Allele-specific RNA N 6-methyladenosine modifications reveal functional genetic variants in human tissues.

An intricate network of cis- and trans-elements acts on RNA N 6-methyladenosine (m6A), which in turn may affect gene expression and, ultimately, human health. A complete understanding of this network requires new approaches to accurately measure the subtle m6A differences arising from genetic variants, many of which have been associated with common diseases. To address this gap, we developed a method to accurately and sensitively detect transcriptome-wide allele-specific m6A (ASm6A) from MeRIP-seq data and applied it to uncover 12,056 high-confidence ASm6A modifications from 25 human tissues. We also identified 1184 putative functional variants for ASm6A regulation, a subset of which we experimentally validated. Importantly, we found that many of these ASm6A-associated genetic variants were enriched for common disease-associated and complex trait-associated risk loci, and verified that two disease risk variants can change m6A modification status. Together, this work provides a tool to detangle the dynamic network of RNA modifications at the allelic level and highlights the interplay of m6A and genetics in human health and disease.

Mitochondrial Outer Membrane Translocase MoTom20 Modulates Mitochondrial Morphology and Is Important for Infectious Growth of the Rice Blast Fungus Magnaporthe oryzae.

Mitochondria are highly dynamic organelles that constantly change their morphology to adapt to the cellular environment through fission and fusion, which is critical for a cell to maintain normal cellular functions. Despite the significance of this process in the development and pathogenicity of the rice blast fungus Magnaporthe oryzae, the underlying mechanism remains largely elusive. Here, we identified and characterized a mitochondrial outer membrane translocase, MoTom20, in M. oryzae. Targeted gene deletion revealed that MoTom20 plays an important role in vegetative growth, conidiogenesis, penetration, and infectious growth of M. oryzae. The growth rate, conidial production, appressorium turgor, and pathogenicity are decreased in the ΔMotom20 mutant compared with the wild-type and complemented strains. Further analysis revealed that MoTom20 localizes in mitochondrion and plays a key role in regulating mitochondrial fission and fusion balance, which is critical for infectious growth. Finally, we found that MoTom20 is involved in fatty-acid utilization, and its yeast homolog ScTom20 is able to rescue the defects of ΔMotom20 in mitochondrial morphology and pathogenicity. Overall, our data demonstrate that MoTom20 is a key regulator for mitochondrial morphology maintenance, which is important for infectious growth of the rice blast fungus M. oryzae. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Common and unique neural mechanisms of social and nonsocial conflict resolving and adaptation.

Humans often need to deal with various forms of information conflicts that arise when they receive inconsistent information. However, it remains unclear how we resolve them and whether the brain may recruit similar or distinct brain mechanisms to process different domains (e.g. social vs. nonsocial) of conflicts. To address this, we used functional magnetic resonance imaging and scanned 50 healthy participants when they were asked to perform 2 Stroop tasks with different forms of conflicts: social (i.e. face-gender incongruency) and nonsocial (i.e. color-word incongruency) conflicts. Neuroimaging results revealed that the ventral lateral prefrontal cortex was generally activated in processing incongruent versus congruent stimuli regardless of the task type, serving as a common mechanism for conflict resolving across domains. Notably, trial-based and model-based results jointly demonstrated that the dorsal and rostral medial prefrontal cortices were uniquely engaged in processing social incongruent stimuli, suggesting distinct neural substrates of social conflict resolving and adaptation. The findings uncover that the common but unique brain mechanisms are recruited when humans resolve and adapt to social conflicts.

New Antifungal and Antifeedant Metabolites from Daldinia eschscholtzii Cocultured with Colletotrichum pseudomajus.

The synchronous co-culture of Daldinia eschscholtzii and Colletotrichum pseudomajus produced one new linear polyketide, eschscholin C (1), along with three known compounds (2-4). One new acorane sesquiterpene, coldaldrin A (5), and one new amide derivative, coldaldamide A (6) as the probe for polyketide intermediate capture, and three known compounds (7-9) were isolated from the sequential co-culture of D. eschscholtzii with C. pseudomajus. The structures and absolute configurations of 1, 5 and 6 were established by spectroscopic analysis including 1D, 2D NMR, the calculations of the NMR, and ECD data. Most compounds showed significant antifungal activities against the tea pathogens C. pseudomajus, and Fusarium asiaticum with MICs of 2-8 µg/mL. Compound 4 also showed antifeedant activity against silkworms with feeding deterrence indices of 79% at the concentration of 50 µg/cm2.

Mutation of CsARC6 affects fruit color and increases fruit nutrition in cucumber.

KEY MESSAGE: A mutation of CsARC6 not only causes white fruit color in cucumber, but also affects plant growth and fruit quality. Fruit color of cucumber is a very important agronomic trait, but most of the genes affecting cucumber white fruit color are still unknow, and no further studies were reported on the effect of cucumber fruit quality caused by white fruit color genes. Here, we obtained a white fruit mutant em41 in cucumber by EMS mutagenesis. The mutant gene was mapped to a 548 kb region of chromosome 2. Through mutation site analysis, it was found to be a null allele of CsARC6 (CsaV3_2G029290). The Csarc6 mutant has a typical phenotype of arc6 mutant that mesophyll cells contained only one or two giant chloroplasts. ARC6 protein was not detected in em41, and the level of FtsZ1 and FtsZ2 was also reduced. In addition, FtsZ2 could not form FtsZ ring-like structures in em41. Although these are typical arc6 mutant phenotypes, some special phenotypes occur in Csarc6 mutant, such as dwarfness with shortened internodes, enlarged fruit epidermal cells, decreased carotenoid contents, smaller fruits, and increased fruit nutrient contents. This study discovered a new gene, CsARC6, which not only controls the white fruit color, but also affects plant growth and fruit quality in cucumber.

cncRNAdb: a manually curated resource of experimentally supported RNAs with both protein-coding and noncoding function.

RNA endowed with both protein-coding and noncoding functions is referred to as 'dual-function RNA', 'binary functional RNA (bifunctional RNA)' or 'cncRNA (coding and noncoding RNA)'. Recently, an increasing number of cncRNAs have been identified, including both translated ncRNAs (ncRNAs with coding functions) and untranslated mRNAs (mRNAs with noncoding functions). However, an appropriate database for storing and organizing cncRNAs is still lacking. Here, we developed cncRNAdb, a manually curated database of experimentally supported cncRNAs, which aims to provide a resource for efficient manipulation, browsing and analysis of cncRNAs. The current version of cncRNAdb documents about 2600 manually curated entries of cncRNA functions with experimental evidence, involving more than 2,000 RNAs (including over 1300 translated ncRNAs and over 600 untranslated mRNAs) across over 20 species. In summary, we believe that cncRNAdb will help elucidate the functions and mechanisms of cncRNAs and develop new prediction methods. The database is available at http://www.rna-society.org/cncrnadb/.

Paricalcitol improved cardiac hypertrophy and fibrosis through upregulation of fibroblast growth factor-23 and downregulation of transforming growth factor-beta in a rat model of isoproterenol-induced cardiomyopathy.

Acute cardiomyopathy is a significant global health concern and one of the leading causes of death in developed countries. Prior studies have shown an association between acute cardiomyopathy and low vitamin D levels. Although paricalcitol, a vitamin D receptor (VDR) activator, has demonstrated clinical benefits in patients with advanced kidney disease, its effect on cardiac remodeling in cardiomyopathy is unknown. This study aimed to investigate the relative effects of paricalcitol on cardiomyopathy in rats. Wistar-Kyoto rats were administered vehicle (sham control group) or isoproterenol to induce cardiomyopathy. Rats administered isoproterenol were subsequently treated with paricalcitol (experimental group) or vehicle (isoproterenol group). Picrosirius red and immunofluorescence staining were used to analyze cardiac fibrosis and hypertrophy. Immunohistochemistry staining was used to confirm the molecular mechanisms involved in isoproterenol-induced cardiomyopathy in rats. Injection of paricalcitol could reduce collagen and transforming growth factor-beta 1 (TGF-ß1) levels while activating fibroblast growth factor receptor 1 (FGFR1) and fibroblast growth factor-23 (FGF23) without the help of Klotho, thereby reducing myocardial hypertrophy and fibrosis. As a VDR activator, paricalcitol reduces isoproterenol-induced cardiac fibrosis and hypertrophy by reducing the expression of TGF-ß1 and enhancing the expression of VDR, FGFR1, and FGF23.

Genome-wide association analysis reveals a novel QTL CsPC1 for pericarp color in cucumber.

BACKGROUND: Cucumber is an important melon crop in the world, with different pericarp colors. However, the candidate genes and the underlying genetic mechanism for such an important trait in cucumber are unknown. In this study, a locus controlling pericarp color was found on chromosome 3 of cucumber genome. RESULTS: In this study, the light green inbred line G35 and the dark green inbred line Q51 were crossed to produce one F2 population. Consequently, we identified a major locus CsPC1 (Pericarp color 1). Next, we mapped the CsPC1 locus to a 94-kb region chromosome 3 which contains 15 genes. Among these genes, Csa3G912920, which encodes a GATA transcription factor, was expressed at a higher level in the pericarp of the NIL-1334 line (with light-green pericarp) than in that of the NIL-1325 line (with dark-green pericarp). This study provides a new allele for the improvement of cucumber pericarp color. CONCLUSION: A major QTL that controls pericarp color in cucumber, CsPC1, was identified in a 94-kb region that harbors the strong candidate gene CsGATA1.

Fine mapping of a novel QTL CsFSG1 for fruit skin gloss in cucumber (Cucumis sativus L.).

Cucumber (Cucumis sativus L.) is an important vegetable crop that is popular with many people. Peel gloss is a highly valued external quality trait that affects the market value of cucumbers, and it directly influences the purchasing psychology of consumers. Nonetheless, the candidate genes and underlying genetic mechanism for this important cucumber trait are not well understood. In this study, we successfully mapped a fruit skin gloss QTL interval to chromosome 3 (26.04-26.14 Mb) using BSA and GWAS methods. Among the eleven candidate genes in the interval, the cytochrome P450 family gene CsCYP86B1 was identified as the candidate for control of fruit skin gloss in cucumber. The expression of CsCYP86B1 in 0-day fruit skin was significantly lower in the low-gloss isogenic line NIL-1334 than in the high-gloss isogenic line NIL-1325. Our findings provide new insights for improving fruit skin gloss in cucumber breeding. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-022-01291-y.

Progress in the Self-Regulation System in Legume Nodule Development-AON (Autoregulation of Nodulation).

The formation and development of legumes nodules requires a lot of energy. Legumes must strictly control the number and activity of nodules to ensure efficient energy distribution. The AON system can limit the number of rhizobia infections and nodule numbers through the systemic signal pathway network that the aboveground and belowground parts participate in together. It can also promote the formation of nodules when plants are deficient in nitrogen. The currently known AON pathway includes four parts: soil NO3- signal and Rhizobium signal recognition and transmission, CLE-SUNN is the negative regulation pathway, CEP-CRA2 is the positive regulation pathway and the miR2111/TML module regulates nodule formation and development. In order to ensure the biological function of this important approach, plants use a variety of plant hormones, polypeptides, receptor kinases, transcription factors and miRNAs for signal transmission and transcriptional regulation. This review summarizes and discusses the research progress of the AON pathway in Legume nodule development.

Preparation, characterization, and antibacterial activity of tigecycline-loaded, ultrasound-activated microbubbles.

Central nervous system infectious disease caused by the multidrug-resistant Acinetobacter baumannii (AB) seriously threatens human life in clinic. Tigecycline has good sensitivity in killing AB, but due to its wide tissue distribution and blood-brain barrier, concentration in cerebrospinal fluid is low, therefore, the clinical effect is limited. Herein, we designed micro-bubbled tigecycline, aimed to enhance its anti-MDRAB effects under ultrasound. The lipid microbubbles with different ratios of lipids to drugs (a ratio of 10:1, 20:1, and 40:1) were prepared by the mechanical shaking method. The morphology, zeta potential and particle size of microbubbles were tested to screen out the much better formulation. Encapsulation efficiency and drug loading amount were determined by ultracentrifugation combined with high-performance liquid chromatography. Then the in vitro antibacterial activity against AB was conducted using the selected ultrasound-activated microbubble. Results showed the selected microbubbles with high encapsulation efficiency and good stability. The mechanical shaking method is feasible for preparation of drug-loaded and ultrasound-activated lipid microbubbles. Using 0.2 mg/mL microbubbles, combined with 1 MHz, 2.5 W/cm2 and 1 min of ultrasound exhibited a potent anit-AB in vitro. This study indicates that tigecycline treatment in form of ultrasound-activated microbubble is a promising strategy against AB infections.

An Optical Fiber Lateral Displacement Measurement Method and Experiments Based on Reflective Grating Panel.

An optical fiber sensing method based on a reflective grating panel is demonstrated for lateral displacement measurement. The reflective panel is a homemade grating with a periodic variation of its refractive index, which is used to modulate the reflected light intensity. The system structure and operation principle are illustrated in detail. The intensity calculation and simulation of the optical path are carried out to theoretically analyze the measurement performance. A distinctive fiber optic grating ruler with a special fiber optic measuring probe and reflective grating panel is set up. Experiments with different grating pitches are conducted, and long-distance measurements are executed to accomplish the functions of counting optical signals, subdivision, and discerning direction. Experimental results show that the proposed measurement method can be used to detect lateral displacement, especially for applications in working environments with high temperatures.

Eplerenone improves hyperglycemia and sympathetic excitation in chronic renocardiac syndrome in rats.

We aimed to assess the efficacy of eplerenone, a steroidal mineralocorticoid receptor antagonist known to reduce blood pressure and mitigate cardiovascular disease (CVD) progression, in retarding the progression of chronic kidney disease (CKD) and CVD in a rat model of type 4 cardiorenal syndrome (CRS). We grouped rats into four experimental categories: sham surgery, sham treatment with eplerenone, nephrectomy without eplerenone (Nx), and nephrectomy with eplerenone (Nx + EP). For the Nx + EP group, rats received five-sixths nephrectomy, inducing CKD and CVD conditions such as renal hypertension and hyperglycemia, and were then treated with eplerenone (100 mg/kg/day, orally) over 4 weeks after an initial 4-week observation period. Heart rate, blood pressure, blood sugar levels, and sympathetic nerve excitation were monitored biweekly. In addition, assessments of renal and cardiac tissues, including evaluation of renal tubulointerstitial injury, glomerular injury, and cardiomyocyte hypertrophy, were conducted at week 8. Eplerenone administration mitigated CKD and CVD progression in the Nx + EP group, evident by improved blood pressure (217.3 ± 5.4 versus 175.3 ± 5.6), blood sugar (121.8 ± 1.3 versus 145.6 ± 6.0) level, reduced sympathetic nerve excitation, and cardiomyocyte hypertrophy compared to the Nx group. However, renal tubulointerstitial injury, glomerular injury, and cardiovascular dysfunction, which were increased in rats with type 4 CRS, did not show significant changes with eplerenone treatment. Our study demonstrated that eplerenone treatment did not exacerbate type 4 CRS but improved blood pressure, blood sugar levels, sympathetic nerve excitation, and cardiomyocyte hypertrophy in this model.

Systems genetics identifies methionine as a high risk factor for Alzheimer's disease.

As a dietary strategy, methionine restriction has been reported to promote longevity and regulate metabolic disorders. However, the role and possible regulatory mechanisms underlying methionine in neurodegenerative diseases such as Alzheimer's disease (AD), remain unexplored. This study utilized the data from BXD recombinant inbred (RI) mice to establish a correlation between the AD phenotype in mice and methionine level. Gene enrichment analysis indicated that the genes associated with the concentration of methionine in the midbrain are involved in the dopaminergic synaptic signaling pathway. Protein interaction network analysis revealed that glycogen synthase kinase 3 beta (GSK-3ß) was a key regulator of the dopaminergic synaptic pathway and its expression level was significantly correlated with the AD phenotype. Finally, in vitro experiments demonstrated that methionine deprivation could reduce the expression of Aß and phosphorylated Tau, suggesting that lowering methionine levels in humans may be a preventive or therapeutic strategy for AD. In conclusion, our findings support that methionine is a high risk factor for AD. These findings predict potential regulatory network, theoretically supporting methionine restriction to prevent AD.

The biological behavior and clinical outcome of pituitary adenoma are affected by the microenvironment.

BACKGROUND: Pituitary adenoma is one of the most common brain tumors. Most pituitary adenomas are benign and can be cured by surgery and/or medication. However, some pituitary adenomas show aggressive growth with a fast growth rate and are resistant to conventional treatments such as surgery, drug therapy, and radiation therapy. These tumors, referred to as refractory pituitary adenomas, often relapse or regrow in the early postoperative period. The tumor microenvironment (TME) has recently been identified as an important factor affecting the biological manifestations of tumors and acts as the main battlefield between the tumor and the host immune system. MAIN BODY: In this review, we focus on describing TME in pituitary adenomas and refractory pituitary adenomas. Research on the immune microenvironment of pituitary adenomas is currently focused on immune cells such as macrophages and lymphocytes, and extensive research and experimental verifications are still required regarding other components of the TME. In particular, studies are needed to determine the role of the TME in the specific biological behaviors of refractory pituitary adenomas, such as high invasion, fast recurrence rate, and high tolerance to traditional treatments and to identify the mechanisms involved. CONCLUSION: Overall, we summarize the similarities and differences between the TME of pituitary adenomas and refractory pituitary adenomas as well as the changes in the biological behavior of pituitary adenomas that may be caused by the microenvironment. These changes greatly affect the outcome of patients.

SGK1 Target Genes Involved in Heart and Blood Vessel Functions in PC12 Cells.

Serum and glucocorticoid-regulated kinase 1 (SGK1) is expressed in neuronal cells and involved in the pathogenesis of hypertension and metabolic syndrome, regulation of neuronal function, and depression in the brain. This study aims to identify the cellular mechanisms and signaling pathways of SGK1 in neuronal cells. In this study, the SGK1 inhibitor GSK650394 is used to suppress SGK1 expression in PC12 cells using an in vitro neuroscience research platform. Comparative transcriptomic analysis was performed to investigate the effects of SGK1 inhibition in nervous cells using mRNA sequencing (RNA-seq), differentially expressed genes (DEGs), and gene enrichment analysis. In total, 12,627 genes were identified, including 675 and 2152 DEGs at 48 and 72 h after treatment with GSK650394 in PC12 cells, respectively. Gene enrichment analysis data indicated that SGK1 inhibition-induced DEGs were enriched in 94 and 173 genes associated with vascular development and functional regulation and were validated using real-time PCR, Western blotting, and GEPIA2. Therefore, this study uses RNA-seq, DEG analysis, and GEPIA2 correlation analysis to identify positive candidate genes and signaling pathways regulated by SGK1 in rat nervous cells, which will enable further exploration of the underlying molecular signaling mechanisms of SGK1 and provide new insights into neuromodulation in cardiovascular diseases.

Adoptive macrophage directed photodynamic therapy of multidrug-resistant bacterial infection.

Multidrug-resistant (MDR) bacteria cause severe clinical infections and a high mortality rate of over 40% in patients with immunodeficiencies. Therefore, more effective, broad-spectrum, and accurate treatment for severe cases of infection is urgently needed. Here, we present an adoptive transfer of macrophages loaded with a near-infrared photosensitizer (Lyso700D) in lysosomes to boost innate immunity and capture and eliminate bacteria through a photodynamic effect. In this design, the macrophages can track and capture bacteria into the lysosomes through innate immunity, thereby delivering the photosensitizer to the bacteria within a single lysosome, maximizing the photodynamic effect and minimizing the side effects. Our results demonstrate that this therapeutic strategy eliminated MDR Staphylococcus aureus (MRSA) and Acinetobacter baumannii (AB) efficiently and cured infected mice in both two models with 100% survival compared to 10% in the control groups. Promisingly, in a rat model of central nervous system bacterial infection, we performed the therapy using bone marrow-divided macrophages and implanted glass fiber to conduct light irradiation through the lumbar cistern. 100% of infected rats survived while none of the control group survived. Our work proposes an efaficient and safe strategy to cure MDR bacterial infections, which may benefit the future clinical treatment of infection.

Silver doped-silica nanoparticles reinforced poly (ethylene glycol) diacrylate/hyaluronic acid hydrogel dressings for synergistically accelerating bacterial-infected wound healing.

Various cutaneous wounds are easily infected with external bacteria, which might result in a chronic wound and ongoing consequences. However, the appropriate development of biomaterials for the controllable delivery of antibacterial silver (Ag) and the simultaneous enhancement of mechanical adhesiveness remains an urgent challenge. Herein, we proposed a double network (DN) hydrogel dressings based on a covalent network of polyethylene glycol diacrylate (PEGDA) and a coordination network between catechol-modified hyaluronic acid (C-HA) and Ag-doped mesoporous silica nanoparticle (AMSN) for promoting the bacterial-infected full-thickness skin wound regeneration. This distinctive dual cross-linked structure of PEGDA/C-HA-AMSN significantly improved physicochemical properties, including gelation time, mechanical performance, and tissue adhesion strength. Importantly, PEGDA/C-HA-AMSN served as a hydrogel dressing that can respond to the acidic environment of bacterial-infected wounds leading to the controllable and optimized delivery of Ag, enabling the durable antibacterial activity accompanied by favorable cytocompatibility and angiogenesis capability. Further in vivo studies validated the higher efficacy of hydrogel dressings in treating wound healing by the synergistic antibacterial, anti-inflammatory, and pro-vascular strategies, meaning the prominent potential of the prepared dressings for overcoming the concerns of wound theranostics.

Variations on the theme: focus on cerebellum and emotional processing.

The cerebellum operates exploiting a complex modular organization and a unified computational algorithm adapted to different behavioral contexts. Recent observations suggest that the cerebellum is involved not just in motor but also in emotional and cognitive processing. It is therefore critical to identify the specific regional connectivity and microcircuit properties of the emotional cerebellum. Recent studies are highlighting the differential regional localization of genes, molecules, and synaptic mechanisms and microcircuit wiring. However, the impact of these regional differences is not fully understood and will require experimental investigation and computational modeling. This review focuses on the cellular and circuit underpinnings of the cerebellar role in emotion. And since emotion involves an integration of cognitive, somatomotor, and autonomic activity, we elaborate on the tradeoff between segregation and distribution of these three main functions in the cerebellum.