International Journal of Molecular Sciences

2024

Jump to: 2023, 2022, 2021, 2020, 2019

17 pages, 3633 KiB

Open AccessArticle

Comparative Analysis of the Codon Usage Pattern in the Chloroplast Genomes of Gnetales Species

by Xiaoming Yang, Yuan Wang, Wenxuan Gong and Yinxiang Li

Int. J. Mol. Sci. 2024, 25(19), 10622; https://doi.org/10.3390/ijms251910622 - 2 Oct 2024

Viewed by 212

Abstract

Codon usage bias refers to the preferential use of synonymous codons, a widespread phenomenon found in bacteria, plants, and animals. Codon bias varies among species, families, and groups within kingdoms and between genes within an organism. Codon usage bias (CUB) analysis sheds light [...] Read more.

Codon usage bias refers to the preferential use of synonymous codons, a widespread phenomenon found in bacteria, plants, and animals. Codon bias varies among species, families, and groups within kingdoms and between genes within an organism. Codon usage bias (CUB) analysis sheds light on the evolutionary dynamics of various species and optimizes targeted gene expression in heterologous host plants. As a significant order of gymnosperms, species within Gnetales possess extremely high ecological and pharmaceutical values. However, comprehensive analyses of CUB within the chloroplast genomes of Gnetales species remain unexplored. A systematic analysis was conducted to elucidate the codon usage patterns in 13 diverse Gnetales species based on the chloroplast genomes. Our results revealed that chloroplast coding sequences (cp CDSs) in 13 Gnetales species display a marked preference for AT bases and A/T-ending codons. A total of 20 predominantly high-frequency codons and between 2 and 7 optimal codons were identified across these species. The findings from the ENC-plot, PR2-plot, and neutrality analyses suggested that both mutation pressure and natural selection exert influence on the codon bias in these 13 Gnetales species, with natural selection emerging as the predominant influence. Correspondence analysis (COA) demonstrated variation in the codon usage patterns among the Gnetales species and indicated mutation pressure is another factor that could impact CUB. Additionally, our research identified a positive correlation between the measure of idiosyncratic codon usage level of conservatism (MILC) and synonymous codon usage order (SCUO) values, indicative of CUB’s potential influence on gene expression. The comparative analysis concerning codon usage frequencies among the 13 Gnetales species and 4 model organisms revealed that Saccharomyces cerevisiae and Nicotiana tabacum were the optimal exogenous expression hosts. Furthermore, the cluster and phylogenetic analyses illustrated distinct patterns of differentiation, implying that codons, even with weak or neutral preferences, could affect the evolutionary trajectories of these species. Our results reveal the characteristics of codon usage patterns and contribute to an enhanced comprehension of evolutionary mechanisms in Gnetales species. Full article

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31 pages, 1770 KiB

Open AccessReview

Genetic and Epigenetic Interactions Involved in Senescence of Stem Cells

by Florin Iordache, Adriana Cornelia Ionescu Petcu and Diana Mihaela Alexandru

Int. J. Mol. Sci. 2024, 25(17), 9708; https://doi.org/10.3390/ijms25179708 - 7 Sep 2024

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Abstract

Cellular senescence is a permanent condition of cell cycle arrest caused by a progressive shortening of telomeres defined as replicative senescence. Stem cells may also undergo an accelerated senescence response known as premature senescence, distinct from telomere shortening, as a response to different [...] Read more.

Cellular senescence is a permanent condition of cell cycle arrest caused by a progressive shortening of telomeres defined as replicative senescence. Stem cells may also undergo an accelerated senescence response known as premature senescence, distinct from telomere shortening, as a response to different stress agents. Various treatment protocols have been developed based on epigenetic changes in cells throughout senescence, using different drugs and antioxidants, senolytic vaccines, or the reprogramming of somatic senescent cells using Yamanaka factors. Even with all the recent advancements, it is still unknown how different epigenetic modifications interact with genetic profiles and how other factors such as microbiota physiological conditions, psychological states, and diet influence the interaction between genetic and epigenetic pathways. The aim of this review is to highlight the new epigenetic modifications that are involved in stem cell senescence. Here, we review recent senescence-related epigenetic alterations such as DNA methylation, chromatin remodeling, histone modification, RNA modification, and non-coding RNA regulation outlining new possible targets for the therapy of aging-related diseases. The advantages and disadvantages of the animal models used in the study of cellular senescence are also briefly presented. Full article

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10 pages, 287 KiB

Open AccessArticle

Association of CETP Gene Polymorphisms and Haplotypes with Acute Heart Rate Response to Exercise

by Habib Al Ashkar, Nóra Kovács, Ilona Veres-Balajti, Róza Ádány and Péter Pikó

Int. J. Mol. Sci. 2024, 25(16), 8587; https://doi.org/10.3390/ijms25168587 - 6 Aug 2024

Viewed by 618

Abstract

Polymorphisms in the cholesteryl ester transfer protein (CETP) gene are known to be strongly associated with increased cardiovascular risk, primarily through their effects on the lipid profile and consequently on atherosclerotic risk. The acute heart rate response (AHRR) to physical activity [...] Read more.

Polymorphisms in the cholesteryl ester transfer protein (CETP) gene are known to be strongly associated with increased cardiovascular risk, primarily through their effects on the lipid profile and consequently on atherosclerotic risk. The acute heart rate response (AHRR) to physical activity is closely related to individual cardiovascular health. This study aimed to investigate the effect of CETP gene polymorphisms on AHRR. Our analysis examines the association of five single nucleotide polymorphisms (SNPs; rs1532624, rs5882, rs708272, rs7499892, and rs9989419) and their haplotypes (H) in the CETP gene with AHRR in 607 people from the Hungarian population. Individual AHRR in the present study was assessed using the YMCA 3-min step test and was estimated as the difference between resting and post-exercise heart rate, i.e., delta heart rate (ΔHR). To exclude the direct confounding effect of the CETP gene on the lipid profile, adjustments for TG and HDL-C levels, next to conventional risk factors, were applied in the statistical analyses. Among the examined five SNPs, two showed a significant association with lower ΔHR (rs1532624—C_dominant: B = −8.41, p < 0.001; rs708272—G_dominant: B = −8.33, p < 0.001) and reduced the risk of adverse AHRR (rs1532624—C_dominant: OR = 0.44, p = 0.004; rs708272—G_dominant: OR = 0.43, p = 0.003). Among the ten haplotypes, two showed significant association with lower ΔHR (H3—CAGCA: B = −6.81, p = 0.003; H9—CGGCG: B = −14.64, p = 0.015) and lower risk of adverse AHRR (H3—CAGCA: OR = 0.58, p = 0.040; H9—CGGCG: OR = 0.05, p = 0.009) compared to the reference haplotype (H1—AGACG). Our study is the first to report a significant association between CETP gene polymorphisms and AHRR. It also confirms that the association of the CETP gene with cardiovascular risk is mediated by changes in heart rate in response to physical activity, in addition to its effect on lipid profile. Full article

13 pages, 1014 KiB

Open AccessArticle

Rare Germline Variants in the Adenomatous Polyposis Coli Gene Associated with Dental and Osseous Anomalies

by Gergely Büki, Gréta Antal and Judit Bene

Int. J. Mol. Sci. 2024, 25(15), 8189; https://doi.org/10.3390/ijms25158189 - 26 Jul 2024

Viewed by 557

Abstract

APC is a tumor suppressor gene that exerts its effect through the regulation of the Wnt signaling pathway. Loss of function mutations of the gene are associated with familial adenomatous polyposis (FAP). Early diagnosis in FAP patients is essential to prevent the development [...] Read more.

APC is a tumor suppressor gene that exerts its effect through the regulation of the Wnt signaling pathway. Loss of function mutations of the gene are associated with familial adenomatous polyposis (FAP). Early diagnosis in FAP patients is essential to prevent the development of colorectal cancer. Extraintestinal manifestations often precede the formation of the polyposis; therefore, these manifestations may serve as a clinical indicator for the condition. The aim of this study was to assess genotype–phenotype associations between the location of APC mutations and various extraintestinal features, mainly focusing on osseous and dental anomalies. Analyses of our cases and the mutations available in the literature with these manifestations revealed that mutations in the N-terminal region (amino acids 1–~1000) of the protein are more frequently associated with only osseous anomalies, whereas dental manifestations are more prevalent in mutations in the middle region (amino acids 1000–~2100). In addition, supernumerary teeth were found to be the most common dental feature. Since dental abnormalities often precede intestinal polyposis, dentists have a crucial role in the early identification of patients at risk. Full article

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25 pages, 9444 KiB

Open AccessArticle

Genome-Wide Association Study with Three Control Cohorts of Japanese Patients with Esotropia and Exotropia of Comitant Strabismus and Idiopathic Superior Oblique Muscle Palsy

by Toshihiko Matsuo, Ichiro Hamasaki, Yoichiro Kamatani, Takahisa Kawaguchi, Izumi Yamaguchi, Fumihiko Matsuda, Akira Saito, Kazuyuki Nakazono and Shigeo Kamitsuji

Int. J. Mol. Sci. 2024, 25(13), 6986; https://doi.org/10.3390/ijms25136986 - 26 Jun 2024

Viewed by 1139

Abstract

Esotropia and exotropia in the entity of comitant strabismus are multifactorial diseases with both genetic and environmental backgrounds. Idiopathic superior oblique muscle palsy, as the predominant entity of non-comitant (paralytic) strabismus, also has a genetic background, as evidenced by varying degrees of muscle [...] Read more.

Esotropia and exotropia in the entity of comitant strabismus are multifactorial diseases with both genetic and environmental backgrounds. Idiopathic superior oblique muscle palsy, as the predominant entity of non-comitant (paralytic) strabismus, also has a genetic background, as evidenced by varying degrees of muscle hypoplasia. A genome-wide association study (GWAS) was conducted of 711 Japanese patients with esotropia (n= 253), exotropia (n = 356), and idiopathic superior oblique muscle palsy (n = 102). The genotypes of single nucleotide polymorphisms (SNPs) were determined by Infinium Asian Screening Array. Three control cohorts from the Japanese population were used: two cohorts from BioBank Japan (BBJ) and the Nagahama Cohort. BBJ (180K) was genotyped by a different array, Illumina Infinium OmniExpressExome or HumanOmniExpress, while BBJ (ASA) and the Nagahama Cohort were genotyped by the same Asian array. After quality control of SNPs and individuals, common SNPs between the case cohort and the control cohort were chosen in the condition of genotyping by different arrays, while all SNPs genotyped by the same array were used for SNP imputation. The SNPs imputed with R-square values ≥ 0.3 were used to compare the case cohort of each entity or the combined entity with the control cohort. In comparison with BBJ (180K), the esotropia group and the exotropia group showed CDCA7 and HLA-F, respectively, as candidate genes at a significant level of p < 5 × 10⁻⁸, while the idiopathic superior oblique muscle palsy group showed DAB1 as a candidate gene which is involved in neuronal migration. DAB1 was also detected as a candidate in comparison with BBJ (ASA) and the Nagahama Cohort at a weak level of significance of p < 1 × 10⁻⁶. In comparison with BBJ (180K), RARB (retinoic acid receptor-β) was detected as a candidate at a significant level of p < 5 × 10⁻⁸ in the combined group of esotropia, exotropia, and idiopathic superior oblique muscle palsy. In conclusion, a series of GWASs with three different control cohorts would be an effective method with which to search for candidate genes for multifactorial diseases such as strabismus. Full article

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18 pages, 2696 KiB

Open AccessArticle

Dysfunction in IGF2R Pathway and Associated Perturbations in Autophagy and WNT Processes in Beckwith–Wiedemann Syndrome Cell Lines

by Silvana Pileggi, Elisa A. Colombo, Silvia Ancona, Roberto Quadri, Clara Bernardelli, Patrizia Colapietro, Michela Taiana, Laura Fontana, Monica Miozzo, Elena Lesma and Silvia M. Sirchia

Int. J. Mol. Sci. 2024, 25(7), 3586; https://doi.org/10.3390/ijms25073586 - 22 Mar 2024

Viewed by 1208

Abstract

Beckwith–Wiedemann Syndrome (BWS) is an imprinting disorder characterized by overgrowth, stemming from various genetic and epigenetic changes. This study delves into the role of IGF2 upregulation in BWS, focusing on insulin-like growth factor pathways, which are poorly known in this syndrome. We examined [...] Read more.

Beckwith–Wiedemann Syndrome (BWS) is an imprinting disorder characterized by overgrowth, stemming from various genetic and epigenetic changes. This study delves into the role of IGF2 upregulation in BWS, focusing on insulin-like growth factor pathways, which are poorly known in this syndrome. We examined the IGF2R, the primary receptor of IGF2, WNT, and autophagy/lysosomal pathways in BWS patient-derived lymphoblastoid cell lines, showing different genetic and epigenetic defects. The findings reveal a decreased expression and mislocalization of IGF2R protein, suggesting receptor dysfunction. Additionally, our results point to a dysregulation in the AKT/GSK-3/mTOR pathway, along with imbalances in autophagy and the WNT pathway. In conclusion, BWS cells, regardless of the genetic/epigenetic profiles, are characterized by alteration of the IGF2R pathway that is associated with the perturbation of the autophagy and lysosome processes. These alterations seem to be a key point of the molecular pathogenesis of BWS and potentially contribute to BWS’s characteristic overgrowth and cancer susceptibility. Our study also uncovers alterations in the WNT pathway across all BWS cell lines, consistent with its role in growth regulation and cancer development. Full article

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10 pages, 1497 KiB

Open AccessCase Report

De Novo p.Asp3368Gly Variant of Dystrophin Gene Associated with X-Linked Dilated Cardiomyopathy and Skeletal Myopathy: Clinical Features and In Silico Analysis

by Maria d’Apolito, Alessandra Ranaldi, Francesco Santoro, Sara Cannito, Matteo Gravina, Rosa Santacroce, Ilaria Ragnatela, Alessandra Margaglione, Giovanna D’Andrea, Grazia Casavecchia, Natale Daniele Brunetti and Maurizio Margaglione

Int. J. Mol. Sci. 2024, 25(5), 2787; https://doi.org/10.3390/ijms25052787 - 28 Feb 2024

Cited by 1 | Viewed by 1175

Abstract

Dystrophin (DMD) gene mutations are associated with skeletal muscle diseases such as Duchenne and Becker Muscular Dystrophy (BMD) and X-linked dilated cardiomyopathy (XL-DCM). To investigate the molecular basis of DCM in a 37-year-old woman. Clinical and genetic investigations were performed. Genetic [...] Read more.

Dystrophin (DMD) gene mutations are associated with skeletal muscle diseases such as Duchenne and Becker Muscular Dystrophy (BMD) and X-linked dilated cardiomyopathy (XL-DCM). To investigate the molecular basis of DCM in a 37-year-old woman. Clinical and genetic investigations were performed. Genetic testing was performed with whole exome sequencing (WES) using the Illumina platform. According to the standard protocol, a variant found by WES was confirmed in all available members of the family by bi-directional capillary Sanger resequencing. The effect of the variant was investigated by using an in silico prediction of pathogenicity. The index case was a 37-year-old woman diagnosed with DCM at the age of 33. A germline heterozygous A>G transversion at nucleotide 10103 in the DMD gene, leading to an aspartic acid–glycine substitution at the amino acid 3368 of the DMD protein (c.10103A>G p.Asp3368Gly), was identified and confirmed by PCR-based Sanger sequencing of the exon 70. In silico prediction suggests that this variant could have a deleterious impact on protein structure and functionality (CADD = 30). The genetic analysis was extended to the first-degree relatives of the proband (mother, father, and sister) and because of the absence of the variant in both parents, the p.Asp3368Gly substitution was considered as occurring de novo. Then, the direct sequencing analysis of her 8-year-old son identified as hemizygous for the same variant. The young patient did not present any signs or symptoms attributable to DCM, but reported asthenia and presented with bilateral calf hypertrophy at clinical examination. Laboratory testing revealed increased levels of creatinine kinase (maximum value of 19,000 IU/L). We report an early presentation of dilated cardiomyopathy in a 33-year-old woman due to a de novo pathogenic variant of the dystrophin (DMD) gene (p.Asp3368Gly). Genetic identification of this variant allowed an early diagnosis of a skeletal muscle disease in her son. Full article

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14 pages, 1376 KiB

Open AccessReview

Chromosome Division in Early Embryos—Is Everything under Control? And Is the Cell Size Important?

by Adela Horakova, Marketa Konecna and Martin Anger

Int. J. Mol. Sci. 2024, 25(4), 2101; https://doi.org/10.3390/ijms25042101 - 9 Feb 2024

Viewed by 1560

Abstract

Chromosome segregation in female germ cells and early embryonic blastomeres is known to be highly prone to errors. The resulting aneuploidy is therefore the most frequent cause of termination of early development and embryo loss in mammals. And in specific cases, when the [...] Read more.

Chromosome segregation in female germ cells and early embryonic blastomeres is known to be highly prone to errors. The resulting aneuploidy is therefore the most frequent cause of termination of early development and embryo loss in mammals. And in specific cases, when the aneuploidy is actually compatible with embryonic and fetal development, it leads to severe developmental disorders. The main surveillance mechanism, which is essential for the fidelity of chromosome segregation, is the Spindle Assembly Checkpoint (SAC). And although all eukaryotic cells carry genes required for SAC, it is not clear whether this pathway is active in all cell types, including blastomeres of early embryos. In this review, we will summarize and discuss the recent progress in our understanding of the mechanisms controlling chromosome segregation and how they might work in embryos and mammalian embryos in particular. Our conclusion from the current literature is that the early mammalian embryos show limited capabilities to react to chromosome segregation defects, which might, at least partially, explain the widespread problem of aneuploidy during the early development in mammals. Full article

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14 pages, 2198 KiB

Open AccessArticle

CircRNAome of Childhood Acute Lymphoblastic Leukemia: Deciphering Subtype-Specific Expression Profiles and Involvement in TCF3::PBX1 ALL

by Angela Gutierrez-Camino, Maxime Caron, Chantal Richer, Claire Fuchs, Unai Illarregi, Lucas Poncelet, Pascal St-Onge, Alain R. Bataille, Pascal Tremblay-Dauphinais, Elixabet Lopez-Lopez, Mireia Camos, Manuel Ramirez-Orellana, Itziar Astigarraga, Éric Lécuyer, Guillaume Bourque, Idoia Martin-Guerrero and Daniel Sinnett

Int. J. Mol. Sci. 2024, 25(3), 1477; https://doi.org/10.3390/ijms25031477 - 25 Jan 2024

Viewed by 1863

Abstract

Childhood B-cell acute lymphoblastic leukemia (B-ALL) is a heterogeneous disease comprising multiple molecular subgroups with subtype-specific expression profiles. Recently, a new type of ncRNA, termed circular RNA (circRNA), has emerged as a promising biomarker in cancer, but little is known about their role [...] Read more.

Childhood B-cell acute lymphoblastic leukemia (B-ALL) is a heterogeneous disease comprising multiple molecular subgroups with subtype-specific expression profiles. Recently, a new type of ncRNA, termed circular RNA (circRNA), has emerged as a promising biomarker in cancer, but little is known about their role in childhood B-ALL. Here, through RNA-seq analysis in 105 childhood B-ALL patients comprising six genetic subtypes and seven B-cell controls from two independent cohorts we demonstrated that circRNAs properly stratified B-ALL subtypes. By differential expression analysis of each subtype vs. controls, 156 overexpressed and 134 underexpressed circRNAs were identified consistently in at least one subtype, most of them with subtype-specific expression. TCF3::PBX1 subtype was the one with the highest number of unique and overexpressed circRNAs, and the circRNA signature could effectively discriminate new patients with TCF3::PBX1 subtype from others. Our results indicated that NUDT21, an RNA-binding protein (RBP) involved in circRNA biogenesis, may contribute to this circRNA enrichment in TCF3::PBX1 ALL. Further functional characterization using the CRISPR-Cas13d system demonstrated that circBARD1, overexpressed in TCF3::PBX1 patients and regulated by NUDT21, might be involved in leukemogenesis through the activation of p38 via hsa-miR-153-5p. Our results suggest that circRNAs could play a role in the pathogenesis of childhood B-ALL. Full article

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15 pages, 3186 KiB

Open AccessArticle

Evaluating the Efficacy of Type 2 Diabetes Polygenic Risk Scores in an Independent European Population

by Monta Brīvība, Ivanna Atava, Raitis Pečulis, Ilze Elbere, Laura Ansone, Maija Rozenberga, Ivars Silamiķelis and Jānis Kloviņš

Int. J. Mol. Sci. 2024, 25(2), 1151; https://doi.org/10.3390/ijms25021151 - 17 Jan 2024

Viewed by 1199

Abstract

Numerous type 2 diabetes (T2D) polygenic risk scores (PGSs) have been developed to predict individuals’ predisposition to the disease. An independent assessment and verification of the best-performing PGS are warranted to allow for a rapid application of developed models. To date, only 3% [...] Read more.

Numerous type 2 diabetes (T2D) polygenic risk scores (PGSs) have been developed to predict individuals’ predisposition to the disease. An independent assessment and verification of the best-performing PGS are warranted to allow for a rapid application of developed models. To date, only 3% of T2D PGSs have been evaluated. In this study, we assessed all (n = 102) presently published T2D PGSs in an independent cohort of 3718 individuals, which has not been included in the construction or fine-tuning of any T2D PGS so far. We further chose the best-performing PGS, assessed its performance across major population principal component analysis (PCA) clusters, and compared it with newly developed population-specific T2D PGS. Our findings revealed that 88% of the published PGSs were significantly associated with T2D; however, their performance was lower than what had been previously reported. We found a positive association of PGS improvement over the years (p-value = 8.01 × 10⁻⁴ with PGS002771 currently showing the best discriminatory power (area under the receiver operating characteristic (AUROC) = 0.669) and PGS003443 exhibiting the strongest association PGS003443 (odds ratio (OR) = 1.899). Further investigation revealed no difference in PGS performance across major population PCA clusters and when compared with newly developed population-specific PGS. Our findings revealed a positive trend in T2D PGS performance, consistently identifying high-T2D-risk individuals in an independent European population. Full article

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14 pages, 1843 KiB

Open AccessArticle

Elucidation of 4-Hydroxybenzoic Acid Catabolic Pathways in Pseudarthrobacter phenanthrenivorans Sphe3

by Epameinondas Tsagogiannis, Stamatia Asimakoula, Alexandros P. Drainas, Orfeas Marinakos, Vasiliki I. Boti, Ioanna S. Kosma and Anna-Irini Koukkou

Int. J. Mol. Sci. 2024, 25(2), 843; https://doi.org/10.3390/ijms25020843 - 10 Jan 2024

Cited by 3 | Viewed by 1327

Abstract

4-hydroxybenzoic acid (4-HBA) is an aromatic compound with high chemical stability, being extensively used in food, pharmaceutical and cosmetic industries and therefore widely distributed in various environments. Bioremediation constitutes the most sustainable approach for the removal of 4-hydroxybenzoate and its derivatives (parabens) from [...] Read more.

4-hydroxybenzoic acid (4-HBA) is an aromatic compound with high chemical stability, being extensively used in food, pharmaceutical and cosmetic industries and therefore widely distributed in various environments. Bioremediation constitutes the most sustainable approach for the removal of 4-hydroxybenzoate and its derivatives (parabens) from polluted environments. Pseudarthrobacter phenanthrenivorans Sphe3, a strain capable of degrading several aromatic compounds, is able to grow on 4-HBA as the sole carbon and energy source. Here, an attempt is made to clarify the catabolic pathways that are involved in the biodegradation of 4-hydroxybenzoate by Sphe3, applying a metabolomic and transcriptomic analysis of cells grown on 4-HBA. It seems that in Sphe3, 4-hydroxybenzoate is hydroxylated to form protocatechuate, which subsequently is either cleaved in ortho- and/or meta-positions or decarboxylated to form catechol. Protocatechuate and catechol are funneled into the TCA cycle following either the β-ketoadipate or protocatechuate meta-cleavage branches. Our results also suggest the involvement of the oxidative decarboxylation of the protocatechuate peripheral pathway to form hydroxyquinol. As a conclusion, P. phenanthrenivorans Sphe3 seems to be a rather versatile strain considering the 4-hydroxybenzoate biodegradation, as it has the advantage to carry it out effectively following different catabolic pathways concurrently. Full article

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2023

Jump to: 2024, 2022, 2021, 2020, 2019

7 pages, 2629 KiB

Open AccessCase Report

Triple Genetic Diagnosis in a Patient with Late-Onset Leukodystrophy and Mild Intellectual Disability

by Domizia Pasquetti, Annalisa Gazzellone, Salvatore Rossi, Daniela Orteschi, Federica Francesca L’Erario, Paola Concolino, Angelo Minucci, Carlo Dionisi-Vici, Maurizio Genuardi, Gabriella Silvestri and Pietro Chiurazzi

Int. J. Mol. Sci. 2024, 25(1), 495; https://doi.org/10.3390/ijms25010495 - 29 Dec 2023

Viewed by 1035

Abstract

We describe the complex case of a 44-year-old man with polycystic kidney disease, mild cognitive impairment, and tremors in the upper limbs. Brain MRI showed lesions compatible with leukodystrophy. The diagnostic process, which included clinical exome sequencing (CES) and chromosomal microarray analysis (CMA), [...] Read more.

We describe the complex case of a 44-year-old man with polycystic kidney disease, mild cognitive impairment, and tremors in the upper limbs. Brain MRI showed lesions compatible with leukodystrophy. The diagnostic process, which included clinical exome sequencing (CES) and chromosomal microarray analysis (CMA), revealed a triple diagnosis: autosomal dominant polycystic kidney disease (ADPKD) due to a pathogenic variant, c.2152C>T-p.(Gln718Ter), in the PKD1 gene; late-onset phenylketonuria due to the presence of two missense variants, c.842C>T-p.(Pro281Leu) and c.143T>C-p.(Leu48Ser) in the PAH gene; and a 915 Kb duplication on chromosome 15. Few patients with multiple concurrent genetic diagnoses are reported in the literature; in this ADPKD patient, genome-wide analysis allowed for the diagnosis of adult-onset phenylketonuria (which would have otherwise gone unnoticed) and a 15q11.2 duplication responsible for cognitive and behavioral impairment with incomplete penetrance. This case underlines the importance of clinical genetics for interpreting complex results obtained by genome-wide techniques, and for diagnosing concurrent late-onset monogenic conditions. Full article

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13 pages, 3588 KiB

Open AccessArticle

Characterization of the Complete Mitochondrial Genome of Agelas nakamurai from the South China Sea

by Zijian Lu, Qiang Lin and Huixian Zhang

Int. J. Mol. Sci. 2024, 25(1), 357; https://doi.org/10.3390/ijms25010357 - 26 Dec 2023

Cited by 1 | Viewed by 1168

Abstract

The Agelas genus sponges are widely distributed and provide shelter for organisms that inhabit reefs. However, there is a lack of research on the genetic diversity of the Agelas sponges. Additionally, only one Agelas mitochondrial genome has been documented, leaving the characteristics of [...] Read more.

The Agelas genus sponges are widely distributed and provide shelter for organisms that inhabit reefs. However, there is a lack of research on the genetic diversity of the Agelas sponges. Additionally, only one Agelas mitochondrial genome has been documented, leaving the characteristics of the Agelas genus’s mitogenome in need of further clarification. To address this research gap, we utilized Illumina HiSeq4000 sequencing and de novo assembly to ascertain the complete mitochondrial genome of Agelas sp. specimens, sourced from the South China Sea. Our analysis of the cox1 barcoding similarity and phylogenetic relationship reveals that taxonomically, the Agelas sp. corresponds to Agelas nakamurai. The mitogenome of Agelas nakamurai is 20,885 bp in length, encoding 14 protein-coding genes, 24 transfer RNA genes, and 2 ribosomal RNA genes. Through a comparison of the mitochondrial genes, we discovered that both Agelas nakamurai and Agelas schmidti have an identical gene arrangement. Furthermore, we observed a deletion in the trnD gene and duplication and remodeling of the trnL gene in the Agelas nakamurai’s mitogenome. Our evolutionary analysis also identified lineage-specific positive selection sites in the nad3 and nad5 genes of the Agelas sponges’ mitogenome. These findings shed light on the gene rearrangement events and positive selection sites in the mitogenome of Agelas nakamurai, providing valuable molecular insights into the evolutionary processes of this genus. Full article

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24 pages, 1980 KiB

Open AccessReview

The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP)

by Danielle Hicks, Krithika Giresh, Lisa A. Wrischnik and Douglas C. Weiser

Int. J. Mol. Sci. 2023, 24(24), 17321; https://doi.org/10.3390/ijms242417321 - 10 Dec 2023

Cited by 5 | Viewed by 2867

Abstract

The vertebrate PPP1R15 family consists of the proteins GADD34 (growth arrest and DNA damage-inducible protein 34, the product of the PPP1R15A gene) and CReP (constitutive repressor of eIF2α phosphorylation, the product of the PPP1R15B gene), both of which function as targeting/regulatory subunits for [...] Read more.

The vertebrate PPP1R15 family consists of the proteins GADD34 (growth arrest and DNA damage-inducible protein 34, the product of the PPP1R15A gene) and CReP (constitutive repressor of eIF2α phosphorylation, the product of the PPP1R15B gene), both of which function as targeting/regulatory subunits for protein phosphatase 1 (PP1) by regulating subcellular localization, modulating substrate specificity and assembling complexes with target proteins. The primary cellular function of these proteins is to facilitate the dephosphorylation of eukaryotic initiation factor 2-alpha (eIF2α) by PP1 during cell stress. In this review, we will provide a comprehensive overview of the cellular function, biochemistry and pharmacology of GADD34 and CReP, starting with a brief introduction of eIF2α phosphorylation via the integrated protein response (ISR). We discuss the roles GADD34 and CReP play as feedback inhibitors of the unfolded protein response (UPR) and highlight the critical function they serve as inhibitors of the PERK-dependent branch, which is particularly important since it can mediate cell survival or cell death, depending on how long the stressful stimuli lasts, and GADD34 and CReP play key roles in fine-tuning this cellular decision. We briefly discuss the roles of GADD34 and CReP homologs in model systems and then focus on what we have learned about their function from knockout mice and human patients, followed by a brief review of several diseases in which GADD34 and CReP have been implicated, including cancer, diabetes and especially neurodegenerative disease. Because of the potential importance of GADD34 and CReP in aspects of human health and disease, we will discuss several pharmacological inhibitors of GADD34 and/or CReP that show promise as treatments and the controversies as to their mechanism of action. This review will finish with a discussion of the biochemical properties of GADD34 and CReP, their regulation and the additional interacting partners that may provide insight into the roles these proteins may play in other cellular pathways. We will conclude with a brief outline of critical areas for future study. Full article

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16 pages, 3404 KiB

Open AccessArticle

Comparison of Conformations and Interactions with Nicotinic Acetylcholine Receptors for E. coli-Produced and Synthetic Three-Finger Protein SLURP-1

by Vladimir Kost, Dmitry Sukhov, Igor Ivanov, Igor Kasheverov, Lucy Ojomoko, Irina Shelukhina, Vera Mozhaeva, Denis Kudryavtsev, Alexey Feofanov, Anastasia Ignatova, Yuri Utkin and Victor Tsetlin

Int. J. Mol. Sci. 2023, 24(23), 16950; https://doi.org/10.3390/ijms242316950 - 29 Nov 2023

Viewed by 1035

Abstract

SLURP-1 is a three-finger human protein targeting nicotinic acetylcholine receptors (nAChRs). The recombinant forms of SLURP-1 produced in E. coli differ in added fusion fragments and in activity. The closest in sequence to the naturally occurring SLURP-1 is the recombinant rSLURP-1, differing by [...] Read more.

SLURP-1 is a three-finger human protein targeting nicotinic acetylcholine receptors (nAChRs). The recombinant forms of SLURP-1 produced in E. coli differ in added fusion fragments and in activity. The closest in sequence to the naturally occurring SLURP-1 is the recombinant rSLURP-1, differing by only one additional N-terminal Met residue. sSLURP-1 can be prepared by peptide synthesis and its amino acid sequence is identical to that of the natural protein. In view of recent NMR analysis of the conformational mobility of rSLURP-1 and cryo-electron microscopy structures of complexes of α-bungarotoxin (a three-finger snake venom protein) with Torpedo californica and α7 nAChRs, we compared conformations of sSLURP-1 and rSLURP-1 by Raman spectroscopy and CD-controlled thermal denaturation, analyzed their competition with α-bungarotoxin for binding to the above-mentioned nAChRs, compared the respective receptor complexes with computer modeling and compared their inhibitory potency on the α9α10 nAChR. The CD revealed a higher thermostability of sSLURP-1; some differences between sSLURP-1 and rSLURP-1 were observed in the regions of disulfides and tyrosine residues by Raman spectroscopy, but in binding, computer modeling and electrophysiology, the proteins were similar. Thus, sSLURP-1 and rSLURP-1 with only one additional Met residue appear close in structure and functional characteristics, being appropriate for research on nAChRs. Full article

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13 pages, 2968 KiB

Open AccessArticle

Harnessing CRISPR/Cas9 for Enhanced Disease Resistance in Hot Peppers: A Comparative Study on CaMLO2-Gene-Editing Efficiency across Six Cultivars

by Jae-Hyeong Park and Hyeran Kim

Int. J. Mol. Sci. 2023, 24(23), 16775; https://doi.org/10.3390/ijms242316775 - 26 Nov 2023

Cited by 3 | Viewed by 1847

Abstract

The Capsicum annuum Mildew Locus O (CaMLO2) gene is vital for plant defense responses against fungal pathogens like powdery mildew, a significant threat to greenhouse pepper crops. Recent advancements in genome editing, particularly using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9, [...] Read more.

The Capsicum annuum Mildew Locus O (CaMLO2) gene is vital for plant defense responses against fungal pathogens like powdery mildew, a significant threat to greenhouse pepper crops. Recent advancements in genome editing, particularly using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9, have unlocked unprecedented opportunities for modifying disease-resistant genes and improving crop characteristics. However, the application of CRISPR technology in pepper cultivars has been limited, and the regeneration process remains challenging. This study addresses these limitations by investigating the feasibility of using the validated CaMLO2 genetic scissors system in six commercial hot pepper cultivars. We assessed the gene-editing efficiency of the previously reported high-efficiency Cas9/CaMLO2single-guide RNA (sgRNA)1-ribonucleoprotein (RNP) and the low-efficiency Cas9/CaMLO2sgRNA2-RNP systems by extending their application from the bell pepper ‘Dempsey’ and the hot pepper ‘CM334’ to six commercial hot pepper cultivars. Across the six cultivars, CaMLO2sgRNA1 demonstrated an editing efficiency ranging from 6.3 to 17.7%, whereas CaMLO2sgRNA2 exhibited no editing efficiency, highlighting the superior efficacy of sgRNA1. These findings indicate the potential of utilizing the verified Cas9/CaMLO2sgRNA1-RNP system to achieve efficient gene editing at the CaMLO2 locus in different Capsicum annuum cultivars regardless of their cultivar genotypes. This study provides an efficacious genome-editing tool for developing improved pepper cultivars with CaMLO2-mediated enhanced disease resistance. Full article

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32 pages, 1546 KiB

Open AccessReview

Molecular Changes Associated with Suicide

by Daniela Navarro, Marta Marín-Mayor, Ani Gasparyan, María Salud García-Gutiérrez, Gabriel Rubio and Jorge Manzanares

Int. J. Mol. Sci. 2023, 24(23), 16726; https://doi.org/10.3390/ijms242316726 - 24 Nov 2023

Cited by 3 | Viewed by 1768

Abstract

Suicide is a serious global public health problem, with a worrying recent increase in suicide rates in both adolescent and adult populations. However, it is essential to recognize that suicide is preventable. A myriad of factors contributes to an individual’s vulnerability to suicide. [...] Read more.

Suicide is a serious global public health problem, with a worrying recent increase in suicide rates in both adolescent and adult populations. However, it is essential to recognize that suicide is preventable. A myriad of factors contributes to an individual’s vulnerability to suicide. These factors include various potential causes, from psychiatric disorders to genetic and epigenetic alterations. These changes can induce dysfunctions in crucial systems such as the serotonergic, cannabinoid, and hypothalamic–pituitary–adrenal axes. In addition, early life experiences of abuse can profoundly impact an individual’s ability to cope with stress, ultimately leading to changes in the inflammatory system, which is a significant risk factor for suicidal behavior. Thus, it is clear that suicidal behavior may result from a confluence of multiple factors. This review examines the primary risk factors associated with suicidal behavior, including psychiatric disorders, early life adversities, and epigenetic modifications. Our goal is to elucidate the molecular changes at the genetic, epigenetic, and molecular levels in the brains of individuals who have taken their own lives and in the plasma and peripheral mononuclear cells of suicide attempters and how these changes may serve as predisposing factors for suicidal tendencies. Full article

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21 pages, 15827 KiB

Open AccessArticle

Genome-Wide Identification and Involvement in Response to Biotic and Abiotic Stresses of lncRNAs in Turbot (Scophthalmus maximus)

by Weiwei Zheng, Yadong Chen, Yaning Wang, Songlin Chen and Xi-wen Xu

Int. J. Mol. Sci. 2023, 24(21), 15870; https://doi.org/10.3390/ijms242115870 - 1 Nov 2023

Viewed by 1003

Abstract

Long non-coding RNAs (lncRNAs) play crucial roles in a variety of biological processes, including stress response. However, the number, characteristics and stress-related expression of lncRNAs in turbot are still largely unknown. In this study, a total of 12,999 lncRNAs were identified at the [...] Read more.

Long non-coding RNAs (lncRNAs) play crucial roles in a variety of biological processes, including stress response. However, the number, characteristics and stress-related expression of lncRNAs in turbot are still largely unknown. In this study, a total of 12,999 lncRNAs were identified at the genome-wide level of turbot for the first time using 24 RNA-seq datasets. Sequence characteristic analyses of transcripts showed that lncRNA transcripts were shorter in average length, lower in average GC content and in average expression level as compared to the coding genes. Expression pattern analyses of lncRNAs in 12 distinct tissues showed that lncRNAs, especially lincRNA, exhibited stronger tissue-specific expression than coding genes. Moreover, 612, 1351, 1060, 875, 420 and 1689 differentially expressed (DE) lncRNAs under Vibrio anguillarum, Enteromyxum scophthalmi, and Megalocytivirus infection and heat, oxygen, and salinity stress conditions were identified, respectively. Among them, 151 and 62 lncRNAs showed differential expression under various abiotic and biotic stresses, respectively, and 11 lncRNAs differentially expressed under both abiotic and biotic stresses were selected as comprehensive stress-responsive lncRNA candidates. Furthermore, expression pattern analysis and qPCR validation both verified the comprehensive stress-responsive functions of these 11 lncRNAs. In addition, 497 significantly co-expressed target genes (correlation coefficient (R) > 0.7 and q-value < 0.05) for these 11 comprehensive stress-responsive lncRNA candidates were identified. Finally, GO and KEGG enrichment analyses indicated that these target genes were enriched mainly in molecular function, such as cytokine activity and active transmembrane transporter activity, in biological processes, such as response to stimulus and immune response, and in pathways, such as protein families: signaling and cellular processes, transporters and metabolism. These findings not only provide valuable reference resources for further research on the molecular basis and function of lncRNAs in turbot but also help to accelerate the progress of molecularly selective breeding of stress-resistant turbot strains or varieties. Full article

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18 pages, 3121 KiB

Open AccessArticle

Mechanism of Salt Tolerance and Plant Growth Promotion in Priestia megaterium ZS-3 Revealed by Cellular Metabolism and Whole-Genome Studies

by Lina Shi, Xiaoxia Zhu, Ting Qian, Jiazhou Du, Yuanyuan Du and Jianren Ye

Int. J. Mol. Sci. 2023, 24(21), 15751; https://doi.org/10.3390/ijms242115751 - 30 Oct 2023

Viewed by 2116

Abstract

Approximately one-third of agricultural land worldwide is affected by salinity, which limits the productivity and sustainability of crop ecosystems. Plant-growth-promoting rhizobacteria (PGPR) are a potential solution to this problem, as PGPR increases crop yield through improving soil fertility and stress resistance. Previous studies [...] Read more.

Approximately one-third of agricultural land worldwide is affected by salinity, which limits the productivity and sustainability of crop ecosystems. Plant-growth-promoting rhizobacteria (PGPR) are a potential solution to this problem, as PGPR increases crop yield through improving soil fertility and stress resistance. Previous studies have shown that Priestia megaterium ZS-3(ZS-3) can effectively help plants tolerate salinity stress. However, how ZS-3 regulates its metabolic adaptations in saline environments remains unclear. In this study, we monitored the metabolic rearrangement of compatibilisers in ZS-3 and combined the findings with genomic data to reveal how ZS-3 survives in stressful environments, induces plant growth, and tolerates stress. The results showed that ZS-3 tolerated salinity levels up to 9%. In addition, glutamate and trehalose help ZS-3 adapt to osmotic stress under low NaCl stress, whereas proline, K⁺, and extracellular polysaccharides regulate the osmotic responses of ZS-3 exposed to high salt stress. Potting experiments showed that applying the ZS-3 strain in saline and neutral soils could effectively increase the activities of soil acid phosphatase, urease, and invertase in both soils, thus improving soil fertility and promoting plant growth. In addition, strain ZS-3-GFP colonised the rhizosphere and leaves of Cinnamomum camphora well, as confirmed by confocal microscopy and resistance plate count analysis. Genomic studies and in vitro experiments have shown that ZS-3 exhibits a variety of beneficial traits, including plant-promoting, antagonistic, and other related traits (such as resistance to saline and heavy metal stress/tolerance, amino acid synthesis and transport, volatile compound synthesis, micronutrient utilisation, and phytohormone biosynthesis/regulatory potential). The results support that ZS-3 can induce plant tolerance to abiotic stresses. These data provide important clues to further reveal the interactions between plants and microbiomes, as well as the mechanisms by which micro-organisms control plant health. Full article

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17 pages, 4470 KiB

Open AccessArticle

The Role of Human Endogenous Retrovirus (HERV)-K119 env in THP-1 Monocytic Cell Differentiation

by Eun-Ji Ko, Min-Hye Kim, Do-Ye Kim, Hyojin An, Sun-Hee Leem, Yung Hyun Choi, Heui-Soo Kim and Hee-Jae Cha

Int. J. Mol. Sci. 2023, 24(21), 15566; https://doi.org/10.3390/ijms242115566 - 25 Oct 2023

Viewed by 1707

Abstract

Human endogenous retrovirus (HERV)-K was reportedly inserted into the human genome millions of years ago and is closely related to various diseases, including cancer and immune regulation. In our previous studies, CRISPR-Cas9-enabled knockout (KO) of the HERV-K env gene was found to potentially [...] Read more.

Human endogenous retrovirus (HERV)-K was reportedly inserted into the human genome millions of years ago and is closely related to various diseases, including cancer and immune regulation. In our previous studies, CRISPR-Cas9-enabled knockout (KO) of the HERV-K env gene was found to potentially reduce cell proliferation, cell migration, and invasion in colorectal and ovarian cancer cell lines. The immune response involves the migration and invasion of cells and is similar to cancer; however, in certain ways, it is completely unlike cancer. Therefore, we induced HERV-K119 env gene KO in THP-1, a monocytic cell that can be differentiated into a macrophage, to investigate the role of HERV-K119 env in immune regulation. Cell migration and invasion were noted to be significantly increased in HERV-K119 env KO THP-1 cells than in MOCK, and these results were contrary to those of cancer cells. To identify the underlying mechanism of HERV-K119 env KO in THP-1 cells, transcriptome analysis and cytokine array analysis were conducted. Semaphorin7A (SEMA7A), which induces the production of cytokines in macrophages and monocytic cells and plays an important role in immune effector cell activation during an inflammatory immune response, was significantly increased in HERV-K119 env KO THP-1 cells. We also found that HERV-K119 env KO THP-1 cells expressed various macrophage-specific surface markers, suggesting that KO of HERV-K119 env triggers the differentiation of THP-1 cells from monocytic cells into macrophages. In addition, analysis of the expression of M1 and M2 macrophage markers showed that M1 macrophage marker cluster of differentiation 32 (CD32) was significantly increased in HERV-K119 env KO cells. These results suggest that HERV-K119 env is implicated in the differentiation of monocytic cells into M1 macrophages and plays important roles in the immune response. Full article

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25 pages, 12701 KiB

Open AccessArticle

Comparative Chloroplast Genomics of 21 Species in Zingiberales with Implications for Their Phylogenetic Relationships and Molecular Dating

by Dong-Mei Li, Hai-Lin Liu, Yan-Gu Pan, Bo Yu, Dan Huang and Gen-Fa Zhu

Int. J. Mol. Sci. 2023, 24(19), 15031; https://doi.org/10.3390/ijms241915031 - 9 Oct 2023

Cited by 3 | Viewed by 1499

Abstract

Zingiberales includes eight families and more than 2600 species, with many species having important economic and ecological value. However, the backbone phylogenetic relationships of Zingiberales still remain controversial, as demonstrated in previous studies, and molecular dating based on chloroplast genomes has not been [...] Read more.

Zingiberales includes eight families and more than 2600 species, with many species having important economic and ecological value. However, the backbone phylogenetic relationships of Zingiberales still remain controversial, as demonstrated in previous studies, and molecular dating based on chloroplast genomes has not been comprehensively studied for the whole order. Herein, 22 complete chloroplast genomes from 21 species in Zingiberales were sequenced, assembled, and analyzed. These 22 genomes displayed typical quadripartite structures, which ranged from 161,303 bp to 163,979 bp in length and contained 111–112 different genes. The genome structures, gene contents, simple sequence repeats, long repeats, and codon usage were highly conserved, with slight differences among these genomes. Further comparative analysis of the 111 complete chloroplast genomes of Zingiberales, including 22 newly sequenced ones and the remaining ones from the national center for biotechnology information (NCBI) database, identified three highly divergent regions comprising ccsA, psaC, and psaC-ndhE. Maximum likelihood and Bayesian inference phylogenetic analyses based on chloroplast genome sequences found identical topological structures and identified a strongly supported backbone of phylogenetic relationships. Cannaceae was sister to Marantaceae, forming a clade that was collectively sister to the clade of (Costaceae, Zingiberaceae) with strong support (bootstrap (BS) = 100%, and posterior probability (PP) = 0.99–1.0); Heliconiaceae was sister to the clade of (Lowiaceae, Strelitziaceae), then collectively sister to Musaceae with strong support (BS = 94–100%, and PP = 0.93–1.0); the clade of ((Cannaceae, Marantaceae), (Costaceae, Zingiberaceae)) was sister to the clade of (Musaceae, (Heliconiaceae, (Lowiaceae, Strelitziaceae))) with robust support (BS = 100%, and PP = 1.0). The results of divergence time estimation of Zingiberales indicated that the crown node of Zingiberales occurred approximately 85.0 Mya (95% highest posterior density (HPD) = 81.6–89.3 million years ago (Mya)), with major family-level lineages becoming from 46.8 to 80.5 Mya. These findings proved that chloroplast genomes could contribute to the study of phylogenetic relationships and molecular dating in Zingiberales, as well as provide potential molecular markers for further taxonomic and phylogenetic studies of Zingiberales. Full article

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26 pages, 7520 KiB

Open AccessArticle

RNA-Based Strategies for Cancer Therapy: In Silico Design and Evaluation of ASOs for Targeted Exon Skipping

by Chiara Pacelli, Alice Rossi, Michele Milella, Teresa Colombo and Loredana Le Pera

Int. J. Mol. Sci. 2023, 24(19), 14862; https://doi.org/10.3390/ijms241914862 - 3 Oct 2023

Cited by 2 | Viewed by 2236

Abstract

Precision medicine in oncology has made significant progress in recent years by approving drugs that target specific genetic mutations. However, many cancer driver genes remain challenging to pharmacologically target (“undruggable”). To tackle this issue, RNA-based methods like antisense oligonucleotides (ASOs) that induce targeted [...] Read more.

Precision medicine in oncology has made significant progress in recent years by approving drugs that target specific genetic mutations. However, many cancer driver genes remain challenging to pharmacologically target (“undruggable”). To tackle this issue, RNA-based methods like antisense oligonucleotides (ASOs) that induce targeted exon skipping (ES) could provide a promising alternative. In this work, a comprehensive computational procedure is presented, focused on the development of ES-based cancer treatments. The procedure aims to produce specific protein variants, including inactive oncogenes and partially restored tumor suppressors. This novel computational procedure encompasses target-exon selection, in silico prediction of ES products, and identification of the best candidate ASOs for further experimental validation. The method was effectively employed on extensively mutated cancer genes, prioritized according to their suitability for ES-based interventions. Notable genes, such as NRAS and VHL, exhibited potential for this therapeutic approach, as specific target exons were identified and optimal ASO sequences were devised to induce their skipping. To the best of our knowledge, this is the first computational procedure that encompasses all necessary steps for designing ASO sequences tailored for targeted ES, contributing with a versatile and innovative approach to addressing the challenges posed by undruggable cancer driver genes and beyond. Full article

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25 pages, 3455 KiB

Open AccessReview

miRNA Studies in Glaucoma: A Comprehensive Review of Current Knowledge and Future Perspectives

by Margarita Dobrzycka, Anetta Sulewska, Przemyslaw Biecek, Radoslaw Charkiewicz, Piotr Karabowicz, Angelika Charkiewicz, Kinga Golaszewska, Patrycja Milewska, Anna Michalska-Falkowska, Karolina Nowak, Jacek Niklinski and Joanna Konopińska

Int. J. Mol. Sci. 2023, 24(19), 14699; https://doi.org/10.3390/ijms241914699 - 28 Sep 2023

Cited by 9 | Viewed by 1835

Abstract

Glaucoma, a neurodegenerative disorder that leads to irreversible blindness, remains a challenge because of its complex nature. MicroRNAs (miRNAs) are crucial regulators of gene expression and are associated with glaucoma and other diseases. We aimed to review and discuss the advantages and disadvantages [...] Read more.

Glaucoma, a neurodegenerative disorder that leads to irreversible blindness, remains a challenge because of its complex nature. MicroRNAs (miRNAs) are crucial regulators of gene expression and are associated with glaucoma and other diseases. We aimed to review and discuss the advantages and disadvantages of miRNA-focused molecular studies in glaucoma through discussing their potential as biomarkers for early detection and diagnosis; offering insights into molecular pathways and mechanisms; and discussing their potential utility with respect to personalized medicine, their therapeutic potential, and non-invasive monitoring. Limitations, such as variability, small sample sizes, sample specificity, and limited accessibility to ocular tissues, are also addressed, underscoring the need for robust protocols and collaboration. Reproducibility and validation are crucial to establish the credibility of miRNA research findings, and the integration of bioinformatics tools for miRNA database creation is a valuable component of a comprehensive approach to investigate miRNA aberrations in patients with glaucoma. Overall, miRNA research in glaucoma has provided significant insights into the molecular mechanisms of the disease, offering potential biomarkers, diagnostic tools, and therapeutic targets. However, addressing challenges such as variability and limited tissue accessibility is essential, and further investigations and validation will contribute to a deeper understanding of the functional significance of miRNAs in glaucoma. Full article

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17 pages, 1504 KiB

Open AccessReview

The Exon 3-Deleted Growth Hormone Receptor (d3GHR) Polymorphism—A Favorable Backdoor Mechanism for the GHR Function

by Ghadeer Falah, Lital Sharvit and Gil Atzmon

Int. J. Mol. Sci. 2023, 24(18), 13908; https://doi.org/10.3390/ijms241813908 - 10 Sep 2023

Cited by 2 | Viewed by 1757

Abstract

Growth hormone (GH) is a peptide hormone that plays a crucial role in controlling growth, development, and lifespan. Molecular regulation of GH is accomplished via the GH receptor (GHR), which is the main factor influencing human development and is essential to [...] Read more.

Growth hormone (GH) is a peptide hormone that plays a crucial role in controlling growth, development, and lifespan. Molecular regulation of GH is accomplished via the GH receptor (GHR), which is the main factor influencing human development and is essential to optimal functioning of the GH/IGF-I axis. Two GHR isoforms have been studied, according to the presence (flGHR) or absence (d3GHR) of exon 3. The d3GHR isoform, which lacks exon 3 has recently been related to longevity; individuals carrying this isoform have higher receptor activity, improved signal transduction, and alterations in the treatment response and efficacy compared with those carrying the wild type (WT) isoform (flGHR). Further, studies performed in patients with acromegaly, Prader–Willi syndrome, Turner syndrome, small for gestational age (SGA), and growth hormone deficiency (GHD) suggested that the d3GHR isoform may have an impact on the relationship between GH and IGF-I levels, height, weight, BMI, and other variables. Other research, however, revealed inconsistent results, which might have been caused by confounding factors, including limited sample sizes and different experimental methods. In this review, we lay out the complexity of the GHR isoforms and provide an overview of the major pharmacogenetic research conducted on this ongoing and unresolved subject. Full article

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22 pages, 7108 KiB

Open AccessArticle

The First Five Mitochondrial Genomes for the Family Nidulariaceae Reveal Novel Gene Rearrangements, Intron Dynamics, and Phylogeny of Agaricales

by Zhao-chen Li, Tian-chen Xie, Xi-long Feng, Zhen-xin Wang, Chao Lin, Guo-ming Li, Xiu-Zhang Li and Jianzhao Qi

Int. J. Mol. Sci. 2023, 24(16), 12599; https://doi.org/10.3390/ijms241612599 - 9 Aug 2023

Cited by 7 | Viewed by 1623

Abstract

The family Nidulariaceae, consisting of five genera including Cyathus, is a unique group of mushrooms commonly referred to as bird’s nest fungi due to their striking resemblance to bird’s nests. These mushrooms are considered medicinal mushrooms in Chinese medicine and have [...] Read more.

The family Nidulariaceae, consisting of five genera including Cyathus, is a unique group of mushrooms commonly referred to as bird’s nest fungi due to their striking resemblance to bird’s nests. These mushrooms are considered medicinal mushrooms in Chinese medicine and have received attention in recent years for their anti-neurodegenerative properties. However, despite the interest in these mushrooms, very little is known about their mitochondrial genomes (mitogenomes). This study is the first comprehensive investigation of the mitogenomes of five Nidulariaceae species with circular genome structures ranging in size from 114,236 bp to 129,263 bp. Comparative analyses based on gene content, gene length, tRNA, and codon usage indicate convergence within the family Nidulariaceae and heterogeneity within the order Agaricales. Phylogenetic analysis based on a combined mitochondrial conserved protein dataset provides a well-supported phylogenetic tree for the Basidiomycetes, which clearly demonstrates the evolutionary relationships between Nidulariaceae and other members of Agaricales. Furthermore, phylogenetic inferences based on four different gene sets reveal the stability and proximity of evolutionary relationships within Agaricales. These results reveal the uniqueness of the family Nidulariaceae and its similarity to other members of Agaricales; provide valuable insights into the origin, evolution, and genetics of Nidulariaceae species; and enrich the fungal mitogenome resource. This study will help to expand the knowledge and understanding of the mitogenomes in mushrooms. Full article

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17 pages, 4678 KiB

Open AccessArticle

Classification of Promoter Sequences from Human Genome

by Konstantin Zaytsev, Alexey Fedorov and Eugene Korotkov

Int. J. Mol. Sci. 2023, 24(16), 12561; https://doi.org/10.3390/ijms241612561 - 8 Aug 2023

Cited by 1 | Viewed by 1933

Abstract

We have developed a new method for promoter sequence classification based on a genetic algorithm and the MAHDS sequence alignment method. We have created four classes of human promoters, combining 17,310 sequences out of the 29,598 present in the EPD database. We searched [...] Read more.

We have developed a new method for promoter sequence classification based on a genetic algorithm and the MAHDS sequence alignment method. We have created four classes of human promoters, combining 17,310 sequences out of the 29,598 present in the EPD database. We searched the human genome for potential promoter sequences (PPSs) using dynamic programming and position weight matrices representing each of the promoter sequence classes. A total of 3,065,317 potential promoter sequences were found. Only 1,241,206 of them were located in unannotated parts of the human genome. Every other PPS found intersected with either true promoters, transposable elements, or interspersed repeats. We found a strong intersection between PPSs and Alu elements as well as transcript start sites. The number of false positive PPSs is estimated to be 3 × 10⁻⁸ per nucleotide, which is several orders of magnitude lower than for any other promoter prediction method. The developed method can be used to search for PPSs in various eukaryotic genomes. Full article

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15 pages, 2097 KiB

Open AccessArticle

Transcriptomic Responses of Salvia hispanica to the Infestation of Red Spider Mites (Tetranychus neocaledonicus)

by May Lee, Le Wang and Gen Hua Yue

Int. J. Mol. Sci. 2023, 24(15), 12261; https://doi.org/10.3390/ijms241512261 - 31 Jul 2023

Viewed by 1129

Abstract

Salvia hispanica (chia) is a highly nutritious food source and has gained popularity due to its high omega-3 fatty acid content. Red spider mites are a serious problem in the production of S. hispanica. However, no study has been conducted to analyze [...] Read more.

Salvia hispanica (chia) is a highly nutritious food source and has gained popularity due to its high omega-3 fatty acid content. Red spider mites are a serious problem in the production of S. hispanica. However, no study has been conducted to analyze the defensive response to the infestation of red spider mites in S. hispanica. To elucidate the molecular mechanisms of the defensive response of S. hispanica to red spider mites, we performed a transcriptomic analysis of S. hispanica when infested by red spider mites. In the comparative assessment of leaf transcriptomes, a total of 1743 differentially expressed genes (DEGs) were identified between control and mite-infested S. hispanica. From these, 1208 (69%) transcripts were upregulated and 535 (31%) were downregulated. The DEGs included transcription factors, defense hormones, and secondary metabolites that were either suppressed or activated in response to spider mite herbivory. Gene Ontology (GO) enrichment analysis revealed that plant secondary metabolites, such as glucosinolates, and signaling pathways, including the jasmonic acid signaling pathway, may play an important role in the defense against red spider mites. This study provides novel insights into the defense response of S. hispanica to insect herbivory and could be a resource for the improvement of pest resistance in the chia. Full article

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10 pages, 527 KiB

Open AccessCommunication

Dynamics of Podospora anserina Genome Evolution in a Long-Term Experiment

by Olga A. Kudryavtseva, Evgeny S. Gerasimov, Elena S. Glagoleva, Anna A. Gasparyan, Saveliy M. Agroskin, Mikhail A. Belozersky and Yakov E. Dunaevsky

Int. J. Mol. Sci. 2023, 24(15), 12009; https://doi.org/10.3390/ijms241512009 - 27 Jul 2023

Viewed by 1047

Abstract

The Podospora anserina long-term evolution experiment (PaLTEE) is the only running filamentous fungus study, which is still going on. The aim of our work is to trace the evolutionary dynamics of the accumulation of mutations in the genomes of eight haploid populations of [...] Read more.

The Podospora anserina long-term evolution experiment (PaLTEE) is the only running filamentous fungus study, which is still going on. The aim of our work is to trace the evolutionary dynamics of the accumulation of mutations in the genomes of eight haploid populations of P. anserina. The results of the genome-wide analysis of all of the lineages, performed 8 years after the start of the PaLTEE, are presented. Data analysis detected 312 single nucleotide polymorphisms (SNPs) and 39 short insertion-deletion mutations (indels) in total. There was a clear trend towards a linear increase in the number of SNPs depending on the experiment duration. Among 312 SNPs, 153 were fixed in the coding regions of P. anserina genome. Relatively few synonymous mutations were found, exactly 38; 42 were classified as nonsense mutations; 72 were assigned to missense mutations. In addition, 21 out of 39 indels identified were also localized in coding regions. Here, we also report the detection of parallel evolution at the paralog level in the P. anserina model system. Parallelism in evolution at the level of protein functions also occurs. The latter is especially true for various transcription factors, which may indicate selection leading to optimization of the wide range of cellular processes under experimental conditions. Full article

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12 pages, 4847 KiB

Open AccessArticle

Multi-Drug Resistance in Bacterial Genomes—A Comprehensive Bioinformatic Analysis

by Célia P. F. Domingues, João S. Rebelo, Francisco Dionisio and Teresa Nogueira

Int. J. Mol. Sci. 2023, 24(14), 11438; https://doi.org/10.3390/ijms241411438 - 14 Jul 2023

Cited by 2 | Viewed by 2792

Abstract

Antimicrobial resistance is presently one of the greatest threats to public health. The excessive and indiscriminate use of antibiotics imposes a continuous selective pressure that triggers the emergence of multi-drug resistance. We performed a large-scale analysis of closed bacterial genomes to identify multi-drug [...] Read more.

Antimicrobial resistance is presently one of the greatest threats to public health. The excessive and indiscriminate use of antibiotics imposes a continuous selective pressure that triggers the emergence of multi-drug resistance. We performed a large-scale analysis of closed bacterial genomes to identify multi-drug resistance considering the ResFinder antimicrobial classes. We found that more than 95% of the genomes harbor genes associated with resistance to disinfectants, glycopeptides, macrolides, and tetracyclines. On average, each genome encodes resistance to more than nine different classes of antimicrobial drugs. We found higher-than-expected co-occurrences of resistance genes in both plasmids and chromosomes for several classes of antibiotic resistance, including classes categorized as critical according to the World Health Organization (WHO). As a result of antibiotic-resistant priority pathogens, higher-than-expected co-occurrences appear in plasmids, increasing the potential for resistance dissemination. For the first time, co-occurrences of antibiotic resistance have been investigated for priority pathogens as defined by the WHO. For critically important pathogens, co-occurrences appear in plasmids, not in chromosomes, suggesting that the resistances may be epidemic and probably recent. These results hint at the need for new approaches to treating infections caused by critically important bacteria. Full article

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17 pages, 3005 KiB

Open AccessArticle

Transcriptional Readthrough Interrupts Boundary Function in Drosophila

by Olga Kyrchanova, Vladimir Sokolov, Maxim Tikhonov, Galya Manukyan, Paul Schedl and Pavel Georgiev

Int. J. Mol. Sci. 2023, 24(14), 11368; https://doi.org/10.3390/ijms241411368 - 12 Jul 2023

Cited by 2 | Viewed by 1219

Abstract

In higher eukaryotes, distance enhancer-promoter interactions are organized by topologically associated domains, tethering elements, and chromatin insulators/boundaries. While insulators/boundaries play a central role in chromosome organization, the mechanisms regulating their functions are largely unknown. In the studies reported here, we have taken advantage [...] Read more.

In higher eukaryotes, distance enhancer-promoter interactions are organized by topologically associated domains, tethering elements, and chromatin insulators/boundaries. While insulators/boundaries play a central role in chromosome organization, the mechanisms regulating their functions are largely unknown. In the studies reported here, we have taken advantage of the well-characterized Drosophila bithorax complex (BX-C) to study one potential mechanism for controlling boundary function. The regulatory domains of BX-C are flanked by boundaries, which block crosstalk with their neighboring domains and also support long-distance interactions between the regulatory domains and their target gene. As many lncRNAs have been found in BX-C, we asked whether readthrough transcription (RT) can impact boundary function. For this purpose, we took advantage of two BX-C boundary replacement platforms, Fab-7^attP50 and F2^attP, in which the Fab-7 and Fub boundaries, respectively, are deleted and replaced with an attP site. We introduced boundary elements, promoters, and polyadenylation signals arranged in different combinations and then assayed for boundary function. Our results show that RT can interfere with boundary activity. Since lncRNAs represent a significant fraction of Pol II transcripts in multicellular eukaryotes, it is therefore possible that RT may be a widely used mechanism to alter boundary function and regulation of gene expression. Full article

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15 pages, 1863 KiB

Open AccessArticle

Complete Mitochondrial Genome Sequence and Phylogenetic Analysis of Procambarus clarkii and Cambaroides dauricus from China

by Liang Luo, Yue Xu, Shihui Wang, Rui Zhang, Kun Guo, Wei Xu and Zhigang Zhao

Int. J. Mol. Sci. 2023, 24(14), 11282; https://doi.org/10.3390/ijms241411282 - 10 Jul 2023

Cited by 5 | Viewed by 2123

Abstract

To enhance the management and protection of crayfish genetic diversity and germplasm resources in Cambaroides dauricus (C. dauricus), a common species of Procambarus clarkii (P. clarkii) was used as a control group to compare the whole mitochondrial genome sequence [...] Read more.

To enhance the management and protection of crayfish genetic diversity and germplasm resources in Cambaroides dauricus (C. dauricus), a common species of Procambarus clarkii (P. clarkii) was used as a control group to compare the whole mitochondrial genome sequence using Illumina sequencing technology. This study found that the mitochondrial genome of C. dauricus is 15580 bp in length, with a base composition of A (31.84%), G (17.66%), C (9.42%), and T (41.08%) and a C + G content of 27.08%. The C + G in the D-loop is rich in 17.06%, indicating a significant preference. The mitochondrial genome of C. dauricus contains 13 protein-coding genes, 22 tRNA genes, and 2 rRNA genes, with most of the genes labeled in the negative direction, except for a few genes that are labeled in the positive direction. The start codons of the ten coding sequences are ATG, and the quintessential TAA and TAG are the stop codons. This study also found that the Ka/Ks ratios of most protein-coding genes in the mitochondria of both shrimps are lower than 1, indicating weak natural selection, except for nad 2, nad 5, and cox 1. The Ka/Ks ratio of cox 3 is the lowest (less than 0.1), indicating that this protein-coding gene bears strong natural selection pressure and functional constraint in the process of mitochondrial genetic evolution of both shrimps. Furthermore, we constructed phylogenetic analyses based on the entire sequence, which effectively distinguishes the high body from other shrimp species of the genus based on the mitochondrial genome. This study provides molecular genetic data for the diversity investigation and protection of fishery resources with Chinese characteristics and a scientific reference for the evolutionary study of Procambarus. Full article

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23 pages, 4922 KiB

Open AccessArticle

Identification of a Gene Signature Predicting (Nano)Particle-Induced Adverse Lung Outcome in Rats

by Sarah Amandine Valentino, Carole Seidel, Mylène Lorcin, Sylvie Sébillaud, Henrik Wolff, Stéphane Grossmann, Stéphane Viton, Hervé Nunge, Laura Aliisa Saarimäki, Dario Greco, Frédéric Cosnier and Laurent Gaté

Int. J. Mol. Sci. 2023, 24(13), 10890; https://doi.org/10.3390/ijms241310890 - 29 Jun 2023

Cited by 1 | Viewed by 1379

Abstract

Nanoparticles are extensively used in industrial products or as food additives. However, despite their contribution to improving our quality of life, concerns have been raised regarding their potential impact on occupational and public health. To speed up research assessing nanoparticle-related hazards, this study [...] Read more.

Nanoparticles are extensively used in industrial products or as food additives. However, despite their contribution to improving our quality of life, concerns have been raised regarding their potential impact on occupational and public health. To speed up research assessing nanoparticle-related hazards, this study was undertaken to identify early markers of harmful effects on the lungs. Female Sprague Dawley rats were either exposed to crystalline silica DQ-12 with instillation, or to titanium dioxide P25, carbon black Printex-90, or multi-walled carbon nanotube Mitsui-7 with nose-only inhalation. Tissues were collected at three post-exposure time points to assess short- and long-term effects. All particles induced lung inflammation. Histopathological and biochemical analyses revealed phospholipid accumulation, lipoproteinosis, and interstitial thickening with collagen deposition after exposure to DQ-12. Exposure to the highest dose of Printex-90 and Mitsui-7, but not P25, induced some phospholipid accumulation. Comparable histopathological changes were observed following exposure to P25, Printex-90, and Mitsui-7. Comparison of overall gene expression profiles identified 15 potential early markers of adverse lung outcomes induced by spherical particles. With Mitsui-7, a distinct gene expression signature was observed, suggesting that carbon nanotubes trigger different toxicity mechanisms to spherical particles. Full article

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17 pages, 985 KiB

Open AccessReview

An Update on MYBPC3 Gene Mutation in Hypertrophic Cardiomyopathy

by Bogdan-Sorin Tudurachi, Alexandra Zăvoi, Andreea Leonte, Laura Țăpoi, Carina Ureche, Silviu Gabriel Bîrgoan, Traian Chiuariu, Larisa Anghel, Rodica Radu, Radu Andy Sascău and Cristian Stătescu

Int. J. Mol. Sci. 2023, 24(13), 10510; https://doi.org/10.3390/ijms241310510 - 22 Jun 2023

Cited by 15 | Viewed by 4607

Abstract

Hypertrophic cardiomyopathy (HCM) is the most prevalent genetically inherited cardiomyopathy that follows an autosomal dominant inheritance pattern. The majority of HCM cases can be attributed to mutation of the MYBPC3 gene, which encodes cMyBP-C, a crucial structural protein of the cardiac muscle. The [...] Read more.

Hypertrophic cardiomyopathy (HCM) is the most prevalent genetically inherited cardiomyopathy that follows an autosomal dominant inheritance pattern. The majority of HCM cases can be attributed to mutation of the MYBPC3 gene, which encodes cMyBP-C, a crucial structural protein of the cardiac muscle. The manifestation of HCM’s morphological, histological, and clinical symptoms is subject to the complex interplay of various determinants, including genetic mutation and environmental factors. Approximately half of MYBPC3 mutations give rise to truncated protein products, while the remaining mutations cause insertion/deletion, frameshift, or missense mutations of single amino acids. In addition, the onset of HCM may be attributed to disturbances in the protein and transcript quality control systems, namely, the ubiquitin–proteasome system and nonsense-mediated RNA dysfunctions. The aforementioned genetic modifications, which appear to be associated with unfavorable lifelong outcomes and are largely influenced by the type of mutation, exhibit a unique array of clinical manifestations ranging from asymptomatic to arrhythmic syncope and even sudden cardiac death. Although the current understanding of the MYBPC3 mutation does not comprehensively explain the varied phenotypic manifestations witnessed in patients with HCM, patients with pathogenic MYBPC3 mutations can exhibit an array of clinical manifestations ranging from asymptomatic to advanced heart failure and sudden cardiac death, leading to a higher rate of adverse clinical outcomes. This review focuses on MYBPC3 mutation and its characteristics as a prognostic determinant for disease onset and related clinical consequences in HCM. Full article

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18 pages, 3743 KiB

Open AccessArticle

Induction of the Erythroid Differentiation of K562 Cells Is Coupled with Changes in the Inter-Chromosomal Contacts of rDNA Clusters

by Nickolai A. Tchurikov, Elena S. Klushevskaya, Ildar R. Alembekov, Antonina N. Kretova, Vladimir R. Chechetkin, Galina I. Kravatskaya and Yuri V. Kravatsky

Int. J. Mol. Sci. 2023, 24(12), 9842; https://doi.org/10.3390/ijms24129842 - 7 Jun 2023

Cited by 5 | Viewed by 2438

Abstract

The expression of clusters of rDNA genes influences pluripotency; however, the underlying mechanisms are not yet known. These clusters shape inter-chromosomal contacts with numerous genes controlling differentiation in human and Drosophila cells. This suggests a possible role of these contacts in the formation [...] Read more.

The expression of clusters of rDNA genes influences pluripotency; however, the underlying mechanisms are not yet known. These clusters shape inter-chromosomal contacts with numerous genes controlling differentiation in human and Drosophila cells. This suggests a possible role of these contacts in the formation of 3D chromosomal structures and the regulation of gene expression in development. However, it has not yet been demonstrated whether inter-chromosomal rDNA contacts are changed during differentiation. In this study, we used human leukemia K562 cells and induced their erythroid differentiation in order to study both the changes in rDNA contacts and the expression of genes. We observed that approximately 200 sets of rDNA-contacting genes are co-expressed in different combinations in both untreated and differentiated K562 cells. rDNA contacts are changed during differentiation and coupled with the upregulation of genes whose products are mainly located in the nucleus and are highly associated with DNA- and RNA-binding, along with the downregulation of genes whose products mainly reside in the cytoplasm or intra- or extracellular vesicles. The most downregulated gene is ID3, which is known as an inhibitor of differentiation, and thus should be switched off to allow for differentiation. Our data suggest that the differentiation of K562 cells leads to alterations in the inter-chromosomal contacts of rDNA clusters and 3D structures in particular chromosomal regions as well as to changes in the expression of genes located in the corresponding chromosomal domains. We conclude that approximately half of the rDNA-contacting genes are co-expressed in human cells and that rDNA clusters are involved in the global regulation of gene expression. Full article

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21 pages, 4235 KiB

Open AccessArticle

Molecular Characterization of Nine TRAF Genes in Yellow Catfish (Pelteobagrus fulvidraco) and Their Expression Profiling in Response to Edwardsiella ictaluri Infection

by Shen-Li You, Xin-Xin Jiang, Gui-Rong Zhang, Wei Ji, Xu-Fa Ma, Xu Zhou and Kai-Jian Wei

Int. J. Mol. Sci. 2023, 24(9), 8363; https://doi.org/10.3390/ijms24098363 - 6 May 2023

Cited by 1 | Viewed by 1983

Abstract

The yellow catfish (Pelteobagrus fulvidraco) is an economic fish with a large breeding scale, and diseases have led to huge economic losses. Tumor necrosis factor receptor-associated factors (TRAFs) are a class of intracellular signal transduction proteins that play an important role [...] Read more.

The yellow catfish (Pelteobagrus fulvidraco) is an economic fish with a large breeding scale, and diseases have led to huge economic losses. Tumor necrosis factor receptor-associated factors (TRAFs) are a class of intracellular signal transduction proteins that play an important role in innate and adaptive immune responses by mediating NF-κB, JNK and MAPK signaling pathways. However, there are few studies on the TRAF gene family in yellow catfish. In this study, the open reading frame (ORF) sequences of TRAF1, TRAF2a, TRAF2b, TRAF3, TRAF4a, TRAF4b, TRAF5, TRAF6 and TRAF7 genes were cloned and identified in yellow catfish. The ORF sequences of the nine TRAF genes of yellow catfish (Pf_TRAF1-7) were 1413–2025 bp in length and encoded 470–674 amino acids. The predicted protein structures of Pf_TRAFs have typically conserved domains compared to mammals. The phylogenetic relationships showed that TRAF genes are conserved during evolution. Gene structure, motifs and syntenic analyses of TRAF genes showed that the exon–intron structure and conserved motifs of TRAF genes are diverse among seven vertebrate species, and the TRAF gene family is relatively conserved evolutionarily. Among them, TRAF1 is more closely related to TRAF2a and TRAF2b, and they may have evolved from a common ancestor. TRAF7 is quite different and distantly related to other TRAFs. Real-time quantitative PCR (qRT-PCR) results showed that all nine Pf_TRAF genes were constitutively expressed in 12 tissues of healthy yellow catfish, with higher mRNA expression levels in the gonad, spleen, brain and gill. After infection with Edwardsiella ictaluri, the expression levels of nine Pf_TRAF mRNAs were significantly changed in the head kidney, spleen, gill and brain tissues of yellow catfish, of which four genes were down-regulated and one gene was up-regulated in the head kidney; four genes were up-regulated and four genes were down-regulated in the spleen; two genes were down-regulated, one gene was up-regulated, and one gene was up-regulated and then down-regulated in the gill; one gene was up-regulated, one gene was down-regulated, and four genes were down-regulated and then up-regulated in the brain. These results indicate that Pf_TRAF genes might be involved in the immune response against bacterial infection. Subcellular localization results showed that all nine Pf_TRAFs were found localized in the cytoplasm, and Pf_TRAF2a, Pf_TRAF3 and Pf_TRAF4a could also be localized in the nucleus, uncovering that the subcellular localization of TRAF protein may be closely related to its structure and function in cellular mechanism. The results of this study suggest that the Pf_TRAF gene family plays important roles in the immune response against pathogen invasion and will provide basic information to further understand the roles of TRAF gene against bacterial infection in yellow catfish. Full article

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14 pages, 4814 KiB

Open AccessArticle

Core Promoter Regions of Antisense and Long Intergenic Non-Coding RNAs

by Ekaterina A. Savina, Tatiana G. Shumilina, Vladimir G. Tumanyan, Anastasia A. Anashkina and Irina A. Il’icheva

Int. J. Mol. Sci. 2023, 24(9), 8199; https://doi.org/10.3390/ijms24098199 - 3 May 2023

Cited by 1 | Viewed by 1642

Abstract

RNA polymerase II (POL II) is responsible for the transcription of messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs). Previously, we have shown the evolutionary invariance of the structural features of DNA in the POL II core promoters of the precursors of mRNAs. [...] Read more.

RNA polymerase II (POL II) is responsible for the transcription of messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs). Previously, we have shown the evolutionary invariance of the structural features of DNA in the POL II core promoters of the precursors of mRNAs. In this work, we have analyzed the POL II core promoters of the precursors of lncRNAs in Homo sapiens and Mus musculus genomes. Structural analysis of nucleotide sequences in positions −50, +30 bp in relation to the TSS have shown the extremely heterogeneous 3D structure that includes two singular regions - hexanucleotide “INR” around the TSS and octanucleotide “TATA-box” at around ~−28 bp upstream. Thus, the 3D structure of core promoters of lncRNA resembles the architecture of the core promoters of mRNAs; however, textual analysis revealed differences between promoters of lncRNAs and promoters of mRNAs, which lies in their textual characteristics; namely, the informational entropy at each position of the nucleotide text of lncRNA core promoters (by the exception of singular regions) is significantly higher than that of the mRNA core promoters. Another distinguishing feature of lncRNA is the extremely rare occurrence in the TATA box of octanucleotides with the consensus sequence. These textual differences can significantly affect the efficiency of the transcription of lncRNAs. Full article

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16 pages, 5691 KiB

Open AccessArticle

Integrating Multiple Single-Cell RNA Sequencing Datasets Using Adversarial Autoencoders

by Xun Wang, Chaogang Zhang, Lulu Wang and Pan Zheng

Int. J. Mol. Sci. 2023, 24(6), 5502; https://doi.org/10.3390/ijms24065502 - 13 Mar 2023

Cited by 1 | Viewed by 2568

Abstract

Single-cell RNA sequencing (RNA-seq) has been demonstrated to be a proven method for quantifying gene-expression heterogeneity and providing insight into the transcriptome at the single-cell level. When combining multiple single-cell transcriptome datasets for analysis, it is common to first correct the batch effect. [...] Read more.

Single-cell RNA sequencing (RNA-seq) has been demonstrated to be a proven method for quantifying gene-expression heterogeneity and providing insight into the transcriptome at the single-cell level. When combining multiple single-cell transcriptome datasets for analysis, it is common to first correct the batch effect. Most of the state-of-the-art processing methods are unsupervised, i.e., they do not utilize single-cell cluster labeling information, which could improve the performance of batch correction methods, especially in the case of multiple cell types. To better utilize known labels for complex dataset scenarios, we propose a novel deep learning model named IMAAE (i.e., integrating multiple single-cell datasets via an adversarial autoencoder) to correct the batch effects. After conducting experiments with various dataset scenarios, the results show that IMAAE outperforms existing methods for both qualitative measures and quantitative evaluation. In addition, IMAAE is able to retain both corrected dimension reduction data and corrected gene expression data. These features make it a potential new option for large-scale single-cell gene expression data analysis. Full article

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23 pages, 4386 KiB

Open AccessArticle

Mitochondrial Genome Sequence of Salvia officinalis (Lamiales: Lamiaceae) Suggests Diverse Genome Structures in Cogeneric Species and Finds the Stop Gain of Genes through RNA Editing Events

by Heyu Yang, Haimei Chen, Yang Ni, Jingling Li, Yisha Cai, Jiehua Wang and Chang Liu

Int. J. Mol. Sci. 2023, 24(6), 5372; https://doi.org/10.3390/ijms24065372 - 11 Mar 2023

Cited by 15 | Viewed by 2614

Abstract

Our previous study was the first to confirm that the predominant conformation of mitochondrial genome (mitogenome) sequence of Salvia species contains two circular chromosomes. To further understand the organization, variation, and evolution of Salvia mitogenomes, we characterized the mitogenome of Salvia officinalis. [...] Read more.

Our previous study was the first to confirm that the predominant conformation of mitochondrial genome (mitogenome) sequence of Salvia species contains two circular chromosomes. To further understand the organization, variation, and evolution of Salvia mitogenomes, we characterized the mitogenome of Salvia officinalis. The mitogenome of S. officinalis was sequenced using Illumina short reads and Nanopore long reads and assembled using a hybrid assembly strategy. We found that the predominant conformation of the S. officinalis mitogenome also had two circular chromosomes that were 268,341 bp (MC1) and 39,827 bp (MC2) in length. The S. officinalis mitogenome encoded an angiosperm-typical set of 24 core genes, 9 variable genes, 3 rRNA genes, and 16 tRNA genes. We found many rearrangements of the Salvia mitogenome through inter- and intra-specific comparisons. A phylogenetic analysis of the coding sequences (CDs) of 26 common protein-coding genes (PCGs) of 11 Lamiales species and 2 outgroup taxa strongly indicated that the S. officinalis was a sister taxon to S. miltiorrhiza, consistent with the results obtained using concatenated CDs of common plastid genes. The mapping of RNA-seq data to the CDs of PCGs led to the identification of 451 C-to-U RNA editing sites from 31 PCGs of the S. officinalis mitogenome. Using PCR amplification and Sanger sequencing methods, we successfully validated 113 of the 126 RNA editing sites from 11 PCGs. The results of this study suggest that the predominant conformation of the S. officinalis mitogenome are two circular chromosomes, and the stop gain of rpl5 was found through RNA editing events of the Salvia mitogenome. Full article

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15 pages, 1139 KiB

Open AccessReview

Inherited Thrombocytopenia Caused by Variants in Crucial Genes for Glycosylation

by Ana Marín-Quílez, Lorena Díaz-Ajenjo, Christian A. Di Buduo, Ana Zamora-Cánovas, María Luisa Lozano, Rocío Benito, José Ramón González-Porras, Alessandra Balduini, José Rivera and José María Bastida

Int. J. Mol. Sci. 2023, 24(6), 5109; https://doi.org/10.3390/ijms24065109 - 7 Mar 2023

Cited by 4 | Viewed by 2705

Abstract

Protein glycosylation, including sialylation, involves complex and frequent post-translational modifications, which play a critical role in different biological processes. The conjugation of carbohydrate residues to specific molecules and receptors is critical for normal hematopoiesis, as it favors the proliferation and clearance of hematopoietic [...] Read more.

Protein glycosylation, including sialylation, involves complex and frequent post-translational modifications, which play a critical role in different biological processes. The conjugation of carbohydrate residues to specific molecules and receptors is critical for normal hematopoiesis, as it favors the proliferation and clearance of hematopoietic precursors. Through this mechanism, the circulating platelet count is controlled by the appropriate platelet production by megakaryocytes, and the kinetics of platelet clearance. Platelets have a half-life in blood ranging from 8 to 11 days, after which they lose the final sialic acid and are recognized by receptors in the liver and eliminated from the bloodstream. This favors the transduction of thrombopoietin, which induces megakaryopoiesis to produce new platelets. More than two hundred enzymes are responsible for proper glycosylation and sialylation. In recent years, novel disorders of glycosylation caused by molecular variants in multiple genes have been described. The phenotype of the patients with genetic alterations in GNE, SLC35A1, GALE and B4GALT is consistent with syndromic manifestations, severe inherited thrombocytopenia, and hemorrhagic complications. Full article

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11 pages, 2068 KiB

Open AccessArticle

Quantitative Analysis of Transcription Termination via Position-Selective Labeling of RNA (PLOR) Method

by Ping-Yi Chien, Lingzhi Gao and Yu Liu

Int. J. Mol. Sci. 2023, 24(5), 4934; https://doi.org/10.3390/ijms24054934 - 3 Mar 2023

Viewed by 2020

Abstract

T7 RNA polymerase is the most widely used enzyme in RNA synthesis, and it is also used for RNA labeling in position-selective labeling of RNA (PLOR). PLOR is a liquid–solid hybrid phase method that has been developed to introduce labels to specific positions [...] Read more.

T7 RNA polymerase is the most widely used enzyme in RNA synthesis, and it is also used for RNA labeling in position-selective labeling of RNA (PLOR). PLOR is a liquid–solid hybrid phase method that has been developed to introduce labels to specific positions of RNA. Here, we applied PLOR as a single-round transcription method to quantify the terminated and read-through products in transcription for the first time. Various factors, including pausing strategies, Mg²⁺, ligand and the NTP concentration at the transcriptional termination of adenine riboswitch RNA have been characterized. This helps to understand transcription termination, which is one of the least understood processes in transcription. Additionally, our strategy can potentially be used to study the co-transcription behavior of general RNA, especially when continuous transcription is not desired. Full article

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13 pages, 1169 KiB

Open AccessArticle

mtR_find: A Parallel Processing Tool to Identify and Annotate RNAs Derived from the Mitochondrial Genome

by Asan M. S. H. Mohideen, Steinar D. Johansen and Igor Babiak

Int. J. Mol. Sci. 2023, 24(5), 4373; https://doi.org/10.3390/ijms24054373 - 22 Feb 2023

Viewed by 1964

Abstract

RNAs originating from mitochondrial genomes are abundant in transcriptomic datasets produced by high-throughput sequencing technologies, primarily in short-read outputs. Specific features of mitochondrial small RNAs (mt-sRNAs), such as non-templated additions, presence of length variants, sequence variants, and other modifications, necessitate the need for [...] Read more.

RNAs originating from mitochondrial genomes are abundant in transcriptomic datasets produced by high-throughput sequencing technologies, primarily in short-read outputs. Specific features of mitochondrial small RNAs (mt-sRNAs), such as non-templated additions, presence of length variants, sequence variants, and other modifications, necessitate the need for the development of an appropriate tool for their effective identification and annotation. We have developed mtR_find, a tool to detect and annotate mitochondrial RNAs, including mt-sRNAs and mitochondria-derived long non-coding RNAs (mt-lncRNA). mtR_find uses a novel method to compute the count of RNA sequences from adapter-trimmed reads. When analyzing the published datasets with mtR_find, we identified mt-sRNAs significantly associated with the health conditions, such as hepatocellular carcinoma and obesity, and we discovered novel mt-sRNAs. Furthermore, we identified mt-lncRNAs in early development in mice. These examples show the immediate impact of miR_find in extracting a novel biological information from the existing sequencing datasets. For benchmarking, the tool has been tested on a simulated dataset and the results were concordant. For accurate annotation of mitochondria-derived RNA, particularly mt-sRNA, we developed an appropriate nomenclature. mtR_find encompasses the mt-ncRNA transcriptomes in unpreceded resolution and simplicity, allowing re-analysis of the existing transcriptomic databases and the use of mt-ncRNAs as diagnostic or prognostic markers in the field of medicine. Full article

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17 pages, 5192 KiB

Open AccessArticle

Identification and Characterization of 5-HT Receptor 1 from Scylla paramamosain: The Essential Roles of 5-HT and Its Receptor Gene during Aggressive Behavior in Crab Species

by Xinlian Huang, Yuanyuan Fu, Wei Zhai, Xiaopeng Wang, Yueyue Zhou, Lei Liu and Chunlin Wang

Int. J. Mol. Sci. 2023, 24(4), 4211; https://doi.org/10.3390/ijms24044211 - 20 Feb 2023

Cited by 2 | Viewed by 1612

Abstract

Biogenic amines (BAs) play an important role in the aggressive behavior of crustaceans. In mammals and birds, 5-HT and its receptor genes (5-HTRs) are characterized as essential regulators involved in neural signaling pathways during aggressive behavior. However, only one 5-HTR transcript has been [...] Read more.

Biogenic amines (BAs) play an important role in the aggressive behavior of crustaceans. In mammals and birds, 5-HT and its receptor genes (5-HTRs) are characterized as essential regulators involved in neural signaling pathways during aggressive behavior. However, only one 5-HTR transcript has been reported in crabs. In this study, the full-length cDNA of the 5-HTR1 gene, named Sp5-HTR1, was first isolated from the muscle of the mud crab Scylla paramamosain using the reverse-transcription polymerase chain reaction (RT-PCR) and rapid-amplification of cDNA ends (RACE) methods. The transcript encoded a peptide of 587 amino acid residues with a molecular mass of 63.36 kDa. Western blot results indicate that the 5-HTR1 protein was expressed at the highest level in the thoracic ganglion. Furthermore, the results of quantitative real-time PCR show that the expression levels of Sp5-HTR1 in the ganglion at 0.5, 1, 2, and 4 h after 5-HT injection were significantly upregulated compared with the control group (p < 0.05). Meanwhile, the behavioral changes in 5-HT-injected crabs were analyzed with EthoVision. After 0.5 h of injection, the speed and movement distance of the crab, the duration of aggressive behavior, and the intensity of aggressiveness in the low-5-HT-concentration injection group were significantly higher than those in the saline-injection and control groups (p < 0.05). In this study, we found that the Sp5-HTR1 gene plays a role in the regulation of aggressive behavior by BAs, including 5-HT in the mud crab. The results provide reference data for the analysis of the genetic mechanism of aggressive behaviors in crabs. Full article

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9 pages, 4922 KiB

Open AccessArticle

Larches of Kuzhanovo Have a Unique Mutation in the atpF–atpH Intergenic Spacer

by Alexander Artyukhin, Yuliya Sharifyanova, Mikhail M. Krivosheev and Elena V. Mikhaylova

Int. J. Mol. Sci. 2023, 24(4), 3939; https://doi.org/10.3390/ijms24043939 - 15 Feb 2023

Viewed by 1292

Abstract

The larches of Kuzhanovo (Larix sibirica Ledeb.) are protected trees with a round crown growing in the Southern Urals. In 2020 vandals sawed the sapwood of these trees, which exposed the problem of insufficient conservation measures. Their origin and genetic characteristics have [...] Read more.

The larches of Kuzhanovo (Larix sibirica Ledeb.) are protected trees with a round crown growing in the Southern Urals. In 2020 vandals sawed the sapwood of these trees, which exposed the problem of insufficient conservation measures. Their origin and genetic characteristics have been of particular interest to breeders and scientists. The larches of Kuzhanovo were screened for polymorphisms using SSR and ISSR analyses and the sequencing of genetic markers and genes GIGANTEA and mTERF, associated with wider crown shape. A unique mutation was discovered in the atpF–atpH intergenic spacer of all protected trees, but it was absent in some of their descendants and larches with similar crown shape. Mutations were discovered in the rpoC1 and mTERF genes of all samples. Flow cytometry did not reveal any changes in genome size. Our results suggest that the unique phenotype arose from point mutations in L. sibirica, but they are yet to be found in the nuclear genome. The concurrent mutations in the rpoC1 and mTERF genes may indicate that the round crown shape originates from the Southern Urals. The atpF–atpH and rpoC1 genetic markers are not common in studies of Larix sp., but their wider use could help to establish the origin of these endangered plants. The discovery of the unique atpF–atpH mutation also allows for stronger conservation and crime detection efforts. Full article

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23 pages, 1531 KiB

Open AccessReview

microRNAs (miRNAs) in Glioblastoma Multiforme (GBM)—Recent Literature Review

by Marianna Makowska, Beata Smolarz and Hanna Romanowicz

Int. J. Mol. Sci. 2023, 24(4), 3521; https://doi.org/10.3390/ijms24043521 - 9 Feb 2023

Cited by 28 | Viewed by 4203

Abstract

Glioblastoma multiforme (GBM) is the most common, malignant, poorly promising primary brain tumor. GBM is characterized by an infiltrating growth nature, abundant vascularization, and a rapid and aggressive clinical course. For many years, the standard treatment of gliomas has invariably been surgical treatment [...] Read more.

Glioblastoma multiforme (GBM) is the most common, malignant, poorly promising primary brain tumor. GBM is characterized by an infiltrating growth nature, abundant vascularization, and a rapid and aggressive clinical course. For many years, the standard treatment of gliomas has invariably been surgical treatment supported by radio- and chemotherapy. Due to the location and significant resistance of gliomas to conventional therapies, the prognosis of glioblastoma patients is very poor and the cure rate is low. The search for new therapy targets and effective therapeutic tools for cancer treatment is a current challenge for medicine and science. microRNAs (miRNAs) play a key role in many cellular processes, such as growth, differentiation, cell division, apoptosis, and cell signaling. Their discovery was a breakthrough in the diagnosis and prognosis of many diseases. Understanding the structure of miRNAs may contribute to the understanding of the mechanisms of cellular regulation dependent on miRNA and the pathogenesis of diseases underlying these short non-coding RNAs, including glial brain tumors. This paper provides a detailed review of the latest reports on the relationship between changes in the expression of individual microRNAs and the formation and development of gliomas. The use of miRNAs in the treatment of this cancer is also discussed. Full article

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29 pages, 10564 KiB

Open AccessArticle

Overnight Corticosterone and Gene Expression in Mouse Hippocampus: Time Course during Resting Period

by Aneta Jaszczyk, Adrian M. Stankiewicz, Joanna Goscik, Alicja Majewska, Tadeusz Jezierski and Grzegorz R. Juszczak

Int. J. Mol. Sci. 2023, 24(3), 2828; https://doi.org/10.3390/ijms24032828 - 1 Feb 2023

Cited by 2 | Viewed by 2559

Abstract

The aim of the experiment was to test the effect of an elevated level of glucocorticoids on the mouse hippocampal transcriptome after 12 h of treatment with corticosterone that was administered during an active phase of the circadian cycle. Additionally, we also tested [...] Read more.

The aim of the experiment was to test the effect of an elevated level of glucocorticoids on the mouse hippocampal transcriptome after 12 h of treatment with corticosterone that was administered during an active phase of the circadian cycle. Additionally, we also tested the circadian changes in gene expression and the decay time of transcriptomic response to corticosterone. Gene expression was analyzed using microarrays. Obtained results show that transcriptomic responses to glucocorticoids are heterogeneous in terms of the decay time with some genes displaying persistent changes in expression during 9 h of rest. We have also found a considerable overlap between genes regulated by corticosterone and genes implicated previously in stress response. The examples of such genes are Acer2, Agt, Apod, Aqp4, Etnppl, Fabp7, Fam107a, Fjx1, Fmo2, Galnt15, Gjc2, Heph, Hes5, Htra1, Jdp2, Kif5a, Lfng, Lrg1, Mgp, Mt1, Pglyrp1, Pla2g3, Plin4, Pllp, Ptgds, Ptn, Slc2a1, Slco1c1, Sult1a1, Thbd and Txnip. This indicates that the applied model is a useful tool for the investigation of mechanisms underlying the stress response. Full article

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17 pages, 98172 KiB

Open AccessArticle

Ultrastructural and Immunohistochemical Detection of Hydroxyapatite Nucleating Role by rRNA and Nuclear Chromatin Derivatives in Aortic Valve Calcification: In Vitro and In Vivo Pro-Calcific Animal Models and Actual Calcific Disease in Humans

by Antonella Bonetti, Magali Contin, Maurizio Marchini and Fulvia Ortolani

Int. J. Mol. Sci. 2023, 24(3), 2667; https://doi.org/10.3390/ijms24032667 - 31 Jan 2023

Cited by 2 | Viewed by 1539

Abstract

Calcification starts with hydroxyapatite (HA) crystallization on cell membranous components, as with aortic valve interstitial cells (AVICs), wherein a cell-membrane-derived substance containing acidic phospholipids (PPM/PPLs) acts as major crystal nucleator. Since nucleic acid removal is recommended to prevent calcification in valve biosubstitutes derived [...] Read more.

Calcification starts with hydroxyapatite (HA) crystallization on cell membranous components, as with aortic valve interstitial cells (AVICs), wherein a cell-membrane-derived substance containing acidic phospholipids (PPM/PPLs) acts as major crystal nucleator. Since nucleic acid removal is recommended to prevent calcification in valve biosubstitutes derived from decellularized valve scaffolds, the involvement of ribosomal RNA (rRNA) and nuclear chromatin (NC) was here explored in three distinct contexts: (i) bovine AVIC pro-calcific cultures; (ii) porcine aortic valve leaflets that had undergone accelerated calcification after xenogeneic subdermal implantation; and (iii) human aortic valve leaflets affected by calcific stenosis. Ultrastructurally, shared AVIC degenerative patterns included (i) the melting of ribosomes with PPM/PPLs, and the same for apparently well-featured NC; (ii) selective precipitation of silver particles on all three components after adapted von Kossa reactions; and (iii) labelling by anti-rRNA immunogold particles. Shared features were also provided by parallel light microscopy. In conclusion, the present results indicate that rRNA and NC contribute to AVIC mineralization in vitro and in vivo, with their anionic charges enhancing the HA nucleation capacity exerted by PPM/PPL substrates, supporting the concept that nucleic acid removal is needed for valve pre-implantation treatments, besides better elucidating the modality of pro-calcific cell death. Full article

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13 pages, 1494 KiB

Open AccessArticle

Alpha-Thalassemia in Southern Italy: Characterization of Five New Deletions Removing the Alpha-Globin Gene Cluster

by Giovanna Cardiero, Gennaro Musollino, Romeo Prezioso, Vincenzo Nigro and Giuseppina Lacerra

Int. J. Mol. Sci. 2023, 24(3), 2577; https://doi.org/10.3390/ijms24032577 - 30 Jan 2023

Cited by 1 | Viewed by 2510

Abstract

α-thalassemia is characterized in about 80% of cases by deletions generated by the presence of duplications and interspersed repeated sequences in the α-globin gene cluster. In a project on the molecular basis of α-thalassemia in Southern Italy, we identified six families, showing an [...] Read more.

α-thalassemia is characterized in about 80% of cases by deletions generated by the presence of duplications and interspersed repeated sequences in the α-globin gene cluster. In a project on the molecular basis of α-thalassemia in Southern Italy, we identified six families, showing an absence of the most common deletions, and normal α-globin gene sequences. Multiplex Ligation-dependent Probe Amplification (MLPA), qRT-PCR, and the sequencing of long-range PCR amplicon have been used for the identification and characterization of new deletions. MLPA analysis for the identification of α- and β-globin rearrangement revealed the presence of five new α-thalassemia deletions. The set-up of qRT-PCR allowed us to delimit the extent of the deletions ranging from about 10 kb to more than 250 kb, two of them being of the telomeric type. The long-range PCR generated a specific anomalous fragment in three deletions, and only several unspecific bands in the other two deletions. The sequencing of the anomalous amplicons revealed the breakpoints of two deletions: the --PA, 34 kb long, identified in two families, and the telomeric --AG, 274 kb long. The anomalous fragment containing the breakpoint of the deletion --FG was partially sequenced, and it was not possible to identify the breakpoints due to the presence of several repetitive Alu sequences. The analysis of the breakpoint regions of the --Sciacca and --Puglia, respectively, are about 10 and 165 kb long, and revealed the presence of repeats that most likely impaired the amplification of a specific fragment for the identification of the breakpoint. MLPA, in association with qRT-PCR and long-range PCR, is a good approach for the identification and molecular characterization of rare or new deletions. Breakpoint analysis confirms that Alu sequences play an important role in favoring unequal crossing-over. Southern Italy shows considerable genetic heterogeneity, as expected with its central position in the Mediterranean basin, favoring migratory flows. Full article

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18 pages, 3275 KiB

Open AccessArticle

A Simplified and Efficient Method for Production of Manganese Ferrite Magnetic Nanoparticles and Their Application in DNA Isolation

by Tímea B. Gerzsenyi, Ágnes M. Ilosvai, Gergely Szilágyi, Milán Szőri, Csaba Váradi, Béla Viskolcz, László Vanyorek and Emma Szőri-Dorogházi

Int. J. Mol. Sci. 2023, 24(3), 2156; https://doi.org/10.3390/ijms24032156 - 21 Jan 2023

Cited by 5 | Viewed by 2983

Abstract

A simplified, fast, and effective production method has been developed for the synthesis of manganese ferrite (MnFe₂O₄) magnetic nanoparticles (MNPs). In addition to the wide applicability of MnFe₂O₄ MNPs, this work also reports their application in [...] Read more.

A simplified, fast, and effective production method has been developed for the synthesis of manganese ferrite (MnFe₂O₄) magnetic nanoparticles (MNPs). In addition to the wide applicability of MnFe₂O₄ MNPs, this work also reports their application in DNA isolation for the first time. An ultrasonic-cavitation-assisted combustion method was applied in the synthesis of MnFe₂O₄ MNPs at different furnace temperatures (573 K, 623 K, 673 K, and 773 K) to optimize the particles’ properties. It was shown that MnFe₂O₄ nanoparticles synthesized at 573 K consist of a spinel phase only with adequate size and zeta potential distributions and superparamagnetic properties. It was also demonstrated that superparamagnetic manganese ferrite nanoparticles bind DNA in buffer with a high NaCl concentration (2.5 M), and the DNA desorbs from the MNPs by decreasing the NaCl concentration of the elution buffer. This resulted in a DNA yield comparable to that of commercial DNA extraction products. Both the DNA concentration measurements and electrophoresis confirmed that a high amount of isolated bacterial plasmid DNA (pDNA) with adequate purity can be extracted with MnFe₂O₄ (573 K) nanoparticles by applying the DNA extraction method proposed in this article. Full article

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16 pages, 3934 KiB

Open AccessArticle

The Chromosome-Level Genome of Hestina assimilis (Lepidoptera: Nymphalidae) Reveals the Evolution of Saprophagy-Related Genes in Brush-Footed Butterflies

by Lu Zhao, Xiao-Dong Li, Tao Jiang, Hang Wang, Zhicuo Dan, Sheng-Quan Xu and De-Long Guan

Int. J. Mol. Sci. 2023, 24(3), 2087; https://doi.org/10.3390/ijms24032087 - 20 Jan 2023

Viewed by 1830

Abstract

Most butterflies feed on nectar, while some saprophagous butterflies forage on various non-nectar foods. To date, little is known about the genomic and molecular shifts associated with the evolution of the saprophagous feeding strategy. Here, we assembled the high-quality chromosome-level genome of Hestina [...] Read more.

Most butterflies feed on nectar, while some saprophagous butterflies forage on various non-nectar foods. To date, little is known about the genomic and molecular shifts associated with the evolution of the saprophagous feeding strategy. Here, we assembled the high-quality chromosome-level genome of Hestina assimilis to explore its saprophagous molecular and genetic mechanisms. This chromosome-level genome of H. assimilis is 412.82 Mb, with a scaffold N50 of 15.70 Mb. In total, 98.11% of contigs were anchored to 30 chromosomes. Compared with H. assimilis and other Nymphalidae butterflies, the genes of metabolism and detoxification experienced expansions. We annotated 80 cytochrome P450 (CYP) genes in the H. assimilis genome, among which genes belonging to the CYP4 subfamily were significantly expanded (p < 0.01). These P450 genes were unevenly distributed and mainly concentrated on chromosomes 6–9. We identified 33 olfactory receptor (OR), 20 odorant-binding protein (OBP), and six gustatory receptor (GR) genes in the H. assimilis genome, which were fewer than in the nectarivorous Danaus plexippus. A decreased number of OBP, OR, and GR genes implied that H. assimilis should resort less to olfaction and gustation than their nectarivorous counterparts, which need highly specialized olfactory and gustatory functions. Moreover, we found one site under positive selection occurred in residue 996 (phenylalanine) of GR genes exclusive to H. assimilis, which is conservative in most lineages. Our study provides support for the adaptive evolution of feeding habits in butterflies. Full article

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22 pages, 2254 KiB

Open AccessReview

Noncoding RNAs: Master Regulator of Fibroblast to Myofibroblast Transition in Fibrosis

by Huamin Zhang, Yutong Zhou, Dada Wen and Jie Wang

Int. J. Mol. Sci. 2023, 24(2), 1801; https://doi.org/10.3390/ijms24021801 - 16 Jan 2023

Cited by 18 | Viewed by 3744

Abstract

Myofibroblasts escape apoptosis and proliferate abnormally under pathological conditions, especially fibrosis; they synthesize and secrete a large amount of extracellular matrix (ECM), such as α-SMA and collagen, which leads to the distortion of organ parenchyma structure, an imbalance in collagen deposition and degradation, [...] Read more.

Myofibroblasts escape apoptosis and proliferate abnormally under pathological conditions, especially fibrosis; they synthesize and secrete a large amount of extracellular matrix (ECM), such as α-SMA and collagen, which leads to the distortion of organ parenchyma structure, an imbalance in collagen deposition and degradation, and the replacement of parenchymal cells by fibrous connective tissues. Fibroblast to myofibroblast transition (FMT) is considered to be the main source of myofibroblasts. Therefore, it is crucial to explore the influencing factors regulating the process of FMT for the prevention, treatment, and diagnosis of FMT-related diseases. In recent years, non-coding RNAs, including microRNA, long non-coding RNAs, and circular RNAs, have attracted extensive attention from scientists due to their powerful regulatory functions, and they have been found to play a vital role in regulating FMT. In this review, we summarized ncRNAs which regulate FMT during fibrosis and found that they mainly regulated signaling pathways, including TGF-β/Smad, MAPK/P38/ERK/JNK, PI3K/AKT, and WNT/β-catenin. Furthermore, the expression of downstream transcription factors can be promoted or inhibited, indicating that ncRNAs have the potential to be a new therapeutic target for FMT-related diseases. Full article

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13 pages, 2784 KiB

Open AccessArticle

Heparin Specifically Interacts with Basic BBXB Motifs of the Chemokine CCL21 to Define CCR7 Signaling

by Marc Artinger, Oliver J. Gerken and Daniel F. Legler

Int. J. Mol. Sci. 2023, 24(2), 1670; https://doi.org/10.3390/ijms24021670 - 14 Jan 2023

Cited by 2 | Viewed by 2050

Abstract

Chemokines are critically involved in controlling directed leukocyte migration. Spatiotemporal secretion together with local retention processes establish and maintain local chemokine gradients that guide directional cell migration. Extracellular matrix proteins, particularly glycosaminoglycans (GAGs), locally retain chemokines through electrochemical interactions. The two chemokines CCL19 [...] Read more.

Chemokines are critically involved in controlling directed leukocyte migration. Spatiotemporal secretion together with local retention processes establish and maintain local chemokine gradients that guide directional cell migration. Extracellular matrix proteins, particularly glycosaminoglycans (GAGs), locally retain chemokines through electrochemical interactions. The two chemokines CCL19 and CCL21 guide CCR7-expressing leukocytes, such as antigen-bearing dendritic cells and T lymphocytes, to draining lymph nodes to initiate adaptive immune responses. CCL21—in contrast to CCL19—is characterized by a unique extended C-terminus composed of highly charged residues to facilitate interactions with GAGs. Notably, both chemokines can trigger common, but also ligand-biased signaling through the same receptor. The underlying molecular mechanism of ligand-biased CCR7 signaling is poorly understood. Using a series of naturally occurring chemokine variants in combination with newly designed site-specific chemokine mutants, we herein assessed CCR7 signaling, as well as GAG interactions. We demonstrate that the charged chemokine C-terminus does not fully confer CCL21-biased CCR7 signaling. Besides the positively charged C-terminus, CCL21 also possesses specific BBXB motifs comprising basic amino acids. We show that CCL21 variants where individual BBXB motifs are mutated retain their capability to trigger G-protein-dependent CCR7 signaling, but lose their ability to interact with heparin. Moreover, we show that heparin specifically interacts with CCL21, but not with CCL19, and thereby competes with ligand-binding to CCR7 and prevents signaling. Hence, we provide evidence that soluble heparin, but not the other GAGs, complexes with CCL21 to define CCR7 signaling in a ligand-dependent manner. Full article

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22 pages, 4315 KiB

Open AccessArticle

A New Face of the Old Gene: Deletion of the PssA, Encoding Monotopic Inner Membrane Phosphoglycosyl Transferase in Rhizobium leguminosarum, Leads to Diverse Phenotypes That Could Be Attributable to Downstream Effects of the Lack of Exopolysaccharide

by Małgorzata Marczak, Kamil Żebracki, Piotr Koper, Aleksandra Horbowicz, Magdalena Wójcik and Andrzej Mazur

Int. J. Mol. Sci. 2023, 24(2), 1035; https://doi.org/10.3390/ijms24021035 - 5 Jan 2023

Cited by 2 | Viewed by 1782

Abstract

The biosynthesis of subunits of rhizobial exopolysaccharides is dependent on glycosyltransferases, which are usually encoded by large gene clusters. PssA is a member of a large family of phosphoglycosyl transferases catalyzing the transfer of a phosphosugar moiety to polyprenol phosphate; thus, it can [...] Read more.

The biosynthesis of subunits of rhizobial exopolysaccharides is dependent on glycosyltransferases, which are usually encoded by large gene clusters. PssA is a member of a large family of phosphoglycosyl transferases catalyzing the transfer of a phosphosugar moiety to polyprenol phosphate; thus, it can be considered as priming glycosyltransferase commencing synthesis of the EPS repeating units in Rhizobium leguminosarum. The comprehensive analysis of PssA protein features performed in this work confirmed its specificity for UDP-glucose and provided evidence that PssA is a monotopic inner membrane protein with a reentrant membrane helix rather than a transmembrane segment. The bacterial two-hybrid system screening revealed interactions of PssA with some GTs involved in the EPS octasaccharide synthesis. The distribution of differentially expressed genes in the transcriptome of the ΔpssA mutant into various functional categories indicated complexity of cell response to the deletion, which can mostly be attributed to the lack of exopolysaccharide and downstream effects caused by such deficiency. The block in the EPS biosynthesis at the pssA step, potentially leading to an increased pool of UDP-glucose, is likely to be filtered through to other pathways, and thus the absence of EPS may indirectly affect the expression of proteins involved in these pathways. Full article

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11 pages, 2140 KiB

Open AccessArticle

The Human Pre-miRNA Distance Distribution for Exploring Disease Association

by Hsiuying Wang and Ching Ho

Int. J. Mol. Sci. 2023, 24(2), 1009; https://doi.org/10.3390/ijms24021009 - 5 Jan 2023

Cited by 2 | Viewed by 1586

Abstract

MicroRNAs (miRNAs), playing an important role in cell differentiation, development, gene regulation, and apoptosis, have attracted much attention in recent years. miRNAs were shown to be involved in the mechanisms of various diseases, and certainly, they can be employed as useful disease biomarkers. [...] Read more.

MicroRNAs (miRNAs), playing an important role in cell differentiation, development, gene regulation, and apoptosis, have attracted much attention in recent years. miRNAs were shown to be involved in the mechanisms of various diseases, and certainly, they can be employed as useful disease biomarkers. The phylogenetic tree analysis of miRNA biomarkers is a useful tool to investigate the association between various diseases as well as the association between viruses and disease. In addition to the phylogenetic tree analysis, a more advanced study is to use the miRNA distance distribution to evaluate the similarity of the miRNA biomarkers. The mature miRNA distance distribution based on mature miRNA sequences has been derived. The averages of the pairwise distances of miRNA biomarkers for several associated diseases were shown to be smaller than the overall mean of all miRNAs, which indicates the high similarity of miRNA biomarkers for associated diseases. In addition to the mature miRNA, the precursor miRNA (pre-miRNA) may be more useful to explore the similarity of miRNAs because the mature miRNA duplex is released from the pre-miRNA. Therefore, in this study, the distance distributions based on human pre-miRNA stem–loop sequences were derived. The 1917 human miRNA stem-loop sequences in the miRBase dataset were used to derive the pre-miRNA distance distribution, and this is the first study to provide the distance distribution based on the human pre-miRNAs. The similarity of miRNA biomarkers for several associated diseases or vaccines was examined using the derived distribution, and the results show that the similarity of pre-miRNA biomarkers may be a feasible way to help explore the disease association. Full article

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13 pages, 2208 KiB

Open AccessArticle

Multi-Omic Factors Associated with Frequency of Upper Respiratory Infections in Developing Infants

by Ramin Beheshti, E. Scott Halstead, Bryan Cusack and Steven D. Hicks

Int. J. Mol. Sci. 2023, 24(2), 934; https://doi.org/10.3390/ijms24020934 - 4 Jan 2023

Cited by 1 | Viewed by 1963

Abstract

Susceptibility to upper respiratory infections (URIs) may be influenced by host, microbial, and environmental factors. We hypothesized that multi-omic analyses of molecular factors in infant saliva would identify complex host-environment interactions associated with URI frequency. A cohort study involving 146 infants was used [...] Read more.

Susceptibility to upper respiratory infections (URIs) may be influenced by host, microbial, and environmental factors. We hypothesized that multi-omic analyses of molecular factors in infant saliva would identify complex host-environment interactions associated with URI frequency. A cohort study involving 146 infants was used to assess URI frequency in the first year of life. Saliva was collected at 6 months for high-throughput multi-omic measurement of cytokines, microRNAs, transcripts, and microbial RNA. Regression analysis identified environmental (daycare attendance, atmospheric pollution, breastfeeding duration), microbial (Verrucomicrobia, Streptococcus phage), and host factors (miR-22-5p) associated with URI frequency (p < 0.05). These results provide pathophysiologic clues about molecular factors that influence URI susceptibility. Validation of these findings in a larger cohort could one day yield novel approaches to detecting and managing URI susceptibility in infants. Full article

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12 pages, 2666 KiB

Open AccessReview

Glucose Homeostasis and Pancreatic Islet Size Are Regulated by the Transcription Factors Elk-1 and Egr-1 and the Protein Phosphatase Calcineurin

by Gerald Thiel and Oliver G. Rössler

Int. J. Mol. Sci. 2023, 24(1), 815; https://doi.org/10.3390/ijms24010815 - 3 Jan 2023

Cited by 2 | Viewed by 2026

Abstract

Pancreatic β-cells synthesize and secrete insulin. A key feature of diabetes mellitus is the loss of these cells. A decrease in the number of β-cells results in decreased biosynthesis of insulin. Increasing the number of β-cells should restore adequate insulin biosynthesis leading to [...] Read more.

Pancreatic β-cells synthesize and secrete insulin. A key feature of diabetes mellitus is the loss of these cells. A decrease in the number of β-cells results in decreased biosynthesis of insulin. Increasing the number of β-cells should restore adequate insulin biosynthesis leading to adequate insulin secretion. Therefore, identifying proteins that regulate the number of β-cells is a high priority in diabetes research. In this review article, we summerize the results of three sophisticated transgenic mouse models showing that the transcription factors Elk-1 and Egr-1 and the Ca²⁺/calmodulin-regulated protein phosphatase calcineurin control the formation of sufficiently large pancreatic islets. Impairment of the biological activity of Egr-1 and Elk-1 in pancreatic β-cells leads to glucose intolerance and dysregulation of glucose homeostasis, the process that maintains glucose concentration in the blood within a narrow range. Transgenic mice expressing an activated calcineurin mutant also had smaller islets and showed hyperglycemia. Calcineurin induces dephosphorylation of Elk-1 which subsequently impairs Egr-1 biosynthesis and the biological functions of Elk-1 and Egr-1 to regulate islet size and glucose homeostasis. Full article

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