The m6A-ncRNAs axis in diabetes complications: novel mechanism and therapeutic potential.

Diabetes, a multifaceted metabolic disorder, poses a significant global health burden with its increasing prevalence and associated complications, such as diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, and diabetic angiopathy. Recent studies have highlighted the intricate interplay between N6-methyladenosine (m6A) and non-coding RNAs (ncRNAs) in key pathways implicated in these diabetes complications, like cell apoptosis, oxidative stress, and inflammation. Thus, understanding the mechanistic insights into how m6A dysregulation impacts the expression and function of ncRNAs opens new avenues for therapeutic interventions targeting the m6A-ncRNAs axis in diabetes complications. This review explores the regulatory roles of m6A modifications and ncRNAs, and stresses the role of the m6A-ncRNA axis in diabetes complications, providing a therapeutic potential for these diseases.

Two genes encoding caffeoyl coenzyme A O-methyltransferase 1 (CCoAOMT1) are candidate genes for physical seed dormancy in cowpea (Vigna unguiculata (L.) Walp.).

KEY MESSAGE: The major QTL Sdp1.1+ controlling seed dormancy in cowpea was finely mapped, and two CCoAOMT1 genes were identified as candidate genes for the dormancy. Seed dormancy in wild cowpea may be useful in breeding cultivated cowpea with pre-harvest sprouting resistance. A previous study identified a major quantitative trait locus (QTL) for seed dormancy, Sdp1.1+ , using the population of the cross between cultivated cowpea 'JP81610' and wild cowpea 'JP89083.' However, the molecular basis of seed dormancy in cowpea is not yet known. In this study, we aimed to finely map the locus Sdp1.1+ and identify candidate gene(s) for it. Germination tests demonstrated that the seed coat is the major factor controlling seed dormancy in the wild cowpea JP89083. Microscopic observations revealed that wild cowpea seeds, unlike cultivated cowpea seeds, possessed a palisade cuticle layer. Fine mapping using a large F2 population of the cross JP81610 × JP89083 grown in Thailand revealed a single QTL, Sdp1.1+ , controlling seed dormancy. The Sdp1.1+ was confirmed using a small F2 population of the same cross grown in Japan. The Sdp1.1+ was mapped to a 37.34-Kb region containing three genes. Two closely linked genes, Vigun03g278900 (VuCCoAOMT1a) and Vigun03g290000 (VuCCoAOMT1b), located 4.844 Kb apart were considered as candidate genes for seed dormancy. The two genes encoded caffeoyl coenzyme A O-methyltransferase 1 (CCoAOMT1). DNA sequencing and alignment of VuCCoAOMT1a and VuCCoAOMT1b between JP89083 and JP81610 revealed a single nucleotide polymorphism (SNP) causing an amino acid change in VuCCoAOMT1a and several SNPs leading to six amino acid changes in VuCCoAOMT1b. Altogether, these results indicate that VuCCoAOMT1a and VuCCoAOMT1b are candidate genes controlling physical seed dormancy in the wild cowpea JP89083.

A Cluster of Peronospora parasitica 13-like (NBS-LRR) Genes Is Associated with Powdery Mildew (Erysiphe polygoni) Resistance in Mungbean (Vigna radiata).

Powdery mildew (PM) caused by Erysiphe polygoni is an important foliar disease in mungbean (Vigna radiata). A previous study showed that QTL qPMRUM5-2 is a major locus for PM resistance in mungbean accession RUM5 (highly resistant). Bioinformatics analysis revealed that flanking markers of the qPMRUM5-2 covered a region of 1.93 Mb. In this study, we conducted fine mapping for the qPMRUM5-2 using the F2 population of 1156 plants of the cross between Chai Nat 60 (CN60; highly susceptible) and RUM5. PM resistance evaluation was performed under field conditions using F2:3 lines grown in three different environments. QTL analyses consistently located the qPMRUM5-2 to a 0.09 cm interval on linkage group 6 between InDel markers VrLG6-InDel05 and VrLG6-InDel10, which corresponded to a 135.0 kb region on chromosome 8 containing nine predicted genes of which five were NBS-LRR-type genes Recognition of Peronospora parasitica 13-like protein (RPP13L). Whole-genome re-sequencing of RUM5 and CN60 showed polymorphisms in four RPP13L genes predictively cause substantial amino acid changes, rendering them important candidate genes for PM resistance. The InDel markers VrLG6-InDel05 and VrLG6-InDel10 flanking to the qPMRUM5-2 would be useful for marker-assisted breeding of PM resistance in the mungbean.

Machine learning deciphers the significance of mitochondrial regulators on the diagnosis and subtype classification in non-alcoholic fatty liver disease.

Background: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent liver disease worldwide and lack of research on the diagnostic utility of mitochondrial regulators in NAFLD. Mitochondrial dysfunction plays a pivotal role in the development and progression of NAFLD, especially oxidative stress and acidity ß-oxidative overload. Thus, we aimed to identify and validate a panel of mitochondrial gene expression biomarkers for detection of NAFLD. Methods: We selected the GSE89632 dataset and identified key mitochondrial regulators by intersecting DEGs, WGCNA modules, and MRGs. Classification of NAFLD subtypes based on these key mitochondrial regulatory factors was performed, and the pattern of immune system infiltration in different NAFLD subtypes were also investigated. RF, LASSO, and SVM-RFE were employed to identify possible diagnostic biomarkers from key mitochondrial regulatory factors and the predictive power was demonstrated through ROC curves. Finally, we validated these potential diagnostic biomarkers in human peripheral blood samples and a high-fat diet-induced NAFLD mouse model. Results: We identified 25 key regulators of mitochondria and two NAFLD subtypes with different immune infiltration patterns. Four potential diagnostic biomarkers (BCL2L11, NAGS, HDHD3, and RMND1) were screened by three machine learning methods thereby establishing the diagnostic model, which showed favorable predictive power and achieved significant clinical benefit at certain threshold probabilities. Then, through internal and external validation, we identified and confirmed that BCL2L11 was significantly downregulated in NAFLD, while the other three were significantly upregulated. Conclusion: The four MRGs, namely BCL2L11, NAGS, HDHD3, and RMND1, are novel potential biomarkers for diagnosing NAFLD. A diagnostic model constructed using the four MRGs may aid early diagnosis of NAFLD in clinics.

Dendritic cells in Parkinson's disease: Regulatory role and therapeutic potential.

Parkinson's Disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons and the presence of Lewy bodies. While the traditional focus has been on neuronal and glial cell dysfunction, recent research has shifted towards understanding the role of the immune system, particularly dendritic cells (DCs), in PD pathogenesis. As pivotal antigen-presenting cells, DCs are traditionally recognized for initiating and regulating immune responses. In PD, DCs contribute to disease progression through the presentation of α-synuclein to T cells, leading to an adaptive immune response against neuronal elements. This review explores the emerging role of DCs in PD, highlighting their potential involvement in antigen presentation and T cell immune response modulation. Understanding the multifaceted functions of DCs could reveal novel insights into PD pathogenesis and open new avenues for therapeutic strategies, potentially altering the course of this devastating disease.

Identification of a novel matrix metalloproteinases-related prognostic signature in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide. Cancer cells' local infiltration, proliferation, and spread are mainly influenced by the protein hydrolyzing function of different matrix metalloproteinases (MMPs). However, no study has determined the relationship between MMPs and prognostic prediction in HCC. METHODS: Expression profiles of mRNA and MMPs-related genes were obtained from publicly available databases. Cox regression and LASSO Cox regression analysis were used to identify and predict MMPs-related prognostic signature and construct predictive models for overall survival (OS). A nomogram was used to validate the accuracy of the prediction model. Drug prediction was performed using the Genomics of Drug Sensitivity in Cancer (GDSC) dataset, and single-cell clustering analysis was performed to further understand the significance of the MMPs-related signature. RESULTS: A MMPs-related prognostic signature (including RNPEPL1, ADAM15, ADAM18, ADAMTS5, CAD, YME1L1, AMZ2, PSMD14, and COPS6) was identified. Using the median value, HCC patients in the high-risk group showed worse OS than those in the low-risk group. Immune microenvironment analysis showed that patients in the high-risk group had higher levels of M0 and M2 macrophages. Drug sensitivity analysis revealed that the IC50 values of sorafenib, cisplatin, and cytarabine were higher in the high-risk group. Finally, the single-cell cluster analysis results showed that YME1L1 and COPS6 were the major genes expressed in the monocyte cluster. CONCLUSIONS: A novel MMPs-related signature can be used to predict the prognosis of HCC. The findings of this research could potentially impact the predictability of the prognosis and treatment of HCC.

Roles and therapeutic targeting of dendritic cells in liver fibrosis.

Liver fibrosis is a common pathological condition marked by excessive accumulation of extracellular matrix proteins, resulting in irreversible cirrhosis and cancer. Dendritic cells (DCs) act as the crucial component of hepatic immunity and are believed to affect fibrosis by regulating the proliferation and differentiation of hepatic stellate cells (HSCs), a key mediator of fibrogenesis, and by interplaying with immune cells in the liver. This review concisely describes the process of fibrogenesis, and the phenotypic and functional characteristics of DCs in the liver. Besides, it focuses on the interaction between DCs and HSCs, T cells, and natural killer (NK) cells, as well as the dual roles of DCs in liver fibrosis, for the sake of exploring the potential of targeting DCs as a therapeutic strategy for the disease.

Cancer energy reprogramming and the immune responses.

Cancer as an uncontrolled growth of cells due to existing mutation in host cells that may proliferate, induce angiogenesis and sometimes metastasize due to the favorable tumor microenvironment (TME). Since it kills more than any disease, biomedical science does not relent in studying the exact pathogenesis. It was believed to be a problem that lies in the nucleus of the host cells; however, recent oncology findings are shifting attention to the mitochondria as an adjuvant to cancer pathogenesis. The changes in the gene are strongly related to cellular metabolism and metabolic reprogramming. It is now understood that reprogramming the TME will have a direct effect on the immune cells' metabolism. Although there are a number of studies on immune cells' response towards tumor energy reprogramming and cancer progression, there is still no existence with the updated collation of these immune cells' response to distinct energy reprogramming in cancer studies. To this end, this mini review shed some light on cancer energy reprogramming mechanisms and enzyme degradation pathways, the cancer pathogenicity activity series involved with reduced lactate production, the specific immune cell responses due to the energy reprogramming. This study highlighted some prospects and future experiments in harnessing the host immune response towards the altered energy metabolism due to cancer.

The regulatory role of miRNA and lncRNA on autophagy in diabetic nephropathy.

Diabetic nephropathy (DN) is a serious complication of diabetes that causes glomerular sclerosis and end-stage renal disease, leading to ascending morbidity and mortality in diabetic patients. Excessive accumulation of aberrantly modified proteins or damaged organelles, such as advanced glycation end-products, dysfunctional mitochondria, and inflammasomes is associated with the pathogenesis of DN. As one of the main degradation pathways, autophagy recycles toxic substances to maintain cellular homeostasis and autophagy dysregulation plays a crucial role in DN progression. MicroRNA (miRNA) and long non-coding RNA (lncRNA) are non-coding RNA (ncRNA) molecules that regulate gene expression and have been implicated in both physiological and pathological conditions. Recent studies have revealed that autophagy-regulating miRNA and lncRNA have been involved in pathological processes of DN, including renal cell injury, mitochondrial dysfunction, inflammation, and renal fibrosis. This review summarizes the role of autophagy in DN and emphasizes the modulation of miRNA and lncRNA on autophagy during disease progression, for the development of promising interventions by targeting these ncRNAs in this disease.

Channel-wise attention enhanced and structural similarity constrained cycleGAN for effective synthetic CT generation from head and neck MRI images.

BACKGROUND: Magnetic resonance imaging (MRI) plays an increasingly important role in radiotherapy, enhancing the accuracy of target and organs at risk delineation, but the absence of electron density information limits its further clinical application. Therefore, the aim of this study is to develop and evaluate a novel unsupervised network (cycleSimulationGAN) for unpaired MR-to-CT synthesis. METHODS: The proposed cycleSimulationGAN in this work integrates contour consistency loss function and channel-wise attention mechanism to synthesize high-quality CT-like images. Specially, the proposed cycleSimulationGAN constrains the structural similarity between the synthetic and input images for better structural retention characteristics. Additionally, we propose to equip a novel channel-wise attention mechanism based on the traditional generator of GAN to enhance the feature representation capability of deep network and extract more effective features. The mean absolute error (MAE) of Hounsfield Units (HU), peak signal-to-noise ratio (PSNR), root-mean-square error (RMSE) and structural similarity index (SSIM) were calculated between synthetic CT (sCT) and ground truth (GT) CT images to quantify the overall sCT performance. RESULTS: One hundred and sixty nasopharyngeal carcinoma (NPC) patients who underwent volumetric-modulated arc radiotherapy (VMAT) were enrolled in this study. The generated sCT of our method were more consistent with the GT compared with other methods in terms of visual inspection. The average MAE, RMSE, PSNR, and SSIM calculated over twenty patients were 61.88 ± 1.42, 116.85 ± 3.42, 36.23 ± 0.52 and 0.985 ± 0.002 for the proposed method. The four image quality assessment metrics were significantly improved by our approach compared to conventional cycleGAN, the proposed cycleSimulationGAN produces significantly better synthetic results except for SSIM in bone. CONCLUSIONS: We developed a novel cycleSimulationGAN model that can effectively create sCT images, making them comparable to GT images, which could potentially benefit the MRI-based treatment planning.

The connection between epigenetics and gut microbiota-current perspective.

Both the epigenetic changes and gut microbiota (GM) have attracted a growing interest in establishing effective diagnostics and potential therapeutic strategies for a number of diseases. These disorders include metabolic, central nervous system-related diseases, autoimmune, and gastrointestinal infections (GI). Despite the number of studies, there is no extensive review that connects the epigenetics modifications and GM as biomarkers that could confer effective diagnostics and confer treatment options. To this end, this review hopes to give detailed information on connecting the modifications in epigenetic and GM. An updated and detailed information on the connection between the epigenetics factors and GM that influence diseases are given. In addition, the review showed some associations between the epigenetics to the maternal GM and offspring health. Finally, the limitations of the concept and prospects into this new emerging discipline were also looked into. Although this review elucidated on the maternal diet and response to offspring health with respect to GM and epigenetic modifications, there still exist various limitations to this newly emerging discipline. In addition to integrating complementary multi-omics data, longitudinal sampling will aid with the identification of functional mechanisms that may serve as therapeutic targets. To this end, this review gave a detailed perspective into harnessing disease diagnostics, prevention and treatment options through epigenetics and GM.

Crosstalk between m6A modification and non-coding RNAs in HCC.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide, with high morbidity and occurrence. Although various therapeutic approaches have been rapidly developed in recent years, the underlying molecular mechanisms in the pathogenesis of HCC remain enigmatic. The N6-methyladenosine (m6A) RNA modification is believed to regulate RNA metabolism and further gene expression. This process is intricately regulated by multiple regulators, such as methylases and demethylases. Non-coding RNAs (ncRNAs) are involved in the regulation of the epigenetic modification, mRNA transcription and other biological processes, exhibiting crucial roles in tumor occurrence and development. The m6A-ncRNA interaction has been implicated in the malignant phenotypes of HCC and plays an important role in drug resistance. This review summarizes the effect of m6A-ncRNA crosstalk on HCC progression and their clinical implications as prognostic markers and therapeutic targets in this disease.

Pathological α-synuclein detected by real-time quaking-induced conversion in synucleinopathies.

synucleinopathies are diseases characterized by the aggregation of α-synuclein (α-syn), which forms fibrils through misfolding and accumulates in a prion-like manner. To detect the presence of these α-syn aggregates in clinical samples, seed amplification assays (SAAs) have been developed. These SAAs are capable of amplifying the α-syn seeds, allowing for their detection. αSyn-SAAs have been reported under the names 'protein misfolding cyclic amplification' (αSyn-PMCA) and 'real-time quaking-induced conversion'α-Syn-RT-QuIC. The α-Syn RT-QuIC, in particular, has been adapted to amplify and detect α-syn aggregates in various biospecimens, including cerebrospinal fluid (CSF), skin, nasal brushing, serum and saliva. The α-syn RT-QuIC assay has demonstrated good sensitivity and specificity in detecting pathological α-syn, particularly in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) cases, with an accuracy rate of up to 80 %. Additionally, differential diagnosis between DLB and PD, as well as PD and multiple system atrophy (MSA), can be achieved by utilizing certain kinetic thioflavin T (ThT) parameters and other parameters. Moreover, the positive detection of α-syn in the prodromal stage of synucleinopathies provides an opportunity for early intervention and management. In summary, the development of the α-syn RT-QuIC assay has greatly contributed to the field of synucleinopathies. Therefore, we review the development of α-syn RT-QuIC assay and describe in detail the recent advancements of α-syn RT-QuIC assay for detecting pathological α-syn in synucleinopathies.

Identification of a Branch Number Locus in Soybean Using BSA-Seq and GWAS Approaches.

The determination of the soybean branch number plays a pivotal role in plant morphogenesis and yield components. This polygenic trait is subject to environmental influences, and despite its significance, the genetic mechanisms governing the soybean branching number remain incompletely understood. To unravel these mechanisms, we conducted a comprehensive investigation employing a genome-wide association study (GWAS) and bulked sample analysis (BSA). The GWAS revealed 18 SNPs associated with the soybean branch number, among which qGBN3 on chromosome 2 emerged as a consistently detected locus across two years, utilizing different models. In parallel, a BSA was executed using an F2 population derived from contrasting cultivars, Wandou35 (low branching number) and Ruidou1 (high branching number). The BSA results pinpointed a significant quantitative trait locus (QTL), designated as qBBN1, located on chromosome 2 by four distinct methods. Importantly, both the GWAS and BSA methods concurred in co-locating qGBN3 and qBBN1. In the co-located region, 15 candidate genes were identified. Through gene annotation and RT-qPCR analysis, we predicted that Glyma.02G125200 and Glyma.02G125600 are candidate genes regulating the soybean branch number. These findings significantly enhance our comprehension of the genetic intricacies regulating the branch number in soybeans, offering promising candidate genes and materials for subsequent investigations aimed at augmenting the soybean yield. This research represents a crucial step toward unlocking the full potential of soybean cultivation through targeted genetic interventions.

The emerging roles of N6-methyladenosine RNA modifications in thyroid cancer.

Thyroid cancer (TC) is the most predominant malignancy of the endocrine system, with steadily growing occurrence and morbidity worldwide. Although diagnostic and therapeutic methods have been rapidly developed in recent years, the underlying molecular mechanisms in the pathogenesis of TC remain enigmatic. The N6-methyladenosine(m6A) RNA modification is designed to impact RNA metabolism and further gene regulation. This process is intricately regulated by a variety of regulators, such as methylases and demethylases. Aberrant m6A regulators expression is related to the occurrence and development of TC and play an important role in drug resistance. This review comprehensively analyzes the effect of m6A methylation on TC progression and the potential clinical value of m6A regulators as prognostic markers and therapeutic targets in this disease.

Comparative transcriptome analysis reveals key pathways and regulatory networks in early resistance of Glycine max to soybean mosaic virus.

As a high-value oilseed crop, soybean [Glycine max (L.) Merr.] is limited by various biotic stresses during its growth and development. Soybean mosaic virus (SMV) is a devastating viral infection of soybean that primarily affects young leaves and causes significant production and economic losses; however, the synergistic molecular mechanisms underlying the soybean response to SMV are largely unknown. Therefore, we performed RNA sequencing on SMV-infected resistant and susceptible soybean lines to determine the molecular mechanism of resistance to SMV. When the clean reads were aligned to the G. max reference genome, a total of 36,260 genes were identified as expressed genes and used for further research. Most of the differentially expressed genes (DEGs) associated with resistance were found to be enriched in plant hormone signal transduction and circadian rhythm according to Kyoto Encyclopedia of Genes and Genomes analysis. In addition to salicylic acid and jasmonic acid, which are well known in plant disease resistance, abscisic acid, indole-3-acetic acid, and cytokinin are also involved in the immune response to SMV in soybean. Most of the Ca2+ signaling related DEGs enriched in plant-pathogen interaction negatively influence SMV resistance. Furthermore, the MAPK cascade was involved in either resistant or susceptible responses to SMV, depending on different downstream proteins. The phytochrome interacting factor-cryptochrome-R protein module and the MEKK3/MKK9/MPK7-WRKY33-CML/CDPK module were found to play essential roles in soybean response to SMV based on protein-protein interaction prediction. Our findings provide general insights into the molecular regulatory networks associated with soybean response to SMV and have the potential to improve legume resistance to viral infection.

Non-coding RNA regulation of macrophage function in asthma.

As a chronic respiratory disease, asthma is related to airway inflammation and remodeling. Macrophages are regarded as main innate immune cells in the airway that exert various functions like antigen recognition and presentation, phagocytosis, and pathogen clearance, playing a crucial role in the pathogeneses of asthma. Non-coding RNAs (ncRNAs), mainly include microRNA, long non-coding RNA and circular RNA, have been extensively investigated on the regulation of pathological process in asthma. Recent studies have indicated that ncRNA-regulated macrophages affect macrophage polarization, airway inflammation, immune regulation and airway remodeling, which suggests that modulating macrophages by ncRNAs may be a promising strategy for the treatment of asthma. This review summarizes the effect of macrophages in asthma and the regulatory mechanisms of ncRNAs, as well as focuses on the role of ncRNAs-regulated macrophages in asthma, for the development of novel therapeutic strategies in this disease.

MiR-669b-5p inhibits the Alzheimer's disease development via regulation of CHEK2 in Neuro2a APPSwe/Δ9 cells.

DNA damage of neurons is accumulated in Alzheimer's disease (AD). DNA damage-activated Checkpoint kinase 2 (CHEK2) is evaluated in Aß-treated Neuro2a APPSwe/Δ9 cells, and the miR-669b-5p was specifically down-regulated. However, the underlying molecular mechanism between CHEK2 and miR-669b-5p in Neuro2a APPSwe/Δ9 cells remains unclear. This research discovers that in A-treated Neuro2a APPSwe/Δ9 cells, CHEK2 expression and miR-669b-5p expression were inversely correlated. In addition, miR-669b-5p mimics increased cell survival and proliferation in Neuro2a APPSwe/Δ9 cells while decreasing the production of inflammatory cytokines and cell death. Furthermore, it is observed that CHEK2 was a miR-669b-5p downstream target gene and that CHEK2 restored the miR-669b-5p's functions. According to this research, miR-669b-5p is a potential therapy for Alzheimer's patients since it slows the advancement of the disease.

A Gene Encoding Xylanase Inhibitor Is a Candidate Gene for Bruchid (Callosobruchus spp.) Resistance in Zombi Pea (Vigna vexillata (L.) A. Rich).

Two bruchid species, Callosobruchus maculatus and Callosobruchus chinensis, are the most significant stored insect pests of tropical legume crops. Previously, we identified a major QTL, qBr6.1, controlling seed resistance to these bruchids in the cultivated zombi pea (Vigna vexillata) accession 'TVNu 240'. In this study, we have narrowed down the qBr6.1 region and identified a candidate gene conferring this resistance. Fine mapping using F2 and F2:3 populations derived from a cross between TVNu 240 and TVNu 1623 (susceptible) revealed the existence of two tightly linked QTLs, designated qBr6.1-A and qBr6.1-B, within the qBr6.1. The QTLs qBr6.1-A and qBr6.1-B explained 37.46% and 10.63% of bruchid resistance variation, respectively. qBr6.1-A was mapped to a 28.24 kb region containing four genes, from which the gene VvTaXI encoding a xylanase inhibitor was selected as a candidate gene responsible for the resistance associated with the qBr6.1-A. Sequencing and sequence alignment of VvTaXI from TVNu 240 and TVNu 1623 revealed a 1-base-pair insertion/deletion and five single-nucleotide polymorphisms (SNPs) in the 5' UTR and 11 SNPs in the exon. Alignment of the VvTAXI protein sequences showed five amino acid changes between the TVNu 240 and TVNu 1623 sequences. Altogether, these results demonstrated that the VvTaXI encoding xylanase inhibitor is the candidate gene conferring bruchid resistance in the zombi pea accession TVNu 240. The gene VvTaXI will be useful for the molecular breeding of bruchid resistance in the zombi pea.