Factors influencing cardiovascular system-related post-COVID-19 sequelae: A single-center cohort study.

Background: COVID-19 sequelae are long-term symptoms of COVID-19. Cardiovascular disease is not only a risk factor for the occurrence of COVID-19 sequelae but also a potential result directly or indirectly caused by COVID-19 infection. Objectives: The aim of this study is to investigate the cardiovascular system-related symptoms of outpatients and inpatients of the Cardiovascular Department of the Affiliated Hospital of Shandong University of Traditional Chinese Medicine after recovery from novel coronavirus infection, analyze the influencing factors, and symptom characteristics of related symptoms, and thereby provide a basis for further formulating a reasonable diagnosis and treatment plan. Materials and methods: From January 15, 2023 to February 15, 2023, 452 recovered patients with novel coronavirus infection who were admitted to the Cardiovascular Department of the Affiliated Hospital of Shandong University of Traditional Chinese Medicine due to symptoms of the cardiovascular system (complaints of chest pain and palpitations) were involved in this study. A unified questionnaire was used to record the general information, past medical history, characteristics of chest pain or palpitations, and other COVID-19-related sequelae of the selected patients. All data were statistically analyzed by SPSS 26.0 statistical software. Results: A total of 226 patients with cardiovascular symptoms and 226 patients without cardiovascular symptoms were included in this study. After univariate and multivariate logistic regression analysis, women (OR 2.081, 95% CI = 1.358-3.189) and young people (OR 2.557, 95% CI = 1.44-4.54) had a higher risk of cardiovascular symptoms; prehypertension (OR 1.905, 95% CI = 1.091-3.329) and hypertension (OR 2.287, 95% CI = 1.433-3.649) increased the risk of cardiovascular symptoms; patients with history of previous cardiovascular disease (OR 1.862, 95% CI = 1.16-2.988) and history of diabetes (OR 2.138, 95% CI = 1.058-4.319) had a higher risk of developing cardiovascular symptoms. The main symptoms related to COVID-19 sequelae reported by all 452 patients were fatigue (76.8%), shortness of breath (54.2%), dry mouth and bitter mouth (46.0%), gastrointestinal symptoms (42.7%), sleep disturbances (37.4%), sweating (31.9%), chills (29%), dizziness (25.7%), confusion of brain fog (25.2%), and tinnitus (14.6%). Compared with patients without cardiovascular symptoms, patients with cardiovascular symptoms were more likely to have shortness of breath (OR 3.521, 95% CI = 2.226-5.472), gastrointestinal symptoms (OR 2.039, 95% CI = 1.226-3.393), and dry mouth and bitter mouth (OR 1.918, 95% CI = 1.229-2.992). The differences were statistically significant (P < 0.05). Conclusion: In this new coronavirus infection, women, young people, the elderly, people with prehypertension, hypertension, and patients with a history of cardiovascular disease and diabetes have a higher risk of developing cardiovascular symptoms, and patients with cardiovascular symptoms are more likely to develop other COVID-19 sequelae.

Association mechanism between Arabidopsis immune coreceptor BAK1 and Pseudomonas syringae effector HopF2.

Brassinosteroid activated kinase 1 (BAK1) is a cell-surface coreceptor which plays multiple roles in innate immunity of plants. HopF2 is an effector secreted by the bacterial pathogen Pseudomonas syringae pv. tomato DC3000 into Arabidopsis and suppresses host immune system through interaction with BAK1 as well as its downstream kinase MKK5. The association mechanism of HopF2 to BAK1 remains unclear, which prohibits our understanding and subsequent interfering of their interaction for pathogen management. Herein, we found the kinase domain of BAK1 (BAK1-KD) is sufficient for HopF2 association. With a combination of hydrogen/deuterium exchange mass spectrometry and mutational assays, we found a region of BAK1-KD N-lobe and a region of HopF2 head subdomain are critical for intermolecular interaction, which is also supported by unbiased protein-protein docking with ClusPro and kinase activity assay. Collectively, this research presents the interaction mechanism between Arabidopsis BAK1 and P. syringae HopF2, which could pave the way for bactericide development that blocking the functioning of HopF2 toward BAK1.

A novel dual serotonin transporter and M-channel inhibitor D01 for antidepression and cognitive improvement.

Cognitive dysfunction is a core symptom common in psychiatric disorders including depression that is primarily managed by antidepressants lacking efficacy in improving cognition. In this study, we report a novel dual serotonin transporter and voltage-gated potassium Kv7/KCNQ/M-channel inhibitor D01 (a 2-methyl-3-aryloxy-3-heteroarylpropylamines derivative) that exhibits both anti-depression effects and improvements in cognition. D01 inhibits serotonin transporters (Ki = 30.1 ± 6.9 nmol/L) and M channels (IC50 = 10.1 ± 2.4 µmol/L). D01 also reduces the immobility duration in the mouse FST and TST assays in a dose-dependent manner without a stimulatory effect on locomotion. Intragastric administrations of D01 (20 and 40 mg/kg) can significantly shorten the immobility time in a mouse model of chronic restraint stress (CRS)-induced depression-like behavior. Additionally, D01 dose-dependently improves the cognitive deficit induced by CRS in Morris water maze test and increases the exploration time with novel objects in normal or scopolamine-induced cognitive deficits in mice, but not fluoxetine. Furthermore, D01 reverses the long-term potentiation (LTP) inhibition induced by scopolamine. Taken together, our findings demonstrate that D01, a dual-target serotonin reuptake and M channel inhibitor, is highly effective in the treatment-resistant depression and cognitive deficits, thus holding potential for development as therapy of depression with cognitive deficits.

CircUSP1 as a novel marker promotes gastric cancer progression via stabilizing HuR to upregulate USP1 and Vimentin.

Circular RNAs (circRNAs) play a crucial role in regulating various tumors. However, their biological functions and mechanisms in gastric cancer (GC) have not been well understood. Here, we discovered a stable cytoplasmic circRNA named circUSP1 (hsa_circ_000613) in GC. CircUSP1 upregulation in GC tissues was correlated with tumor size and differentiation. We observed that circUSP1 promoted GC growth and metastasis. Mechanistically, circUSP1 mainly interacted with the RRM1 domain of an RNA-binding protein (RBP) called HuR, stabilizing its protein level by inhibiting ß-TrCP-mediated ubiquitination degradation. The oncogenic properties of HuR mediated promotive effects of circUSP1 in GC progression. Moreover, we identified USP1 and Vimentin as downstream targets of HuR in post-transcriptional regulation, mediating the effects of circUSP1. The parent gene USP1 also enhanced the viability and mobility of GC cells. Additionally, tissue-derived circUSP1 could serve as an independent prognostic factor for GC, while plasma-derived circUSP1 showed promise as a diagnostic biomarker, outperforming conventional markers including serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA19-9). Our study highlights that circUSP1 promotes GC progression by binding to and stabilizing oncogenic HuR, thereby facilitating the upregulation of USP1 and Vimentin at the post-transcriptional level. These findings suggest that circUSP1 could be a potential therapeutic target and a diagnostic and prognostic biomarker for GC.

The synthetic NLR RGA5HMA5 requires multiple interfaces within and outside the integrated domain for effector recognition.

Some plant sensor nucleotide-binding leucine-rich repeat (NLR) receptors detect pathogen effectors through their integrated domains (IDs). Rice RGA5 sensor NLR recognizes its corresponding effectors AVR-Pia and AVR1-CO39 from the blast fungus Magnaporthe oryzae through direct binding to its heavy metal-associated (HMA) ID to trigger the RGA4 helper NLR-dependent resistance in rice. Here, we report a mutant of RGA5 named RGA5HMA5 that confers complete resistance in transgenic rice plants to the M. oryzae strains expressing the noncorresponding effector AVR-PikD. RGA5HMA5 carries three engineered interfaces, two of which lie in the HMA ID and the other in the C-terminal Lys-rich stretch tailing the ID. However, RGA5 variants having one or two of the three interfaces, including replacing all the Lys residues with Glu residues in the Lys-rich stretch, failed to activate RGA4-dependent cell death of rice protoplasts. Altogether, this work demonstrates that sensor NLRs require a concerted action of multiple surfaces within and outside the IDs to both recognize effectors and activate helper NLR-mediated resistance, and has implications in structure-guided designing of sensor NLRs.

Mortality Risk Factors Among People Living with HIV Receiving Second--line Antiretroviral Therapy in Rural China.

BACKGROUND: Second-line antiretroviral therapy (ART) was introduced in Henan Province in 2009. The number of people living with human immunodeficiency virus (HIV) starting this therapy is increasing. OBJECTIVE: This study aimed to investigate the survival and factors affecting mortality among this group. METHODS: We conducted a retrospective cohort study of people living with HIV (PLHIV) who switched to second-line ART between May 1, 2010, and May 1, 2016., using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: We followed 3,331 PLHIV for 26,988 person-years, of whom 508 (15.3%) died. The mortality rate was 1.88/100 person-years. After adjusting for confounding factors, we found being a woman (hazard ratio [HR], 0.66; 95% confidence interval [CI] 0.55-0.79), > 50 years old (HR, 2.69; 95%CI, 2.03-3.56), single/windowed (HR, 1.26; 95%CI, 1.04-1.52), having > 6 years of education (HR, 0.78; 95%CI, 0.65-0.94), Chinese medicine (HR, 0.75; 95%CI, 0.52-0.96), liver injury (HR, 1.58; 95%CI, 1.19-2.10), and CD4+ T cell count <200 cells/µl (HR, 1.94; 95%CI, 1.47-2.55), or 200-350 cells/µl (HR, 1.37; 95%CI, 1.03-1.82) were associated with mortality risk. CONCLUSIONS: We found lower mortality among PLHIV who switched to second-line ART than most previous studies. The limitations of a retrospective cohort may, therefore, have biased the data, and prospective studies are needed to confirm the results. Moreover, Chinese medicine combined with second-line ART shows potential as a treatment for HIV.

Designer artificial chiral kagome lattice with tunable flat bands and topological boundary states.

The kagome lattice is a well-known model system for the investigation of strong correlation and topological electronic phenomena due to the intrinsic flat band, magnetic frustration, etc. Introducing chirality into the kagome lattice would bring about new physics due to the unique symmetry, which is still yet to be fully explored. Here we report the investigation on a two-dimensional chiral kagome lattice utilizing tight binding band calculation and topological index analysis. It is found that the periodic chiral kagome lattice would bring about a robust zero-energy flat band. Furthermore, in the Su-Schrieffer-Heeger type dimer-/trimerized breathing chiral kagome lattice with particular edge terminations, topological corner states or metallic edge states would appear, implying new candidates for the second-order topological insulator. We also proposed the construction strategy for such lattices employing the scanning tunneling microscope atom manipulation technique.

Iron-doped swine bone char as hydrogen peroxide activator for efficient removal of acetaminophen in water.

Bone char is a functional material obtained by calcining animal bones and is widely used for environmental remediation. In this work, iron was inserted into porcine bone-derived bone char via ion exchange to synthesize iron-doped bone char (Fe-BC) for efficient catalysis of hydrogen peroxide. This is the first time that Fe-BC has been used as a catalyst for the activation of H2O2. The effectiveness of the Fe-BC catalyst was influenced by the annealing temperature and the amount of iron doping. The results showed that the activation of H2O2 by the Fe-BC catalyst with the best catalytic performance could achieve 97.6% of APAP degradation within 30 min. Insights from electron paramagnetic resonance (EPR), free radical scavenging experiments and linear sweep voltammetry (LSV) proposed a reaction mechanism based on free radicals dominated degradation pathways (OH and O2-). Iron served as the primary active site in Fe-BC, with defect sites and oxygen-containing groups in the catalyst also contributing to the removal of pollutants. The Fe-BC/H2O2 system demonstrated resilience to interference from common anions (Cl-, NO3-, SO42- and HCO3-) in water, but was less effective against humic acid (HA). Based on the detection of intermediates produced during APAP degradation, possible degradation pathways of APAP were proposed and the toxicity of intermediates was evaluated. This work provides fresh insights into the use of heterogeneous Fenton catalysts for the removal of organic pollutants from water.

Dual-Specificity Inhibitor Targets Enzymes of the Trehalose Biosynthesis Pathway.

To reduce the risk of resistance development, a novel fungicide with dual specificity is demanded. Trehalose is absent in animals, and its synthases, trehalose-6-phosphate synthase (TPS) and trehalose-6-phosphate phosphatase (TPP), are safe fungicide targets. Here, we report the discovery of a dual-specificity inhibitor of MoTps1 (Magnaporthe oryzae Tps1, TPS) and MoTps2 (M. oryzae Tps2, TPP). The inhibitor, named A1-4, was obtained from a virtual screening and subsequent surface plasmon resonance screening. In in vitro assays, A1-4 interacts with MoTps1 and MoTps2-TPP (MoTps2 TPP domain) and inhibits their enzyme activities. In biological activity assays, A1-4 not only inhibits the virulence of M. oryzae on host but also causes aggregation of conidia cytosol, which is a characteristic phenotype of MoTps2. Furthermore, hydrogen/deuterium exchange mass spectrometry assays support the notion that A1-4 binds to the substrate pockets of TPS and TPP. Collectively, A1-4 is a promising hit compound for the development of safe fungicide with dual-target specificity.

Timing umbilical therapy in treatment of neurogenic bladder after spinal cord injury based on midnight-noon and ebb-flow doctrine: a randomized controlled trial. / åŸºäºŽå­åˆæµæ³¨ç†è®ºæ‹©æ—¶è„ç–—æ²»ç–—è„Šé«“æŸä¼¤åŽç¥žç»æºæ€§è†€èƒ±ï¼šéšæœºå¯¹ç §è¯•éªŒ.

OBJECTIVES: To observe the clinical efficacy of timing umbilical therapy for neurogenic bladder after spinal cord injury based on the midnight-noon and ebb-flow doctrine. METHODS: Sixty patients with neurogenic bladder after spinal cord injury were randomly divided into a trial group and a control group, with 30 patients in each group. In the trial group, based on the midnight-noon and ebb-flow doctrine, umbilical therapy was given at the time zone, 15:00 to 17:00. In the control group, umbilical therapy was delivered at any time zones except the period 15:00 to 17:00. The herbal plaster was remained on the umbilicus for 4 h each time, once daily. One course of treatment was composed of 2 weeks and the treatment lasted 4 weeks. Before and after treatment, the urodynamic indexes (maximum urinary flow rate [Qmax], maximum detrusor pressure [Pdet-max], residual urine volume [RUV]), voiding diary (average daily number of voiding, average daily number of leakage, average daily voided volume), neurogenic bladder symptom score (NBSS), the score of urinary symptom distress scale (USDS) and the score of World Health Organization quality of life assessment-BREF (WHOQOL-BREF) were compared between the two groups; and the clinical efficacy of the two groups was assessed. RESULTS: After treatment, Qmax, Pdet-max, the average daily voided volume and the scores of WHOQOL-BREF were increased (P<0.05); and RUV, the average daily number of voiding, the average daily number of leakage, NBSS and the scores of USDS were all reduced (P<0.05) in comparison with those before treatment in the two groups. When compared with those in the control group, Qmax, Pdet-max, the average daily voided volume and the score of WHOQOL-BREF were all higher (P<0.05); and RUV, the average daily number of voiding, the average daily number of leakage, NBSS and the score of USDS were lower (P<0.05) in the trial group. The total effective rate was 96.7% (29/30) in the trial group, higher than that (76.7%, 23/30) in the control group (P<0.05). CONCLUSIONS: Timing umbilical therapy, based on the midnight-noon and ebb-flow doctrine, effectively relieves the symptoms of dysuria and improves the quality of life in patients with neurogenic bladder after spinal cord injury.

Interactions between nitrogen and phosphorus in modulating soil respiration: A meta-analysis.

BACKGROUND: Economic and social development worldwide increases the input of nutrients, especially nitrogen (N) and phosphorus (P), to soils. These nutrients affect soil respiration (Rs) in terrestrial ecosystems. They may act independently or have interactive effects on Rs. The effect of N and P on Rs and its components (autotrophic respiration [Ra] and heterotrophic respiration [Rh]), however, either individually or together, is poorly understood. We performed a meta-analysis of 130 studies to examine the effects of different fertilization treatments on Rs and its components across terrestrial ecosystems. RESULTS: Our results showed that (1) The impact of fertilizer addition on Rs varies among different fertilizer types. N addition reduced Rs and Rh significantly but did not affect Ra; P addition had no significant effect on Rs, Rh, and Ra; NP addition increased Rs significantly but did not affect Rh and Ra. (2) Ecosystem type, duration of fertilization, fertilization rate, and fertilizer form influenced the response of Rs and its components to fertilizer application. (3) Based on our study, the annual average temperature may be a driving factor of Rs response to fertilizer addition, while soil total nitrogen may be an important predictor of Rs response to fertilizer addition. CONCLUSION: Overall, our study highlights the complex and multifaceted nature of the response of soil Rs and its components to fertilizer application, underscoring the importance of considering multiple factors when predicting and modeling future Rs and its feedback to global change.

Discovery of novel isopropanolamine inhibitors against MoTPS1 as potential fungicides with unique mechanisms.

The resistance and ecotoxicity of fungicides seriously restrict our ability to effectively control Magnaporthe oryzae. Discovering fungicidal agents based on novel targets, including MoTPS1, could efficiently address this situation. Here, we identified a hit VS-10 containing an isopropanolamine fragment as a novel MoTPS1 inhibitor through virtual screening, and forty-four analogs were synthesized by optimizing the structure of VS-10. Utilizing our newly established ion-pair chromatography (IPC) and leaf inoculation methods, we found that compared to VS-10, its analog j11 exhibited substantially greater inhibitory activity against both MoTPS1 and the pathogenicity of M. oryzae. Molecular simulations clarified that the electrostatic interactions between the bridging moiety of isopropanolamine and residue Glu396 of contributed significantly to the binding of j11 and MoTPS1. We preliminarily revealed the unique fungicidal mechanism of j11, which mainly impeded the infection of M. oryzae by decreasing sporulation, killing a small portion of conidia and interfering with the accumulation of turgor pressure in appressoria. Thus, in this study, a novel fungicide candidate with a unique mechanism targeting MoTPS1 was screened and discovered.

Alternative splicing of TaHSFA6e modulates heat shock protein-mediated translational regulation in response to heat stress in wheat.

Heat stress greatly threatens crop production. Plants have evolved multiple adaptive mechanisms, including alternative splicing, that allow them to withstand this stress. However, how alternative splicing contributes to heat stress responses in wheat (Triticum aestivum) is unclear. We reveal that the heat shock transcription factor gene TaHSFA6e is alternatively spliced in response to heat stress. TaHSFA6e generates two major functional transcripts: TaHSFA6e-II and TaHSFA6e-III. TaHSFA6e-III enhances the transcriptional activity of three downstream heat shock protein 70 (TaHSP70) genes to a greater extent than does TaHSFA6e-II. Further investigation reveals that the enhanced transcriptional activity of TaHSFA6e-III is due to a 14-amino acid peptide at its C-terminus, which arises from alternative splicing and is predicted to form an amphipathic helix. Results show that knockout of TaHSFA6e or TaHSP70s increases heat sensitivity in wheat. Moreover, TaHSP70s are localized in stress granule following exposure to heat stress and are involved in regulating stress granule disassembly and translation re-initiation upon stress relief. Polysome profiling analysis confirms that the translational efficiency of stress granule stored mRNAs is lower at the recovery stage in Tahsp70s mutants than in the wild types. Our finding provides insight into the molecular mechanisms by which alternative splicing improves the thermotolerance in wheat.

Structural mechanism of heavy metal-associated integrated domain engineering of paired nucleotide-binding and leucine-rich repeat proteins in rice.

Plant nucleotide-binding and leucine-rich repeat (NLR) proteins are immune sensors that detect pathogen effectors and initiate a strong immune response. In many cases, single NLR proteins are sufficient for both effector recognition and signaling activation. These proteins possess a conserved architecture, including a C-terminal leucine-rich repeat (LRR) domain, a central nucleotide-binding (NB) domain, and a variable N-terminal domain. Nevertheless, many paired NLRs linked in a head-to-head configuration have now been identified. The ones carrying integrated domains (IDs) can recognize pathogen effector proteins by various modes; these are known as sensor NLR (sNLR) proteins. Structural and biochemical studies have provided insights into the molecular basis of heavy metal-associated IDs (HMA IDs) from paired NLRs in rice and revealed the co-evolution between pathogens and hosts by combining naturally occurring favorable interactions across diverse interfaces. Focusing on structural and molecular models, here we highlight advances in structure-guided engineering to expand and enhance the response profile of paired NLR-HMA IDs in rice to variants of the rice blast pathogen MAX-effectors (Magnaporthe oryzae AVRs and ToxB-like). These results demonstrate that the HMA IDs-based design of rice materials with broad and enhanced resistance profiles possesses great application potential but also face considerable challenges.

ABO blood groups and nosocomial infection.

The timely identification of the high-risk groups for nosocomial infections (NIs) plays a vital role in its prevention and control. Therefore, it is crucial to investigate whether the ABO blood group is a risk factor for NI. In this study, patients with NI and non-infection were matched by the propensity score matching method and a logistic regression model was used to analyse the matched datasets. The study found that patients with the B&AB blood group were susceptible to Escherichia coli (OR = 1.783, p = 0.039); the A blood group were susceptible to Staphylococcus aureus (OR = 2.539, p = 0.019) and Pseudomonas aeruginosa (OR = 5.724, p = 0.003); the A&AB blood group were susceptible to Pseudomonas aeruginosa (OR = 4.061, p = 0.008); the AB blood group were vulnerable to urinary tract infection (OR = 13.672, p = 0.019); the B blood group were susceptible to skin and soft tissue infection (OR = 2.418, p = 0.016); and the B&AB blood group were vulnerable to deep incision infection (OR = 4.243, p = 0.043). Summarily, the patient's blood group is vital for identifying high-risk groups for NIs and developing targeted prevention and control measures for NIs.

Research Progress on Factors Affecting Oil-Absorption Performance of Cement-Based Materials.

With the wide application of petroleum resources, oil substances have polluted the environment in every link from crude oil extraction to utilization. Cement-based materials are the main materials in civil engineering, and the study of their adsorption capacity for oil pollutants can expand the scope of functional engineering applications of cement-based materials. Based on the research status of the oil-wet mechanism of different kinds of oil-absorbing materials, this paper lists the types of conventional oil-absorbing materials and introduces their application in cement-based materials while outlining the influence of different oil-absorbing materials on the oil-absorbing properties of cement-based composites. The analysis found that 10% Acronal S400F emulsion can reduce the water absorption rate of cement stone by 75% and enhance the oil-absorption rate by 62%. Adding 5% polyethylene glycol can increase the oil-water relative permeability of cement stone to 1.2. The oil-adsorption process is described by kinetic and thermodynamic equations. Two isotherm adsorption models and three adsorption kinetic models are explained, and oil-absorbing materials and adsorption models are matched. The effects of specific surface area, porosity, pore interface, material outer surface, oil-absorption strain, and pore network on the oil-absorption performance of materials are reviewed. It was found that the porosity has the greatest influence on the oil-absorbing performance. When the porosity of the oil-absorbing material increases from 72% to 91%, the oil absorption can increase to 236%. In this paper, by analyzing the research progress of factors affecting oil-absorption performance, ideas for multi-angle design of functional cement-based oil-absorbing materials can be obtained.

The tandem EH domains of End3 cooperate to interact with dual XPF motifs of Sla1 for the connection of early and late stages in fungal endocytosis.

Clathrin-mediated endocytosis (CME) is imperative for physiological processes in eukaryotic cells. In fungi, the Pan1/End3/Sla1 complex controls the transition between early and late stages of CME. Although it is acknowledged that End3 uses its N-terminal to interact with the C-terminal of Sla1, detailed mechanism remains obscure. Magnaporthe oryzae, the pathogenic fungus of rice, cause blast disease that threatens rice production worldwide. Here we report the detailed interaction mechanism between End3 and Sla1 of M. oryzae, i.e. MoEnd3 and MoSla1. The two EH domains of MoEnd3 (MoEnd3-EH1 and MoEnd3-EH2) is different both in evolution and calcium binding, but are indispensable for conformational stability of each other, an unreported effect of tandem-arranged EH domains. MoEnd3-EH1 and MoEnd3-EH2 interact with peptide MoSla11145-1155 containing a NPF motif with a conserved mode, and MoEnd3-EHs (containing both EH1 and EH2 domains) binds MoSla11145-1155 with a higher affinity, supporting the synergetic effect of EH domains. In addition, MoEnd3-EHs also recognize peptide MoSla1971-981 with a new MPF motif that has not been reported before, while Sla1 of yeast contains a DPF motif that bears EH domain interaction ability. Collectively, our research shows that the two EH domains of End3 synergize to interact with dual XPF motifs of Sla1, which conforms to a bivalent receptor-bivalent ligand model to improve both affinity and specificity.

Tungsten disulfide (WS2) is a highly active co-catalyst in Fe(III)/H2O2 Fenton-like reactions for efficient acetaminophen degradation.

The most important factor that restricts the decomposition of H2O2 in the Fe3+/H2O2 reaction is the slow cycling efficiency of reducing Fe3+ to Fe2+. In this study, the addition of tungsten disulfide (WS2) as a co-catalyst achieved a rapid cycling of the reaction rate-limiting step and a significant enhancement of H2O2 decomposition, which resulted in the effective degradation of acetaminophen (APAP). Results show that 99.6% of APAP (5 mg L-1) could be degraded by H2O2/Fe3+/WS2 system within 2.5 min. The conversion of Fe3+ to Fe2+ occurred mainly on the surface of WS2 due to the redox reaction of the exposed W4+ active sites with Fe3+ after the unsaturated S atoms were bound to protons. Electron paramagnetic resonance (EPR) and radical quenching experiments evaluated the contribution of hydroxyl radical (•OH) and superoxide radical (O2•-) in the degradation of pollutants. WS2 showed good recoverability after four cycles of the reaction. This study provides a new perspective to improve the efficiency of Fe3+/H2O2 and provides a reference for the involvement of transition metal sulfides in advanced oxidation processes (AOPs).

Structure-Aided Identification of an Inhibitor Targets Mps1 for the Management of Plant-Pathogenic Fungi.

Blast disease caused by Magnaporthe oryzae threatens rice production worldwide, and chemical control is one of the main methods of its management. The high mutation rate of the M. oryzae genome results in drug resistance, which calls for novel fungicide targets. Fungal proteins that function during the infection process might be potential candidates, and Mps1 (M. oryzae mitogen-activated protein kinase 1) is such a protein that plays a critical role in appressorium penetration of the plant cell wall. Here, we report the structure-aided identification of a small-molecule inhibitor of Mps1. High-throughput screening was performed with Mps1 against a DNA-encoded compound library, and one compound, named A378-0, with the best performance was selected for further verification. A378-0 exhibits a higher binding affinity than the kinase cosubstrate ATP and can inhibit the enzyme activity of Mps1. Cocrystallization of A378-0 with Mps1 revealed that A378-0 binds to the catalytic pocket of Mps1, while the three ring-type substructures of A378-0 constitute a triangle that squeezes into the pocket. In planta assays showed that A378-0 could inhibit both the appressorium penetration and invasive growth but not the appressorium development of M. oryzae, which is consistent with the biological function of Mps1. Furthermore, A378-0 exhibits binding and activity inhibition abilities against Mpk1, the Mps1 ortholog of the soilborne fungal pathogen Fusarium oxysporum. Collectively, these results show that Mps1 as well as its orthologs can be regarded as fungicide targets, and A378-0 might be used as a hit compound for the development of a broad-spectrum fungicide. IMPORTANCE M. oryzae is the causal agent of rice blast, one of the most devastating diseases of cultivated rice. Chemical control is still the main strategy for its management, and the identification of novel fungicide targets is indispensable for overcoming existing problems such as drug resistance and food safety. With a combination of structural, biochemical, and in planta assays, our research shows that Mps1 may serve as a fungicide target and confirms that compound A378-0 binds to Mps1 and possesses bioactivity in inhibiting M. oryzae virulence. As fungal orthologs of Mps1 are conserved, A378-0 may serve as a hit for broad-spectrum fungicide development, as evidenced with Mpk1, the Mps1 ortholog of F. oxysporum. Additionally, A378-0 contains a novel chemical scaffold that has not been reported in approved kinase inhibitors, suggesting its potential to be considered the basis for the development of other kinase inhibitors.

Melatonin functions as a broad-spectrum antifungal by targeting a conserved pathogen protein kinase.

Melatonin is a low-cost natural small indole molecule with versatile biological functions. However, melatonin's fungicidal potential has not been fully exploited, and the mechanism remains elusive. Here, we report that melatonin broadly inhibited 13 plant pathogens. In the rice blast fungal pathogen Magnaporthe oryzae, melatonin inhibited fungal growth, formation of infection-specific structures named appressoria, and plant infection, reducing disease severity. Melatonin entered fungal cells efficiently and colocalized with the critical mitogen-activated protein kinase named Mps1, suppressing phosphorylation of Mps1. Melatonin's affinity for Mps1 via two hydrogen bonds was demonstrated using surface plasmon resonance and chemical modifications. To improve melatonin's efficiency, we obtained 20 melatonin derivatives. Tert-butyloxycarbonyl melatonin showed a 25-fold increase in fungicidal activities, demonstrating the feasibility of chemical modifications in melatonin modification. Our study demonstrated the broad-spectrum fungicidal effect of melatonin by suppressing Mps1 as one of the targets. Through further systematic modifications, developing an eco-friendly melatonin derivative of commercial values for agricultural applications appears promising.