Evaluation of maize varieties via multivariate analysis: Roles of ionome, antioxidants, and autophagy in salt tolerance.

Salt stress presents a major obstacle to maize (Zea mays L.) production globally, impeding its growth and development. In this study, we aimed to identify salt-tolerant maize varieties through evaluation using multivariate analysis and shed light on the role of ionome, antioxidant capacity, and autophagy in salt tolerance. We investigated multiple growth indices, including shoot fresh weight, shoot dry weight, plant height, chlorophyll content, electrolyte leakage, potassium and sodium contents, and potassium-to-sodium ratio, in 20 maize varieties at the V3 stage under salt stress (200 mm NaCl). The results showed significant differences in the growth indices, accompanied by a wide range in their coefficient of variation, suggesting their suitability for screening salt tolerance. Based on D values, clustering analysis categorized the 20 varieties into 4 distinct groups. TG88, KN20, and LR888 (group I) emerged as the most salt-tolerant varieties, while YD9, XD903, and LH151 (group IV) were identified as the most sensitive. TG88 showcased nutrient preservation and redistribution under salt stress, surpassing YD9. It maintained nitrogen and iron levels in roots, while YD9 experienced decreases. TG88 redistributed more nitrogen, zinc, and potassium to its leaves, outperforming YD9. TG88 preserved sulfur levels in both roots and leaves, unlike YD9. Additionally, TG88 demonstrated higher enzymatic antioxidant capacity (superoxide dismutase, peroxidase, ascorbate peroxidase, and glutathione reductase) at both the enzyme and gene expression levels, upregulation of autophagy-related (ATG) genes (ZmATG6, ZmATG8a, and ZmATG10), and increased autophagic activity. Overall, this study offers insights into accurate maize varieties evaluation methods and the physiological mechanisms underlying salt tolerance and identifies promising materials for further research.

Modulating endothelial cell dynamics in fat grafting: the impact of DLL4 siRNA via adipose stem cell extracellular vesicles.

In the context of improving the efficacy of autologous fat grafts (AFGs) in reconstructive surgery, this study delineates the novel use of adipose-derived mesenchymal stem cells (ADSCs) and their extracellular vesicles (EVs) as vehicles for delivering delta-like ligand 4 (DLL4) siRNA. The aim was to inhibit DLL4, a gene identified through transcriptome analysis as a critical player in the vascular endothelial cells of AFG tissues, thereby negatively affecting endothelial cell functions and graft survival through the Notch signaling pathway. By engineering ADSC EVs to carry DLL4 siRNA (ADSC EVs-siDLL4), the research demonstrated a marked improvement in endothelial cell proliferation, migration, and lumen formation, and enhanced angiogenesis in vivo, leading to a significant increase in the survival rate of AFGs. This approach presents a significant advancement in the field of tissue engineering and regenerative medicine, offering a potential method to overcome the limitations of current fat grafting techniques.NEW & NOTEWORTHY This study introduces a groundbreaking method for enhancing autologous fat graft survival using adipose-derived stem cell extracellular vesicles (ADSC EVs) to deliver DLL4 siRNA. By targeting the delta-like ligand 4 (DLL4) gene, crucial in endothelial cell dynamics, this innovative approach significantly improves endothelial cell functions and angiogenesis, marking a substantial advancement in tissue engineering and regenerative medicine.

Genetic landscape of human mitochondrial genome using whole-genome sequencing.

Increasing evidences suggest that mitochondrial dysfunction is implicated in diseases and aging, and whole-genome sequencing (WGS) is the most unbiased method in analyzing the mitochondrial genome (mtDNA). However, the genetic landscape of mtDNA in the Chinese population has not been fully examined. Here, we described the genetic landscape of mtDNA using WGS data from Chinese individuals (n = 3241). We identified 3892 mtDNA variants, of which 3349 (86%) were rare variants. Interestingly, we observed a trend toward extreme heterogeneity of mtDNA variants. Our study observed a distinct purifying selection on mtDNA, which inhibits the accumulation of harmful heteroplasmies at the individual level: (1) mitochondrial dN/dS ratios were much <1; (2) the dN/dS ratio of heteroplasmies was higher than homoplasmies; (3) heteroplasmies had more indels and predicted deleterious variants than homoplasmies. Furthermore, we found that haplogroup M (20.27%) and D (20.15%) had the highest frequencies in the Chinese population, followed by B (18.51%) and F (16.45%). The number of variants per individual differed across haplogroup groups, with a higher number of homoplasmies for the M lineage. Meanwhile, mtDNA copy number was negatively correlated with age but positively correlated with the female sex. Finally, we developed an mtDNA variation database of Chinese populations called MTCards (http://genemed.tech/mtcards/) to facilitate the query of mtDNA variants in this study. In summary, these findings contribute to different aspects of understanding mtDNA, providing a better understanding of the genetic basis of mitochondrial-related diseases.

Maize/soybean intercropping increases nutrient uptake, crop yield and modifies soil physio-chemical characteristics and enzymatic activities in the subtropical humid region based in Southwest China.

Intercropping, a widely adopted agricultural practice worldwide, aims to increase crop yield, enhance plant nutrient uptake, and optimize the utilization of natural resources, contributing to sustainable farming practices on a global scale. However, the underlying changes in soil physio-chemical characteristics and enzymatic activities, which contribute to crop yield and nutrient uptake in the intercropping systems are largely unknown. Consequently, a two-year (2021-2022) field experiment was conducted on the maize/soybean intercropping practices with/without nitrogen (N) fertilization (i.e., N0; 0 N kg ha-1 and N1; 225 N kg ha-1 for maize and 100 N kg ha-1 for soybean ) to know whether such cropping system can improve the nutrients uptake and crop yields, soil physio-chemical characteristics, and soil enzymes, which ultimately results in enhanced crop yield. The results revealed that maize intercropping treatments (i.e., N0MI and N1MI) had higher crop yield, biomass dry matter, and 1000-grain weight of maize than mono-cropping treatments (i.e., N0MM, and N1MM). Nonetheless, these parameters were optimized in N1MI treatments in both years. For instance, N1MI produced the maximum grain yield (10,105 and 11,705 kg ha-1), biomass dry matter (13,893 and 14,093 kg ha-1), and 1000-grain weight (420 and 449 g) of maize in the year 2021 and 2022, respectively. Conversely, soybean intercropping treatments (i.e., N0SI and N1SI) reduced such yield parameters for soybean. Also, the land equivalent ratio (LER) and land equivalent ratio for N fertilization (LERN) values were always greater than 1, showing the intercropping system's benefits in terms of yield and improved resource usage. Moreover, maize intercropping treatments (i.e., N0MI and N1MI) and soybean intercropping treatments (i.e., N0SI and N1SI) significantly (p < 0.05) enhanced the nutrient uptake (i.e., N, P, K, Ca, Fe, and Zn) of maize and soybean, however, these nutrients uptakes were more prominent in N1MI and N1SI treatments of maize and soybean, respectively in both years (2021 and 2022) compared with their mono-cropping treatments. Similarly, maize-soybean intercropping treatments (i.e., N0MSI and N1MSI) significantly (p < 0.05) improved the soil-based N, P, K, NH4, NO3, and soil organic matter, but, reduced the soil pH. Such maize-soybean intercropping treatments also improved the soil enzymatic activities such as protease (PT), sucrose (SC), acid phosphatase (AP), urease (UE), and catalase (CT) activities. This indicates that maize-soybean intercropping could potentially contribute to higher and better crop yield, enhanced plant nutrient uptake, improved soil nutrient pool, physio-chemical characteristics, and related soil enzymatic activities. Thus, preferring intercropping to mono-cropping could be a preferable choice for ecologically viable agricultural development.

Straw incorporation and nitrogen fertilization regulate soil quality, enzyme activities and maize crop productivity in dual maize cropping system.

BACKGROUND: Straw incorporation serves as an effective strategy to enhance soil fertility and soil microbial biomass carbon (SMBC), which in turn improves maize yield and agricultural sustainability. However, our understanding of nitrogen (N) fertilization and straw incorporation into soil microenvironment is still evolving. This study explored the impact of six N fertilization rates (N0, N100, N150, N200, N250, and N300) with and without straw incorporation on soil fertility, SMBC, enzyme activities, and maize yield. RESULTS: Results showed that both straw management and N fertilization significantly affected soil organic carbon (SOC), total N, SMBC, soil enzyme activities, and maize yield. Specifically, the N250 treatment combined with straw incorporation significantly increased SOC, total N, and SMBC compared to lower fertilization rates. Additionally, enzyme activities such as urease, cellulase, sucrose, catalase, and acid phosphatase reached their peak during the V6 growth stage in the N200 treatment under for both straw management conditions. Compared to N250 and N300 treatments of traditional planting, the N200 treatment with residue incorporation significantly increased yield by 8.30 and 4.22%, respectively. All measured parameters, except for cellulase activity, were significantly higher in spring than in the autumn across both study years, with notable increases observed in 2021. CONCLUSIONS: These findings suggest that optimal levels of SOC, soil total N (STN), and SMBC, along with increased soil enzyme activities, is crucial for sustaining soil fertility and enhancing maize grain yield under straw incorporation and N200 treatments.

Prediction of antimicrobial resistance in Klebsiella pneumoniae using genomic and metagenomic next-generation sequencing data.

OBJECTIVES: Klebsiella pneumoniae is a significant pathogen with increasing resistance and high mortality rates. Conventional antibiotic susceptibility testing methods are time-consuming. Next-generation sequencing has shown promise for predicting antimicrobial resistance (AMR). This study aims to develop prediction models using whole-genome sequencing data and assess their feasibility with metagenomic next-generation sequencing data from clinical samples. METHODS: On the basis of 4170 K. pneumoniae genomes, the main genetic characteristics associated with AMR were identified using a LASSO regression model. Consequently, the prediction model was established, validated and optimized using clinical isolate read simulation sequences. To evaluate the efficacy of the model, clinical specimens were collected. RESULTS: Four predictive models for amikacin, ciprofloxacin, levofloxacin, and piperacillin/tazobactam, initially had positive predictive values (PPVs) of 92%, 98%, 99%, 94%, respectively, when they were originally constructed. When applied to clinical specimens, their PPVs were 96%, 96%, 95%, and 100%, respectively. Meanwhile, there were negative predictive values (NPVs) of 100% for ciprofloxacin and levofloxacin, and 'not applicable' (NA) for amikacin and piperacillin/tazobactam. Our method achieved antibacterial phenotype classification accuracy rates of 95.92% for amikacin, 96.15% for ciprofloxacin, 95.31% for levofloxacin and 100% for piperacillin/tazobactam. The sequence-based prediction antibiotic susceptibility testing (AST) reported results in an average time of 19.5 h, compared with the 67.9 h needed for culture-based AST, resulting in a significant reduction of 48.4 h. CONCLUSIONS: These preliminary results demonstrated that the performance of prediction model for a clinically significant antimicrobial-species pair was comparable to that of phenotypic methods, thereby encouraging the expansion of sequence-based susceptibility prediction and its clinical validation and application.

A novel antimicrobial peptide S24 combats serious wound infections caused by Pseudomonas aeruginosa and Acinetobacter baumannii.

OBJECTIVES: Pseudomonas aeruginosa and Acinetobacter baumannii are ranked as top-priority organisms by WHO. Antimicrobial peptides (AMPs) are promising antimicrobial agents that are highly effective against serious bacterial infections. METHODS: In our previous study, a series of α-helical AMPs were screened using a novel multiple-descriptor strategy. The current research suggested that S24 exhibited strong antimicrobial activity against major pathogenic bacteria, and displayed minimal haemolysis, good serum stability and maintained salt resistance. RESULTS: We found that S24 exerted an antimicrobial effect by destroying outer membrane permeability and producing a strong binding effect on bacterial genomic DNA that inhibits genomic DNA migration. Furthermore, S24 exerted a strong ability to promote healing in wound infected by P. aeruginosa, A. baumannii and mixed strains in a mouse model. CONCLUSIONS: Overall, S24 showed good stability under physiological conditions and excellent antimicrobial activity, suggesting it may be a potential candidate for the development of serious bacterial infection treatment.

Melatonin-priming enhances maize seedling drought tolerance by regulating the antioxidant defense system.

Drought stress (DS) challenges sustainable agriculture production by limiting crop growth and development. The objective of the study was to evaluate the effect of melatonin-priming on enzymatic and non-enzymatic antioxidant defense mechanisms and its relation with leaf ultrastructure and stomatal traits in maize (Zea mays L) seedlings under DS (PEG-6000). DS drastically decreased seed germination, plant growth, and leaf chlorophyll content due to excessive reactive oxygen species (ROS) production. Melatonin-priming significantly (P < 0.05) increased seed germination, root length, shoot length, fresh seedling weight, proline content, total soluble protein content, sugar content, chlorophyll content, and stomatal aperture size by 101%, 30%, 133%, 51%, 22%, 59%, 54%, 20%, and 424%, compared to no priming (NP) under DS, respectively. Similarly, priming improved leaf ultrastructure and reduced the amount of chlorophyll loss and oxidative damage in maize seedlings. Melatonin seed priming with 500 µM melatonin (M2) greatly increased superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), glutathione, and ascorbate (AsA) activity, by 65%, 63%, 94%, 41%, and 55% compared to NP under DS and by 0.26%, 8%, 33%, 42%, and 15% under no-stress (NS), respectively. Melatonin-priming also reduced malondialdehyde content, electrolyte leakage, hydrogen peroxide (H2O2) content, and superoxide anion (O2-) content by 26%, 31%, 31%, and 33% compared to NP under DS and by 8%, 18%, 10%, and 11% under NS, respectively. In response to DS, melatonin-priming also stabilized the chloroplast structure, sustained cell expansion, protected cell walls, and greatly improved stomatal traits, including stomatal number, length, and width. Our results suggest that melatonin-priming improves drought tolerance in maize seedlings by alleviating the negative effect of ROS.

Multivariate analysis compares and evaluates drought and flooding tolerances of maize germplasm.

Drought and flooding are the two most important environmental factors limiting maize (Zea mays L.) production globally. This study aimed to investigate the physiological mechanisms and accurate evaluation indicators and methods of maize germplasm involved in drought and flooding stresses. The twice replicated pot experiments with 60 varieties, combined with the field validation experiment with 3 varieties, were conducted under well-watered, drought, and flooding conditions. Most varieties exhibited stronger tolerance to drought than flooding due to higher antioxidant enzyme activities, osmotic adjustment substances, and lower reactive oxygen species. In contrast, flooding stress resulted in higher levels of reactive oxygen species (particularly O2-), ascorbate peroxidase, catalase, peroxidase, and soluble sugars but lower levels of superoxide dismutase, proline, and soluble protein compared with well-watered conditions. Superoxide dismutase, peroxidase, catalase, ascorbate peroxidase, proline, soluble sugars, and protein contents, in addition to plant height, leaf area/plant, and stem diameter, were accurate and representative indicators for evaluating maize tolerance to drought and flooding stresses and could determine a relatively high mean forecast accuracy of 100.0% for the comprehensive evaluation value. A total of 4 principal components were extracted, in which different principal components played a vital role in resisting different water stresses. Finally, the accuracy of the 3 varieties screened by multivariate analysis was verified in the field. This study provides insights into the different physiological mechanisms and accurate evaluation methods of maize germplasm involved in drought and flooding stresses, which could be valuable for further research and breeding.

STK10 mutations block erythropoiesis in acquired pure red cell aplasia via impairing ribosome biogenesis.

Acquired pure red cell aplasia (PRCA) is anemia associated with the absence of erythroblasts and is characterized by persistent and easy recurrence. However, the underlying mechanisms of acquired PRCA remain obscure, and the role of gene mutations in the pathogenesis of acquired PRCA is not fully characterized. In the present study, we detected thirty newly diagnosed patients with acquired PRCA using whole exome sequencing, and a potential role for STK10 in acquired PRCA was uncovered. The mRNA levels of STK10 in three patients with STK10 mutations were decreased. These three patients had a poor response to immunosuppressive therapy and two died in the follow-up period. Here we report that knockdown of STK10 inhibits erythroid differentiation and promotes apoptosis of K562 cells. We show that knockdown of STK10 resulted in inhibition of ribosome biogenesis and reduced ribosome levels in K562 cells. We also show that the p53 signaling pathway is activated by knockdown of STK10. Our results imply that ribosome biogenesis downregulation together with pathological p53 activation prevents normal erythropoiesis. Our study uncovers a new pathophysiological mechanism leading to acquired PRCA driven by STK10 mutations.

GGC expansions in NOTCH2NLC contribute to Parkinson disease and dopaminergic neuron degeneration.

BACKGROUND AND PURPOSE: The role of GGC repeat expansions within NOTCH2NLC in Parkinson's disease (PD) and the substantia nigra (SN) dopaminergic neuron remains unclear. Here, we profile the NOTCH2NLC GGC repeat expansions in a large cohort of patients with PD. We also investigate the role of GGC repeat expansions within NOTCH2NLC in the dopaminergic neurodegeneration of SN. METHODS: A total of 2,522 patients diagnosed with PD and 1,085 health controls were analyzed for the repeat expansions of NOTCH2NLC by repeat-primed PCR and GC-rich PCR assay. Furthermore, the effects of GGC repeat expansions in NOTCH2NLC on dopaminergic neurons were investigated by using recombinant adeno-associated virus (AAV)-mediated overexpression of NOTCH2NLC with 98 GGC repeats in the SN of mice by stereotactic injection. RESULTS: Four PD pedigrees (4/333, 1.2%) and three sporadic PD patients (3/2189, 0.14%) were identified with pathogenic GGC repeat expansions (larger than 60 GGC repeats) in the NOTCH2NLC gene, while eight PD patients and one healthy control were identified with intermediate GGC repeat expansions ranging from 41 to 60 repeats. No significant difference was observed in the distribution of intermediate NOTCH2NLC GGC repeat expansions between PD cases and controls (Fisher's exact test p-value = 0.29). Skin biopsy showed P62-positive intranuclear NOTCH2NLC-polyGlycine (polyG) inclusions in the skin nerve fibers of patient. Expanded GGC repeats in NOTCH2NLC produced widespread intranuclear and perinuclear polyG inclusions, which led to a severe loss of dopaminergic neurons in the SN. Consistently, polyG inclusions were presented in the SN of EIIa-NOTCH2NLC-(GGC)98 transgenic mice and also led to dopaminergic neuron loss in the SN. CONCLUSIONS: Overall, our findings provide strong evidence that GGC repeat expansions within NOTCH2NLC contribute to the pathogenesis of PD and cause degeneration of nigral dopaminergic neurons.

Melatonin mitigates drought stress by increasing sucrose synthesis and suppressing abscisic acid biosynthesis in tomato seedlings.

The increasing prevalence of drought events poses a major challenge for upcoming crop production. Melatonin is a tiny indolic tonic substance with fascinating regulatory functions in plants. While plants can respond in several ways to alleviate drought stress, the processes underpinning stress sensing and signaling are poorly understood. Hereafter, the objectives of this investigation were to explore the putative functions of melatonin in the regulation of sugar metabolism and abscisic acid biosynthesis in drought-stressed tomato seedlings. Melatonin (100 µM) and/or water were foliar sprayed, followed by the plants being imposed to drought stress for 14 days. Drought stress significantly decreased biomass accumulation, inhibited photosynthetic activity, and stimulated senescence-associated gene 12 (SAG12) expression. Melatonin treatment effectively reversed drought-induced growth retardation as evidenced by increased leaf pigment and water balance and restricted abscisic acid (ABA) accumulation. Sugar accumulation, particularly sucrose content, was higher in drought-imposed seedlings, possibly owing to higher transcription levels of sucrose non-fermenting 1-related protein kinase 2 (SnKR2.2) and ABA-responsive element binding factors 2 (AREB2). Melatonin addition further uplifted the sucrose content, which coincided with increased activity of sucrose synthase (SS, 130%), sucrose phosphate synthase (SPS, 137%), starch degradation encoding enzyme ß-amylase (BAM, 40%) and α-amylase (AMY, 59%) activity and upregulated their encoding BAM1(10.3 folds) and AMY3 (8.1 folds) genes expression at day 14 relative to the control. Under water deficit conditions, melatonin supplementation decreased the ABA content (24%) and its biosynthesis gene expressions. Additionally, sugar transporter subfamily genes SUT1 and SUT4 expression were upregulated by the addition of melatonin. Collectively, our findings illustrate that melatonin enhances drought tolerance in tomato seedlings by stimulating sugar metabolism and negatively regulating ABA synthesis.

Least-cost decarbonization pathways for electricity generation in Finland: A convex quantile regression approach.

This study investigates the least-cost decarbonization pathways in the Finnish electricity generation industry in order to achieve the national carbon neutrality goal by 2035. Various abatement measures, such as downscaling production, capital investment, and increasing labor and intermediate inputs, are considered. The marginal abatement costs (MACs) of greenhouse gas emissions are estimated using the convex quantile regression method and applied to unique register-based firm-level greenhouse gas emission data merged with financial statement data. We adjust the MAC estimates for the sample selection bias caused by zero-emission firms by applying the two-stage Heckman correction. Our empirical findings reveal that the median MAC ranges from 0.1 to 3.5 euros per tonne of CO2 equivalent. The projected economic cost of a 90% reduction in emissions is 62 million euros, while the estimated cost of achieving zero emissions is 83 million euros.

Insight into the Role of Fluoroethylene Carbonate on the Stability of Sb||Graphite Dual-Ion Batteries in Propylene Carbonate-Based Electrolyte.

Sodium dual-ion batteries (Na-DIBs) have attracted increasing attention due to their high operative voltages and low-cost raw materials. However, the practical applications of Na-DIBs are still hindered by the issues, such as low capacity and poor Coulombic efficiency, which is highly correlated with the compatibility between electrode and electrolyte but rarely investigated. Herein, fluoroethylene carbonate (FEC) is introduced into the electrolyte to regulate cation/anion solvation structure and the stability of cathode/anode-electrolyte interphase of Na-DIBs. The FEC modulates the environment of PF6 - solvation sheath and facilitates the interaction of PF6 - on graphite. In addition, the NaF-rich interphase caused by the preferential decomposition of FEC effectively inhibits side reactions and pulverization of anodes with the electrolyte. Consequently, Sb||graphite full cells in FEC-containing electrolyte achieve an improved capacity, cycling stability and Coulombic efficiency. This work elucidates the underlying mechanism of bifunctional FEC and provides an alternative strategy of building high-performance dual ion batteries.

Ubiquitin-specific protease 11 promotes partial epithelial-to-mesenchymal transition by deubiquitinating the epidermal growth factor receptor during kidney fibrosis.

The aberrant expression of ubiquitin-specific protease 11 (USP11) is believed to be related to tumor progression. However, few studies have reported the biological function and clinical importance of USP11 in kidney fibrosis. Here, we demonstrated USP11 was highly upregulated in the kidneys from patients with chronic kidney disease and correlated positively with fibrotic lesion but negatively with kidney function. Conditional USP11 deletion or pharmacologic inhibition with Mitoxantrone attenuated pathological lesions and improved kidney function in both hyperuricemic nephropathy (HN)- and folic acid (FA)-induced mouse models of kidney fibrosis. Mechanistically, by RNA sequencing, USP11 was found to be involved in nuclear gene transcription of the epidermal growth factor receptor (EGFR). USP11 co-immunoprecipitated and co-stained with extra-nuclear EGFR and deubiquitinated and protected EGFR from proteasome-dependent degradation. Genetic or pharmacological depletion of USP11 facilitated EGFR degradation and abated augmentation of TGF-ß1 and downstream signaling. This consequently alleviated the partial epithelial-mesenchymal transition, G2/M arrest and aberrant secretome of profibrogenic and proinflammatory factors in uric acid-stimulated tubular epithelial cells. Moreover, USP11 deletion had anti-fibrotic and anti-inflammatory kidney effects in the murine HN and FA models. Thus, our study provides evidence supporting USP11 as a promising target for minimizing kidney fibrosis and that inhibition of USP11 has potential to be an effective strategy for patients with chronic kidney disease.

Insertion of ISPa1635 in ISCR1 Creates a Hybrid Promoter for blaPER-1 Resulting in Resistance to Novel ß-lactam/ß-lactamase Inhibitor Combinations and Cefiderocol.

Eleven blaPER-1-positive Pseudomonas aeruginosa clinical isolates showed variable susceptibility to ceftazidime-avibactam (CZA). The genetic contexts of blaPER-1 were identical (ISCR1-blaPER-1-gst) except for the ST697 isolate HS204 (ISCR1-ISPa1635-blaPER-1-gst). The insertion of ISPa1635 in ISCR1 upstream of blaPER-1 created a hybrid promoter, which elevated the blaPER-1 transcription level and resulted in increased resistance to CZA, ceftolozane-tazobactam, cefepime-zidebactam, and cefiderocol. Diversity in the promoter activity of blaPER-1 partially explains the variable susceptibility to CZA in PER-producing isolates.

Elucidating the Mechanism of Action of the Gram-Negative-Pathogen-Selective Cyclic Antimicrobial Lipopeptide Brevicidine.

Due to the accelerated appearance of antimicrobial-resistant (AMR) pathogens in clinical infections, new first-in-class antibiotics, operating via novel modes of action, are desperately needed. Brevicidine, a bacterial nonribosomally produced cyclic lipopeptide, has shown potent and selective antimicrobial activity against Gram-negative pathogens. However, before our investigations, little was known about how brevicidine exerts its potent bactericidal effect against Gram-negative pathogens. In this study, we find that brevicidine has potent antimicrobial activity against AMR Enterobacteriaceae pathogens, with MIC values ranging between 0.5 µM (0.8 mg/L) and 2 µM (3.0 mg/L). In addition, brevicidine showed potent antibiofilm activity against the Enterobacteriaceae pathogens, with the same 100% inhibition and 100% eradication concentration of 4 µM (6.1 mg/L). Further mechanistic studies showed that brevicidine exerts its potent bactericidal activity by interacting with lipopolysaccharide in the outer membrane, targeting phosphatidylglycerol and cardiolipin in the inner membrane, and dissipating the proton motive force of bacteria. This results in metabolic perturbation, including the inhibition of ATP synthesis; the inhibition of the dehydrogenation of NADH; the accumulation of reactive oxygen species in bacteria; and the inhibition of protein synthesis. Finally, brevicidine showed a good therapeutic effect in a mouse peritonitis-sepsis model. Our findings pave the way for further research on the clinical applications of brevicidine to combat prevalent infections caused by AMR Gram-negative pathogens worldwide.

Medication Status and Related Factors in Essential Tremor Patients: A Cross-Sectional Study in China.

INTRODUCTION: Essential tremor (ET) is one of the most common movement disorders. Oral drugs play a crucial role in treating ET, with various available options such as propranolol, primidone, and topiramate. However, the medication status and related factors among Chinese ET patients are unknown yet. METHODS: This study used the baseline data from the National Survey of Essential Tremor Plus in China cohort. ET patients with information related to medication intake were included. Medication patients were defined as patients who were taking medication at the time of the survey. We further defined recommended medication users according to Chinese guideline recommendations and clinical knowledge. We used mean and standard deviation (SD), median and interquartile range (IQR), or frequencies and percentages when appropriate for descriptive analysis. We used multivariate logistic regression analyses to explore factors related to medication intake in all ET patients and in recommended medication users. RESULTS: Of 1,153 included ET participants, 207 (18.0%) took medication. Arotinolol (115, 55.6%) and propranolol (63, 30.4%) were the top 2 used medicines. Patients with middle school education (odds ratio 0.57, 95% confidence interval 0.39-0.83), college or higher level education (0.46, 0.28-0.76), and late-onset ET (LO-ET) (0.38, 0.23-0.63) were less likely to take medication. Patients with intention tremor (1.90, 1.38-2.62), every 10-unit increase in age (1.10, 1.00-1.21), Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) Part 1 (1.63, 1.37-1.93), and TETRAS Part 2 (1.81, 1.48-2.22) were more likely to take medication. Among 332 recommended medication users, only 104 (31.3%) took medicine. The associations of LO-ET (0.36, 0.17-0.75), intention tremor (2.27, 1.35-3.81), TETRAS Part 1 (1.52, 1.09-2.13), and TETRAS Part 2 (1.59, 1.15-2.20) with medication were similar to all ET patients. CONCLUSION: The proportion of medication intake is low among both all ET patients and recommended medication users. The top 2 commonly used medications among all ET patients are arotinolol and propranolol. Influencing factors of medication intake are different between all ET patients and recommended medication users. Clinicians are suggested to provide counseling and education on ET medication to promote medication intake.

High Peroxidase-Mimicking Metal-Organic Frameworks Decorated with Platinum Nanozymes for the Colorimetric Detection of Acetylcholine Chloride and Organophosphorus Pesticides via Enzyme Cascade Reaction.

The sensitive detection of acetylcholinesterase (AChE) and organophosphorus pesticides (OPs) is very important for the protection of human health. Herein, a hybrid material, Pt NPs/Fe-MOF, consisting of a metal-organic framework (MIL-88B-NH2, Fe-MOF) decorated with platinum nanoparticles (Pt NPs), was prepared first and exhibited remarkably improved and excellent peroxidase-mimicking activity compared to the Fe-MOF material resulting from the synergistic catalysis effect between Fe-MOF and Pt NPs, which can effectively catalyze 3,3',5,5'-tetramethylbenzidine (TMB) oxidation to generate a blue product (oxidized TMB, oxTMB). Interestingly, in the presence of AChE and acetylcholinesterase, the peroxidase-mimicking activity from Pt NPs/Fe-MOF was inhibited obviously, and thus, a colorimetric sensing platform for AChE can be constructed; more importantly, after the addition of OPs, this nanozyme activity can be recovered, inducing the further successful construction of a sensitive colorimetric sensing platform for OPs. The related sensing mechanism and condition optimization were studied, and the as-prepared Pt NPs/Fe-MOF nanozyme-based colorimetric method for AChE and OP detection displayed superior analytical performances with wide linearities and low detection limits. Furthermore, the designed method offers satisfactory real application ability. We expect the as-proposed Pt NPs/Fe-MOF nanozyme-based colorimetric sensing platform for AChE and OPs via the enzyme cascade reaction to show great potential application.

Inhibition of EZH2 suppresses peritoneal angiogenesis by targeting a VEGFR2/ERK1/2/HIF-1α-dependent signaling pathway.

The catalytic subunit of polycomb repressive complex 2 (PRC2), enhancer of zeste homolog 2 (EZH2), has been reported to be involved in angiogenesis in some tumors and autoimmune diseases. However, the mechanisms by which EZH2 regulates peritoneal angiogenesis remain unclear. We detected the expression of EZH2 in clinical samples and the peritoneal tissue of a mouse peritoneal fibrosis model induced by chlorhexidine gluconate (CG). In addition, we further investigated the mechanisms by which inhibition of EZH2 by 3-deazaneplanocin A (3-DZNeP) alleviated the CG-induced peritoneal fibrosis mouse model in vivo and 3-DZNeP or EZH2 siRNA treatment in cultured human peritoneal mesothelial cells (HPMCs) and human umbilical vein endothelial cells (HUVECs). The expression of EZH2 in the peritoneum of long-term peritoneal dialysis (PD) patients and the CG-induced peritoneal fibrosis mouse model was remarkably increased and this was positively associated with higher expression of vascular markers (CD31, CD34, VEGF, p-VEGFR2). Peritoneal injection of 3-DZNeP attenuated angiogenesis in the peritoneum of CG-injured mice; improved peritoneal membrane function; and decreased phosphorylation of STAT3, ERK1/2, and activation of Wnt1/ß-catenin. In in vitro experiments, we demonstrated that inhibition of EZH2 by 3-DZNeP or EZH2 siRNA decreased tube formation and the migratory ability of HUVECs via two pathways: the Wnt1/ß-catenin pathway and the IL-6/STAT3 pathway. Suppression of the Wnt1/ß-catenin pathway and the IL-6/STAT3 pathway subsequently reduced VEGF production in HPMCs. Using specific inhibitors of VEGFR2, ERK1/2, and HIF-1α, we found that a VEGFR2/ERK1/2/HIF-1α axis existed and contributed to angiogenesis in vitro. Moreover, phosphorylation of VEGFR2 and activation of the ERK1/2 pathway and HIF-1α in HUVECs could be suppressed by inhibition of EZH2. Taken together, the results of this study suggest that EZH2 may be a novel target for preventing peritoneal angiogenesis in PD patients. © 2022 The Pathological Society of Great Britain and Ireland.