CVD-associated SNPs with regulatory potential reveal novel non-coding disease genes.

BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Genome-wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) appearing in non-coding genomic regions in CVDs. The SNPs may alter gene expression by modifying transcription factor (TF) binding sites and lead to functional consequences in cardiovascular traits or diseases. To understand the underlying molecular mechanisms, it is crucial to identify which variations are involved and how they affect TF binding. METHODS: The SNEEP (SNP exploration and analysis using epigenomics data) pipeline was used to identify regulatory SNPs, which alter the binding behavior of TFs and link GWAS SNPs to their potential target genes for six CVDs. The human-induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs), monoculture cardiac organoids (MCOs) and self-organized cardiac organoids (SCOs) were used in the study. Gene expression, cardiomyocyte size and cardiac contractility were assessed. RESULTS: By using our integrative computational pipeline, we identified 1905 regulatory SNPs in CVD GWAS data. These were associated with hundreds of genes, half of them non-coding RNAs (ncRNAs), suggesting novel CVD genes. We experimentally tested 40 CVD-associated non-coding RNAs, among them RP11-98F14.11, RPL23AP92, IGBP1P1, and CTD-2383I20.1, which were upregulated in hiPSC-CMs, MCOs and SCOs under hypoxic conditions. Further experiments showed that IGBP1P1 depletion rescued expression of hypertrophic marker genes, reduced hypoxia-induced cardiomyocyte size and improved hypoxia-reduced cardiac contractility in hiPSC-CMs and MCOs. CONCLUSIONS: IGBP1P1 is a novel ncRNA with key regulatory functions in modulating cardiomyocyte size and cardiac function in our disease models. Our data suggest ncRNA IGBP1P1 as a potential therapeutic target to improve cardiac function in CVDs.

Screening and Identification of Garlic Leaf Blight (Pleospora herbarum)-Resistant Mutants Induced by Ethyl Methane Sulphonate.

Garlic (Allium sativum L.) is a popular condiment used as both medicine and food. Garlic production in China is severely affected by continuous cropping and is especially affected by leaf blight disease. Garlic is sterile, so it is very important to develop specialized genotypes, such as those for disease resistance, nutritional quality, and plant architecture, through genetic modification and innovation. In this experiment, we applied the induction method using EMS to mutate garlic cloves of cultivar G024. From the mutations, 5000 M0 mutants were generated and planted in the field. Then, 199 M1 mutant lines were screened according to growth potential and resistance to leaf blight. From M2 to M3, 169 generational lines were selected that grew well and were resistant to leaf blight in the field. Thereafter, their resistance to leaf blight was further analyzed in the lab; 21 lines resistant to leaf blight that had good growth potential were identified, among which 3 mutants were significantly different, and these were further screened. Also, transcriptome analysis of two mutants infected with Pleospora herbarum, A150 and G024, was performed, and the results revealed 2026 and 4678 differentially expressed genes (DEGs), respectively. These DEGs were highly enriched in hormone signaling pathway, plant-pathogen interaction, and MAPK signaling pathway. Therefore, the results provide a theoretical and technical basis for the creation of garlic germplasm resistant to leaf blight.

Mitochondrial-cell cycle cross-talk drives endoreplication in heart disease.

Endoreplication, duplication of the nuclear genome without cell division, occurs in disease to drive morphologic growth, cell fate, and function. Despite its criticality, the metabolic underpinnings of disease-induced endoreplication and its link to morphologic growth are unknown. Heart disease is characterized by endoreplication preceding cardiac hypertrophy. We identify ATP synthase as a central control node and determinant of cardiac endoreplication and hypertrophy by rechanneling free mitochondrial ADP to methylenetetrahydrofolate dehydrogenase 1 L (MTHFD1L), a mitochondrial localized rate-limiting enzyme of formate and de novo nucleotide biosynthesis. Concomitant activation of the adenosine monophosphate­activated protein kinase (AMPK)­retinoblastoma protein (Rb)-E2F axis co-opts metabolic products of MTHFD1L function to support DNA endoreplication and pathologic growth. Gain- and loss-of-function studies in genetic and surgical mouse heart disease models and correlation in individuals confirm direct coupling of deregulated energetics with endoreplication and pathologic overgrowth. Together, we identify cardiometabolic endoreplication as a hitherto unknown mechanism dictating pathologic growth progression in the failing myocardium.

Transcriptomic and Histological Analysis of the Response of Susceptible and Resistant Cucumber to Meloidogyne incognita Infection Revealing Complex Resistance via Multiple Signaling Pathways.

The root-knot nematode (RKN), Meloidogyne incognita, is a devastating pathogen for cucumber (Cucumis sativus L.) specially in production under protected environments or continuous cropping. High level RKN resistance has been identified in African horned melon Cucumis metuliferus (CM). However, the resistance mechanism remains unclear. In this study, the comparative analysis on phenotypic and transcriptomic responses in the susceptible cucumber inbred line Q24 and the resistant CM, after M. incognita infection, was performed. The results showed that, in comparison with Q24, the CM was able to significantly reduce penetration numbers of second stage juveniles (J2), slow its development in the roots resulting in fewer galls and smaller giant cells suggesting the presence of host resistance in CM. Comparative transcriptomes analysis of Q24 and CM before and after M. incognita infection was conducted and differentially expressed genes (DEGs) associated with host resistance were identified in CM. Enrichment analyses revealed most enriched DEGs in Ca2+ signaling, salicylic acid (SA)/jamonate signaling (JA), as well as auxin (IAA) signaling pathways. In particular, in CM, DEGs in the Ca2+ signaling pathway such as those for the calmodulin and calcium-binding proteins were upregulated at the early stage of M. incognita infection; genes for SA/JA synthesis/signal transduction were markedly activated, whereas the IAA signaling pathway genes were inhibited upon infection suggesting the importance of SA/JA signaling pathways in mediating M. incognita resistance in CM. A model was established to explain the different molecular mechanisms on M. incognita susceptibility in cucumber and resistance to M. incognita infection in CM.

Comparing the diagnostic value of 18F-FDG-PET/CT versus CT for differentiating benign and malignant solitary pulmonary nodules: a meta-analysis.

BACKGROUND: This quantitative meta-analysis was conducted to provide an indirect comparison of the diagnostic value of computed tomography (CT) with positron emission tomography (PET)/CT for differentiating benign and malignant solitary pulmonary nodules (SPNs). METHODS: PubMed, Embase, and the Cochrane Library were searched to identify eligible studies throughout November 2018, which differentiated benign and malignant SPNs using CT or PET/CT. The summary sensitivity, specificity, positive and negative likelihood ratio (PLR and NLR), diagnostic odds ratio (DOR), and area under the receiver operating characteristic curve (AUC) were calculated using bivariate generalized linear mixed model and random-effects model. The diagnostic value of CT with PET/CT was indirectly evaluated using the ratio for diagnostic parameters. RESULTS: The sensitivity, specificity, PLR, NLR, DOR, and AUC for CT were 0.94 [95% confidence interval (CI): 0.87-0.97], 0.73 (95% CI: 0.64-0.80), 3.45 (95% CI: 2.60-4.58), 0.09 (95% CI: 0.04-0.17), 32.01 (95% CI: 15.10-67.86), and 0.89 (95% CI: 0.86-0.91), respectively. The pooled sensitivity, specificity, PLR, NLR, DOR, and AUC for PET/CT were 0.89 (95% CI: 0.85-0.92), 0.78 (95% CI: 0.66-0.86), 3.97 (95% CI: 2.57-6.13), 0.15 (95% CI: 0.10-0.20), 24.04 (95% CI: 12.71-45.48), and 0.91 (95% CI: 0.89-0.94), respectively. No significant differences were observed between CT and PET/CT for sensitivity, specificity, PLR, NLR, DOR, and AUC. CONCLUSIONS: This study used both CT and PET/CT with a moderate-to-high diagnostic value for differentiating benign and malignant SPNs and showed no significant differences in diagnostic parameters between CT and PET/CT.

[Clinical observation on selection of acupoints on the same nerve segment for treatment of prolapxe of lumber intervertebral disc].

OBJECTIVE: To search for an effective therapy for prolapse of lumber intervertebral disc. METHODS: One hundred and sixteen cases of such disease were randomly divided into a treatment group (n=66) and a control group (n=50). They were treated respectively with needling acupoints at the same nervous segment and acupoints selected routinely. The clinical therapeutic effects after 2 and 3 courses were observed. RESULTS: The cured and markedly effective rate of 2 courses and the cured rate of 3 courses were 90.9% and 74.2% in the treatment group, respectively, which were better than 66.0% and 32.0% in the control group (P < 0.01). CONCLUSION: The acupoint selection of the same nervous segment is an effective therapy for prolapse of lumber intervertebral disc.