionary events specifically identical in primates (i.e. Homo sapiens, Pan troglodytes, and Gorilla gorilla gorilla) vs. non-primate out-groups. The average frequency of the identically shared STR motifs across those primates ranged between 0.00005 and 0.06. The identified genes are involved in important evolutionary and developmental processes, such as normal craniofacial development (TFAP2B), regulation of cell shape (PALMD), learning and long-term memory (RGS14), nervous system development (GFRA2), embryonic limb morphogenesis (PBX2), and forebrain development (APAF1). We provide evidence of core promoter STRs as evolutionary switch codes for primate speciation, and the first instance of identity-by-descent for those motifs at the interspecies level.