Exogenous Regulators Research Articles

5178 TNFα-dependent altered miRNA expression regulates endometrial stromal cell proliferation

Abstract Disclosure: I. Chowdhury: None. S. Banerjee: None. W. Xu: None. A. Driss: None. C. Nezhat: None. N. Sidell: None. R.N. Taylor: None. W.E. Thompson: None. Abstract: Aberrant upregulation of cytokines, including tumor necrosis factor α (TNFα) and activation of nuclear factor κB (NF-κB) with disbalance of microRNAs (miRNAs) are often found in endometrium of endometriosis subjects, which causes directly or indirectly pelvic inflammation, pain, and infertility, Although, the pathophysiology of endometriosis is not clearly established yet, inflammation is an essential feature. MicroRNAs are emerging as potential regulatory factors in cellular processes such as cell growth, survival, migration, and invasion. In the current study, we examined the direct effects of exogenous recombinant TNFα dependent regulation of miRNAs involved in proliferation in primary cultures of normal endometrial stromal cells (NESC) and compared with the untreated cells derived from endometriosis-ESC (EESC). NanoString nCounter-based assays and quantitative real-time polymerase chain reaction (RT-PCR) were used to identify and validate differentially expressed miRNAs linked to cell proliferation in EESC compared to NESC and TNFα treated NESCs. The expression level of miRNAs linked to cell cycle was downregulated significantly in EESCs compared to NESCs. Interestingly, a dose and time-dependent exogenous TNFα treatment in NESCs showed a similar cell cycle regulator miRNAs expression pattern with EESCs. In further studies, protein analysis by Western Blots of selective cell cycle regulators such as PCNA, Ki67, CDK2, CDK4, CDK6, p21, and p27, and cell proliferation assay demonstrated an inverse correlation between cell cycle regulators and miRNA expression pattern both in EESC and TNFα treated NESCs. These findings suggest that TNFα dependent dysregulation of miRNAs in EESCs may promote proliferation of endometriosis. Further research is needed to investigate the detailed mechanisms by which TNFα regulates miRNA expression and determine these findings' potential therapeutic implications. Acknowledgments: This study was supported in part by National Institutes of Health Grants 1SC3 GM113751, 1SC1 GM130544, U01 HD66439, 1R01HD057235, U54 CA118948, HD41749, S21MD000101, and G12-RR03034. This investigation was conducted in a facility constructed with support from Research Facilities Improvement Grant #C06 RR18386 from NIH/NCRR. Presentation: 6/2/2024

Physiological Parameters and Transcriptomic Levels Reveal the Response Mechanism of Maize to Deep Sowing and the Mechanism of Exogenous MeJA to Alleviate Deep Sowing Stress

Deep sowing, as a method to mitigate drought and preserve soil moisture and seedlings, can effectively mitigate the adverse effects of drought stress on seedling growth. The elongation of the hypocotyl plays an important role in the emergence of maize seeds from deep-sowing stress. This study was designed to explore the function of exogenous methyl jasmonate (MeJA) in the growth of the maize mesocotyl and to examine its regulatory network. The results showed that the addition of a 1.5 μ mol L−1 MeJA treatment significantly increased the mesocotyl length (MES), mesocotyl and coleoptile length (MESCOL), and seedling length (SDL) of maize seedlings. Transcriptome analysis showed that exogenous MeJA can alleviate maize deep-sowing stress, and the differentially expressed genes (DEGs) mainly include ornithine decarboxylase, terpene synthase 7, ethylene responsive transcription factor 11, and so on. In addition, candidate genes that may regulate the length of maize hypocotyls were screened by Weighted Gene Co-expression Network Analysis (WGCNA). These genes may be involved in the growth of maize hypocotyls through transcriptional regulation, histones, ubiquitin protease, protein binding, and chlorophyll biosynthesis and play an important role in maize deep-sowing tolerance. Our research findings may provide a theoretical basis for determining the tolerance of maize to deep-sowing stress and the mechanism of exogenous hormone regulation of deep-sowing stress.

An Overview of the Mechanisms through Which Plants Regulate ROS Homeostasis under Cadmium Stress.

Cadmium (Cd2+) is a non-essential and highly toxic element to all organic life forms, including plants and humans. In response to Cd stress, plants have evolved multiple protective mechanisms, such as Cd2+ chelation, vesicle sequestration, the regulation of Cd2+ uptake, and enhanced antioxidant defenses. When Cd2+ accumulates in plants to a certain level, it triggers a burst of reactive oxygen species (ROS), leading to chlorosis, growth retardation, and potentially death. To counteract this, plants utilize a complex network of enzymatic and non-enzymatic antioxidant systems to manage ROS and protect cells from oxidative damage. This review systematically summarizes how various elements, including nitrogen, phosphorus, calcium, iron, and zinc, as well as phytohormones such as abscisic acid, auxin, brassinosteroids, and ethylene, and signaling molecules like nitric oxide, hydrogen peroxide, and hydrogen sulfide, regulate the antioxidant system under Cd stress. Furthermore, it explores the mechanisms by which exogenous regulators can enhance the antioxidant capacity and mitigate Cd toxicity.

Use of the Novel Site-Directed Enzyme Enhancement Therapy (SEE-Tx) Drug Discovery Platform to Identify Pharmacological Chaperones for Glutaric Acidemia Type 1.

Allosteric regulators acting as pharmacological chaperones hold promise for innovative therapeutics since they target noncatalytic sites and stabilize the folded protein without competing with the natural substrate, resulting in a net gain of function. Exogenous allosteric regulators are typically more selective than active site inhibitors and can be more potent than competitive inhibitors when the natural substrate levels are high. To identify novel structure-targeted allosteric regulators (STARs) that bind to and stabilize the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH), the computational site-directed enzyme enhancement therapy (SEE-Tx) technology was applied. SEE-Tx is an innovative drug discovery platform with the potential to identify drugs for treating protein misfolding disorders, such as glutaric acidemia type 1 (GA1) disease. Putative allosteric regulators were discovered using structure- and ligand-based virtual screening methods and validated using orthogonal biophysical and biochemical assays. The computational approach presented here could be used to discover allosteric regulators of other protein misfolding disorders.

Urban Lake Health Assessment Based on the Synergistic Perspective of Water Environment and Social Service Functions.

Urban lakes serve as vital ecological and recreational anchors within built environments, essential for enhancing urban resilience. Evaluating lake health predominantly focuses on water quality, assessing indicators such as nutrient levels, toxicity, pH balance, and water clarity to monitor changes. This study proposes a comprehensive evaluation framework that systematically describes specific spatiotemporal manifestations and periodic exogenous regulation characteristics across five dimensions: physical structure, water quality, shoreline dynamics, external regulation, and social service. Furthermore, it introduces an urban lake health assessment model based on synergistic development to evaluate the integrated development and interaction between water environments and social services. This model is applied across urban lakes in various developmental stages in China. Key findings include: 1) Urban development often impacts lake health disparately, with varying degrees of synergy observed between water environments and social services across different urban lakes. However, shifts in urban ideologies and improvements in governance, along with protective policies and project implementations, have contributed to improving water quality to some extent. 2) Engineering interventions do not consistently correspond with improvements in water quality, and governance measures sometimes yield mixed outcomes, underscoring the necessity for systematic solutions to lake health. Restoring hydrological processes emerges as crucial for enhancing sustainability.

Effects of Exogenous Regulation of PPARγ on Ovine Oocyte Maturation and Embryonic Development In Vitro.

Lactating oocytes consume a lot of energy during maturation, a large part of which comes from lipid metabolism. PPARγ is a key regulator of lipid metabolism. In this study, rosiglitazone (RSG), an activator of PPARγ, was added to a mature medium to investigate its effects on the levels of spindle and the chromosome arrangement, lipid deposition, reactive oxygen species (ROS), and glutathione (GSH) levels, oocyte secretion factors, apoptosis and lipid metabolism-related gene expression, and subsequent embryonic development during the maturation of sheep oocytes. The oocyte secretion factor affects gene expression related to apoptosis and lipid metabolism and subsequent embryonic development. The results showed that the proportion of spindle and normal chromosome arrangements increased in the 5 μM RSG treatment group, the lipid content increased after cell maturation, the ROS level decreased, and the GSH level increased. The expressions of oocyte secretion factor (GDF9 and BMP15), anti-apoptosis gene (BCL2), and lipid metabolism-related genes (ACAA1, CPT1A, PLIN2) were increased in the 5 μM treatment group. Finally, the development of blastocysts was examined. After the oocytes were treated with 5 μM RSG, the blastocyst rate and the gene expression of the totipotency gene (OCT4) were increased. It was concluded that increasing PPARγ activity during ovine oocyte maturation could promote lipid metabolism, reduce oxidative stress, and improve the ovine oocyte maturation rate and subsequent embryo development.

Metabolite and Transcriptome Profiling Analysis Provides New Insights into the Distinctive Effects of Exogenous Melatonin on Flavonoids Biosynthesis in Rosa rugosa.

Although the petals of Rosa rugosa are rich in flavonoids and their bioactivity has a significant impact on human health, the flavonoid content decreases during flower development. In this study, R. rugosa 'Feng hua' was used to investigate the effects of the melatonin foliar spray on enhancing the quality of rose by focusing on major flavonoids. The results showed that the contents of total flavonoids in rose petals at the full bloom stage induced by melatonin obeyed a bell-shaped curve, with a maximum at 0.3 mM, indicating the concentration-dependent up-regulation of flavonoid biosynthesis. In the treatment with 0.3 mM melatonin, metabolomic analyses showed that the concentrations of ten main flavonoids were identified to be increased by melatonin induction, with high levels and increases observed in three flavonols and two anthocyanins. KEGG enrichment of transcriptomic analysis revealed a remarkable enrichment of DEGs in flavonoid and flavonol biosynthesis, such as Rr4CL, RrF3H, and RrANS. Furthermore, functional validation using virus-induced gene silencing technology demonstrated that Rr4CL3 is the crucial gene regulating flavonoid biosynthesis in response to the stimulant of melatonin. This study provides insights into the exogenous melatonin regulation mechanism of biosynthesis of flavonoids, thereby offering potential industrial applications.

ERK5 promotes autocrine expression to sustain mitogenic balance for cell fate specification in human pluripotent stem cells

The homeostasis of human pluripotent stem cells (hPSCs) requires the signaling balance of extracellular factors. Exogenous regulators from cell culture medium have been widely reported, but little attention has been paid to the autocrine factor from hPSCs themselves. In this report, we demonstrate that extracellular signal-related kinase 5 (ERK5) regulates endogenous autocrine factors essential for pluripotency and differentiation. ERK5 inhibition leads to erroneous cell fate specification in all lineages even under lineage-specific induction. hPSCs can self-renew under ERK5 inhibition in the presence of fibroblast growth factor 2 (FGF2) and transforming growth factor β (TGF-β), although NANOG expression is partially suppressed. Further analysis demonstrates that ERK5 promotes the expression of autocrine factors such as NODAL, FGF8, and WNT3. The addition of NODAL protein rescues NANOG expression and differentiation phenotypes under ERK5 inhibition. We demonstrate that constitutively active ERK5 pathway allows self-renewal even without essential growth factors FGF2 and TGF-β. This study highlights the essential contribution of autocrine pathways to proper maintenance and differentiation.

Study of the Effect of Palmitic Acid on the Expression of Myostatin mRNA and its Cytotoxic Properties in the Culture of Myoblast Cells and the Possibility of Exogenous Regulation

Objective: To study the cytotoxic effect of palmitic acid on myoblasts in vitro and the influence of this toxicant on the expression of myostatin mRNA in myoblast culture. Methods: To research the protective action against these processes of a compound with antioxidant activity, for which 2-ethyl-6-methyl-3-hydroxypyridine malate (ethoxidol) was chosen. Results: Our studies have shown that palmitic acid has a noticeable cytostatic effect on myoblasts in vitro, significantly suppressing their proliferation: the rate of MTT recovery in myoblasts treated with palmitate was only 9.6% of that rate in control myoblasts. In experiments, it was shown that palmitic acid slightly activated the expression of myostatin mRNA. At the same time, the protective effect of 2-ethyl-6-methyl-3-hydroxypyridine malate was not so pronounced. Conclusion: The results of our research indicate that the activation of myostatin synthesis is not one of the main causes of the development of myodystrophy in obese people or people following a high-lipid diet, while the direct cytotoxic effect of palmitic acid on myoblasts is. It is obvious that the use of antioxidants such as ethoxide has a protective effect on myoblasts in the experiment and may have a certain potential in clinical practice.

Effect of Hb conformational changes on oxygen transport physiology.

Red blood cells (RBCs) are the primary mediators of oxygen transport in the human body, and their function is mainly achieved through conformational changes of hemoglobin (Hb). Hb is a tetramer composed of four subunits, with HbA being the predominant Hb in healthy adults, existing in two forms: tense state (T state) and relaxed state (R state). Endogenous regulators of Hb conformation include 2,3-diphosphoglyceric acid, carbon dioxide, protons, and chloride ions, while exogenous regulators include inositol hexaphosphate, inositol tripyrophosphate, benzabate, urea derivative L35, and vanillin, each with different mechanisms of action. The application of Hb conformational regulators provides new insights into the study of hypoxia oxygen supply issues and the treatment of sickle cell disease.

Integrated Transcriptomic and Metabolomic Analysis of Exogenous NAA Effects on Maize Seedling Root Systems under Potassium Deficiency.

Auxin plays a crucial role in regulating root growth and development, and its distribution pattern under environmental stimuli significantly influences root plasticity. Under K deficiency, the interaction between K+ transporters and auxin can modulate root development. This study compared the differences in root morphology and physiological mechanisms of the low-K-tolerant maize inbred line 90-21-3 and K-sensitive maize inbred line D937 under K-deficiency (K+ = 0.2 mM) with exogenous NAA (1-naphthaleneacetic acid, NAA = 0.01 mM) treatment. Root systems of 90-21-3 exhibited higher K+ absorption efficiency. Conversely, D937 seedling roots demonstrated greater plasticity and higher K+ content. In-depth analysis through transcriptomics and metabolomics revealed that 90-21-3 and D937 seedling roots showed differential responses to exogenous NAA under K-deficiency. In 90-21-3, upregulation of the expression of K+ absorption and transport-related proteins (proton-exporting ATPase and potassium transporter) and the enrichment of antioxidant-related functional genes were observed. In D937, exogenous NAA promoted the responses of genes related to intercellular ethylene and cation transport to K-deficiency. Differential metabolite enrichment analysis primarily revealed significant enrichment in flavonoid biosynthesis, tryptophan metabolism, and hormone signaling pathways. Integrated transcriptomic and metabolomic analyses revealed that phenylpropanoid biosynthesis is a crucial pathway, with core genes (related to peroxidase enzyme) and core metabolites upregulated in 90-21-3. The findings suggest that under K-deficiency, exogenous NAA induces substantial changes in maize roots, with the phenylpropanoid biosynthesis pathway playing a crucial role in the maize root's response to exogenous NAA regulation under K-deficiency.

Metal-Organic Framework-Based Nanomaterials for Regulation of the Osteogenic Microenvironment.

As the global population ages, bone diseases have become increasingly prevalent in clinical settings. These conditions often involve detrimental factors such as infection, inflammation, and oxidative stress that disrupt bone homeostasis. Addressing these disorders requires exogenous strategies to regulate the osteogenic microenvironment (OME). The exogenous regulation of OME can be divided into four processes: induction, modulation, protection, and support, each serving a specific purpose. To this end, metal-organic frameworks (MOFs) are an emerging focus in nanomedicine, which show tremendous potential due to their superior delivery capability. MOFs play numerous roles in OME regulation such as metal ion donors, drug carriers, nanozymes, and photosensitizers, which have been extensively explored in recent studies. This review presents a comprehensive introduction to the exogenous regulation of OME by MOF-based nanomaterials. By discussing various functional MOF composites, this work aims to inspire and guide the creation of sophisticated and efficient nanomaterials for bone disease management.

Exogenous melatonin promotes salt tolerance in smooth bromegrass seedlings: physiological, transcriptomic, and metabolomic evidence.

Soil salinization, which severely limits crop yield and quality, has become a global environmental and resource issue. Melatonin plays an important role in plant responses to salt stress. Smooth bromegrass is an important forage with excellent feed value and is widely grown in northern and north-west China for pasture and sand binding. However, the physiological and molecular mechanisms underlying exogenous melatonin regulation of salt stress in smooth bromegrass are not clear. This study compared the phenotype, physiological, transcriptome, and metabolome profiles of two varieties with contrasting salt tolerance attributes under salt and melatonin treatment. After melatonin treatment, the catalase (CAT) and ascorbate peroxidase (APX) activity, proline content, actual photochemical efficiency (Y(II)), relative water content, and fresh weight above ground were significantly higher than under salt treatment, while relative conductivity, H2O2 content, and Na+/K+ ratio were significantly lower than salt treatment. The transcriptome and metabolite profiling analysis of smooth bromegrass seedlings treated without melatonin under salt stress identified the presence of 22522 differentially expressed genes (DEGs) and 862 differentially expressed metabolites (DEMs) in SS, 17809 DEGs and 812 DEMs in ST, while treated with melatonin under salt stress identified the presence of 7033 DEGs and 177 DEMs in SS, 2951 DEGs and 545 DEMs in ST. Furthermore, in response to salt stress, melatonin may be involved in regulating the correlation between DEGs and DEMs in flavonoid biosynthesis, proline biosynthesis, and melatonin biosynthesis. Moreover, melatonin participated in mediating melatonin biosynthesis pathways and affected the expression of ASMT in response to salt stress.

The Specific Impact of Environmental Regulations on the Comparative Advantage of Resource-Based Industries

With the increasing emphasis on global environmental issues and the deepening of the concept of sustainable development, the application and impact of environmental regulation are becoming increasingly prominent. Especially for pollution-intensive products, the impact of environmental regulation on the import and export trade of different pollution-intensive products is subject to various factors. The impact of environmental regulation on different resource-based industries still needs a lot of research. Through the method of literature analysis, this paper integrates the literature on the impact of environmental regulation on resource-based industries and concludes that the overall impact of environmental regulation on resource-based industries is positive and significant. For the paper and pulp industry, both exogenous and endogenous environmental regulations have enhanced its comparative advantage. For the non-ferrous metal and non-metallic mineral industry, environmental regulation can promote its technological progress and gain comparative advantage.

Integrated transcriptomic and proteomic analysis of exogenous abscisic acid regulation on tuberous root development in Pseudostellaria heterophylla.

Abscisic acid (ABA) significantly regulates plant growth and development, promoting tuberous root formation in various plants. However, the molecular mechanisms of ABA in the tuberous root development of Pseudostellaria heterophylla are not yet fully understood. This study utilized Illumina sequencing and de novo assembly strategies to obtain a reference transcriptome associated with ABA treatment. Subsequently, integrated transcriptomic and proteomic analyses were used to determine gene expression profiles in P. heterophylla tuberous roots. ABA treatment significantly increases the diameter and shortens the length of tuberous roots. Clustering analysis identified 2,256 differentially expressed genes and 679 differentially abundant proteins regulated by ABA. Gene co-expression and protein interaction networks revealed ABA positively induced 30 vital regulators. Furthermore, we identified and assigned putative functions to transcription factors (PhMYB10, PhbZIP2, PhbZIP, PhSBP) that mediate ABA signaling involved in the regulation of tuberous root development, including those related to cell wall metabolism, cell division, starch synthesis, hormone metabolism. Our findings provide valuable insights into the complex signaling networks of tuberous root development modulated by ABA. It provided potential targets for genetic manipulation to improve the yield and quality of P. heterophylla, which could significantly impact its cultivation and medicinal value.

Anthocyanins as an element of nutritional support for athletes: effects and molecular mechanisms of action

Antioxidants are among the common components of sports nutrition designed to counteract oxidative stress that develops during intense physical activity. One of the promising antioxidants are anthocyanins which belong to polyphenolic compounds of plant origin (class of flavonoids). The purpose of the research was to analyze the results of prospective controlled studies on the effect of anthocyanins on physical performance, and to consider the possible molecular mechanisms of their action. Material and methods. Sources were searched in PubMed, Google Scholar, and CyberLeninka databases of peer-reviewed scientific literature without restrictions on the year of publication using the following keywords: anthocyanins, physical performance, recovery, sport and exercise nutrition, oxidative stress, inflammation. Results. The main data set on the effects of anthocyanins in athletes was obtained using extracts of blackcurrant and Montmorency tart cherry. Volunteers received anthocyanins at a dose of 86-547 mg per day for 1 to 10 days with subsequent evaluation of their performance in cycling, running and fitness activities. The possibility of favorable effect of anthocyanins on physical performance and acceleration of its recovery after exertion has been shown. The source, dose and duration of intake did not significantly influence the established effects of anthocyanins. Acting as exogenous regulators of metabolism, anthocyanins can activate several mechanisms of performance enhancement, including influence on antioxidant and immune status and apoptosis intensity. Anthocyanins prevent the formation of reactive oxygen species, neutralize electrophilic compounds by direct interaction or through activation of Nrf2 factor, which regulates the transcription of antioxidant enzyme genes. The basis of the anti-inflammatory action of anthocyanins is their ability to inhibit MARK and NF-κB mediated signal transduction. Inclusion of bilberry and blackcurrant extract in the diet prevented the intensification of myocyte apoptosis and suppression of cellular immunity induced by exhausting exercise. An additional mechanism of anthocyanin action on physical performance may be an increase in blood supply of organs and tissues due to vascular dilation caused by activation of endothelial nitric oxide synthase. Conclusion. The intake of plant extracts with a high anthocyanin content can increase physical performance and improve recovery after physical exertion, which may be due to the antioxidant and anti-inflammatory effects of anthocyanins, their ability to regulate apoptosis processes and improve blood supply to organs and tissues.

Effects of exogenous plant regulators on growth and development of "Kyoho" grape under salt alkali stress.

Salinity is one of the major abiotic stresses besides drought and cold stress. The application of plant growth regulators (PGRs) is an effective method to mitigate yield losses caused by salinity. However, we investigated the effects of exogenous regulatory substances (γ-aminobutyric acid (GABA), salicylic acid (SA), and brassinolide (BR) on the growth and development of "Kyoho" grapevine under salt stress. The results showed that exogenous regulators GABA, SA, and BR alleviated the inhibition of grape growth by saline stress and regulated the effects of salinity stress on grape fruit development and quality. All three regulators significantly increased fruit set, cross-sectional diameter, weight per unit, and anthocyanin content. In conclusion, this study provides a theoretical basis for grape production practices by using exogenous aminobutyric acid (GABA), salicylic acid (SA), and brassinolide (BR) to mitigate the hazards of salinity stress.

New insights into the dihydro-mureidomycin biosynthesis controlled by two unusual proteins in Streptomyces roseosporus

BackgroundUridyl peptide compounds are renowned as a subclass of nucleoside antibiotics for their highly specific antibacterial activity against Gram-negative bacteria and the unique target of action. We previously activated the biosynthetic gene cluster of a uridyl peptide antibiotic, mureidomycin, in Streptomyces roseosporus NRRL 15998 by introducing an exogenous positive regulator gene ssaA, and the generated strain was designated as Sr-hA. This study aims to further explore mureidomycin analogs from Sr-hA as well as the collaborative roles of two wide-spread genes, SSGG-02980 and SSGG-03002 encoding putative nuclease/phosphatase and oxidoreductase respectively, in mureidomycin diversification.ResultsIn order to understand how SSGG-02980 and SSGG-03002 contribute to mureidomycin biosynthesis, the gene disruption mutants and complementary strains were constructed. Mass spectrometry analyses revealed that two series of pairwise mureidomycin analogs were synthesized in Sr-hA with a two-dalton difference in molecular weight for each pair. By disruption of SSGG-03002, only mureidomycins with lower molecular weight (MRDs, 1–6) could be specifically accumulated in the mutant (∆03002-hA), whereas the other series of products with molecular weight plus 2 Da (rMRDs, 1ʹ–6ʹ) became dominant in SSGG-02980 disruption mutant (∆02980-hA). Further comprehensive NMR analyses were performed to elucidate the structures, and three MRDs (3, 4, 5) with unsaturated double bond at C5-C6 of uracil group were characterized from ∆03002-hA. In contrast, the paired rMRDs analogs (3ʹ, 4ʹ, 5ʹ) from ∆SSGG-02980 corresponding to 3, 4 and 5 were shown to contain a single bond at this position. The results verified that SSGG-03002 participates in the reduction of uracil ring, whereas SSGG-02980 antagonizes the effect of SSGG-03002, which has been rarely recognized for a phosphatase.ConclusionsOverall, this study revealed the key roles of two wide-spread families of enzymes in Streptomyces. Of them, oxidoreductase, SSGG-03002, is involved in dihydro-mureidomycin biosynthesis of S. roseosporus, whereas nuclease/phosphatase, SSGG-02980, has an adverse effect on SSGG-03002. This kind of unusual regulation model between nuclease/phosphatase and oxidoreductase is unprecedented, providing new insights into the biosynthesis of mureidomycins in Streptomyces. The findings would be of significance for structural diversification of more uridyl peptide antibiotics against Gram-negative bacteria.

CRISPR/Cas9 Directed Reprogramming of iPSC for Accelerated Motor Neuron Differentiation Leads to Dysregulation of Neuronal Fate Patterning and Function.

Neurodegeneration causes a significant disease burden and there are few therapeutic interventions available for reversing or slowing the disease progression. Induced pluripotent stem cells (iPSCs) hold significant potential since they are sourced from adult tissue and have the capacity to be differentiated into numerous cell lineages, including motor neurons. This differentiation process traditionally relies on cell lineage patterning factors to be supplied in the differentiation media. Genetic engineering of iPSC with the introduction of recombinant master regulators of motor neuron (MN) differentiation has the potential to shorten and streamline cell developmental programs. We have established stable iPSC cell lines with transient induction of exogenous LHX3 and ISL1 from the Tet-activator regulatory region and have demonstrated that induction of the transgenes is not sufficient for the development of mature MNs in the absence of neuron patterning factors. Comparative global transcriptome analysis of MN development from native and Lhx-ISL1 modified iPSC cultures demonstrated that the genetic manipulation helped to streamline the neuronal patterning process. However, leaky gene expression of the exogenous MN master regulators in iPSC resulted in the premature activation of genetic pathways characteristic of the mature MN function. Dysregulation of metabolic and regulatory pathways within the developmental process affected the MN electrophysiological responses.

Trichoderma-derived emodin competes with ExpR and ExpI of Pectobacterium carotovorum subsp. carotovorum to biocontrol bacterial soft rot.

Quorum sensing inhibitors (QSIs) are an emerging control tool that inhibits the quorum sensing (QS) system of pathogenic bacteria. We aimed to screen for potential QSIs in the metabolites of Trichoderma and to explore their inhibitory mechanisms. We screened a strain of Trichoderma asperellum LN004, which demonstrated the ability to inhibit the color development of Chromobacterium subtsugae CV026, primarily attributed to the presence of emodin as its key QSI component. The quantitative polymerase chain reaction with reverse transcription results showed that after emodin treatment of Pectobacterium carotovorum subsp. carotovorum (Pcc), plant cell wall degrading enzyme-related synthetic genes were significantly downregulated, and the exogenous enzyme synthesis gene negative regulator (rsmA) was upregulated 3.5-fold. Docking simulations indicated that emodin could be a potential ligand for ExpI and ExpR proteins because it exhibited stronger competition than the natural ligands in Pcc. In addition, western blotting showed that emodin attenuated the degradation of n-acylhomoserine lactone on the ExpR protein and protected it. Different concentrations of emodin reduced the activity of pectinase, cellulase, and protease in Pcc by 20.81%-72.21%, 8.38%-52.73%, and 3.57%-47.50%. Lesion size in Chinese cabbages, carrots and cherry tomatoes following Pcc infestation was reduced by 10.02%-68.57%, 40.17%-88.56% and 11.36%-86.17%. Emodin from T. asperellum LN004 as a QSI can compete to bind both ExpI and ExpR proteins, interfering with the QS of Pcc and reducing the production of virulence factors. The first molecular mechanism reveals the ability of emodin as a QSI to competitively inhibit two QS proteins simultaneously. © 2023 Society of Chemical Industry.