Aberrant Expression of SLC7A11 Impairs the Antimicrobial Activities of Macrophages in Staphylococcus Aureus Osteomyelitis in Mice.

Staphylococcus aureus (S. aureus) persistence in macrophages, potentially a reservoir for recurrence of chronic osteomyelitis, contributes to resistance and failure in treatment. As the mechanisms underlying survival of S. aureus in macrophages remain largely unknown, there has been no treatment approved. Here, in a mouse model of S. aureus osteomyelitis, we identified significantly up-regulated expression of SLC7A11 in both transcriptomes and translatomes of CD11b+F4/80+ macrophages, and validated a predominant distribution of SLC7A11 in F4/80+ cells around the S. aureus abscess. Importantly, pharmacological inhibition or genetic knockout of SLC7A11 promoted the bactericidal function of macrophages, reduced bacterial burden in the bone and improved bone structure in mice with S. aureus osteomyelitis. Mechanistically, aberrantly expressed SLC7A11 down-regulated the level of intracellular ROS and reduced lipid peroxidation, contributing to the impaired bactericidal function of macrophages. Interestingly, blocking SLC7A11 further activated expression of PD-L1 via the ROS-NF-κB axis, and a combination therapy of targeting both SLC7A11 and PD-L1 significantly enhanced the efficacy of clearing S. aureus in vitro and in vivo. Our findings suggest that targeting both SLC7A11 and PD-L1 is a promising therapeutic approach to reprogram the bactericidal function of macrophages and promote bacterial clearance in S. aureus osteomyelitis.

Welfare effect analysis of pay-as-you-go pension system: Deconstruction from the perspective of relative utility and social equality.

This paper studies the redistributive effects of two major pay-as-you-go pension systems by constructing an intergenerational iterative model which does not only considers standard utility but also relative utility. The study find that the two main pay-as-you-go pension systems are both sustainable. If we consider different preferences, then the choice of pension system should depend on the question of whether individuals are more interested in the absolute level of consumption or in the consumption related to a reference group. If the latter is more important, the Beveridgean system is superior, it provides greater protection for vulnerable groups than the Bismarck pension system, and the pension income after retirement is relatively more balanced, but the price is a lower level of consumption in the long run compared to an economy with Bismarckian system. If individuals prefer instead the absolute level of consumption, the Bismarckian system is better, because it guarantees a comparable higher level of consumption, but the disadvantaged groups face a higher risk of poverty and the degree of social inequality will be relatively higher. However, it is important to note that in the long run, only the level of consumption differs, not the speed of growth or number of children.

Pentacyclic triterpenoids as potential ACL inhibitors from the rare medicinal plant Semiliquidambar cathayensis.

An extensive phytochemical investigation on the rare medicinal plant Semiliquidambar cathayensis (family: Hamamelidaceae) led to the isolation of four new (1-4, named semiliquidacids A-D, respectively) and 25 related known pentacyclic triterpenoids. The new structures with absolute configurations were elucidated by spectroscopic methods, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analysis. Compound 1 represents the first naturally occurring ursane-type triterpenoid featuring an uncommon C-25 formyl group. Compound 4 and oleanolic acid (13) exhibited remarkable inhibitory effects against the ATP-citrate lyase (ACL, an emerging drug target for hyperlipidemia and related metabolic disorders) with IC50 values of 6.5 and 11.9 µM, respectively. The molecular interaction and binding mode between the bioactive triterpenoids and ACL were elaborated by conducting a molecular docking study. Meanwhile, the chemotaxonomic significance of the isolated triterpenoids has been briefly discussed.

Preparation of NIR-II Polymer Nanoprobe Through Twisted Intramolecular Charge Transfer and Förster Resonance Energy Transfer of NIR-I Dye.

Near-infrared-II (NIR-II) fluorescence imaging is pivotal in biomedical research. Organic probes exhibit high potential in clinical translation, due to advantages such as precise structure design, low toxicity, and post-modifications convenience. In related preparation, enhancement of NIR-II tail emission from NIR-I dyes is an efficient method. In particular, the promotion of twisted intramolecular charge transfer (TICT) of relevant NIR-I dyes is a convenient protocol. However, present TICT-type probes still show disadvantages in relatively low emission, large particle sizes, or limited choice of NIR-I dyes, etc. Herein, the synthesis of stable small-sized polymer NIR-II fluoroprobes (e.g., 7.2 nm), integrating TICT and Förster resonance energy transfer process to synergistically enhance the NIR-II emission is reported. Strong enhanced emissions can be obtained from various NIR-I dyes and lanthanide elements (e.g., twelvefold at 1250 nm from Nd-DTPA/IR-808 sample). The fluorophore provides high-resolution angiography, with high-contrast imaging on middle cerebral artery occlusion model mice for distinguishing occlusion. The fluorophore can be rapidly excreted from the kidney (urine ≈65% within 4 h) in normal mice and exhibits long-term renal retention on acute kidney injury mice, showing potential applications in the prognosis of kidney diseases. This development provides an effective strategy to design and synthesize effective NIR-II fluoroprobes.

Neuroinflammation in dementia: A meta-analysis of PET imaging studies.

BACKGROUND: Dementia is a major public health challenge for aging societies worldwide. Neuroinflammation is thought to be a key factor in dementia development. The aim of this study was to comprehensively assess translocator protein (TSPO) expression by positron emission tomography (PET) imaging to reveal the characteristics of neuroinflammation in dementia. METHODS: We used a meta-analysis to retrieve literature on TSPO expression in dementia using PET imaging technology, including but not limited to the quality of the study design, sample size, and the type of TSPO ligand used in the study. For the included studies, we extracted key data, including TSPO expression levels, clinical characteristics of the study participants, and specific information on brain regions. Meta-analysis was performed using R software to assess the relationship between TSPO expression and dementia. RESULTS: After screening, 12 studies that met the criteria were included. The results of the meta-analysis showed that the expression level of TSPO was significantly elevated in patients with dementia, especially in the hippocampal region. The OR in the hippocampus was 1.50 with a 95% CI of 1.09 to 1.25, indicating a significant increase in the expression of TSPO in this region compared to controls. Elevated levels of inflammation in the prefrontal lobe and cingulate gyrus are associated with cognitive impairment in patients. This was despite an OR of 1.00 in the anterior cingulate gyrus, indicating that TSPO expression in this region did not correlate significantly with the findings. The overall heterogeneity test showed I² = 51%, indicating moderate heterogeneity. CONCLUSION: This study summarizes the existing literature on TSPO expression in specific regions of the brain in patients with dementia, and also provides some preliminary evidence on the possible association between neuroinflammation and dementia. However, the heterogeneity of results and limitations of the study suggest that we need to interpret these findings with caution. Future studies need to adopt a more rigorous and consistent methodological design to more accurately assess the role of neuroinflammation in dementia, thereby providing a more reliable evidence base for understanding pathological mechanisms and developing potential therapeutic strategies.

Osteopontin-driven partial epithelial-mesenchymal transition governs the development of middle ear cholesteatoma.

Cholesteatoma is a common disease of the middle ear. Currently, surgical removal is the only treatment option and patients face a high risk of relapse. The molecular basis of cholesteatoma remains largely unknown. Here, we show that Osteopontin (OPN), a predominantly secreted protein, plays a crucial role in the development of middle ear cholesteatoma. Global transcriptome analysis revealed the loss of epithelial features and an enhanced immune response in human cholesteatoma tissues. Quantitative RT-PCR and immunohistochemical staining of middle ear cholesteatoma validated the reduced expression of epithelial markers, as well as the elevated expression of mesenchymal markers including Vimentin and Fibronectin, but not N-Cadherin, α-smooth muscle actin (α-SMA) or ferroptosis suppressor protein 1 (FSP1), indicating a partial epithelial-mesenchymal transition (EMT) state. Besides, the expression of OPN was significantly elevated in human cholesteatoma tissues. Treatment with OPN promoted cell proliferation, survival and migration and led to a partial EMT in immortalized human keratinocyte cells. Importantly, blockade of OPN signaling could remarkably improve the cholesteatoma-like symptoms in SD rats. Our mechanistic study demonstrated that the AKT-zinc finger E-box binding homeobox 2 (ZEB2) axis mediated the effects of OPN. Overall, these findings suggest that targeting the OPN signaling represents a promising strategy for the treatment of middle ear cholesteatoma.

Evolution of the FLOWERING LOCUS T-like genes in angiosperms: a core-Lamiales-specific diversification.

Plant life-history is determined by two transitions, the germination and the flowering times, in which the phosphatidylethanolamine-binding proteins (PEBP) FLOWERING LOCUS T (FT) and TERMINAL FLOWER1 (TFL1) play key regulatory roles. Compared to the highly conserved TFL1-likes, FT-like genes vary in copy numbers significantly in gymnosperms and monocots of the angiosperms, while sporadic duplications can be observed in eudicots. Here, via a systematic analysis of the PEBPs in angiosperms with a special focus on twelve representative species featuring high-quality genomes in the Lamiales order, we identified a successive lineage-specific but systematic expansion of FT-like genes in the families of core Lamiales. The first expansion event generated FT1-likes mainly via a core-Lamiales-specific whole-genome-duplication (cL-WGD), while on the other hand, a likely random duplication produced the FT2-likes in the lineages containing Scrophulariaceae and rest of the core Lamiales. Both FT1- and FT2-like genes were further amplified tandemly in some families. These expanded FT-likes featured highly diverged expression patterns and structural variation, indicating functional diversification. Intriguingly, some core Lamiales contained the relict MOTHER OF FT AND TFL1 like 2 (MFT2) that likely expanded in the common ancestor of angiosperms. Our data showcase the highly dynamic lineage-specific expansion of the FT-like genes, thus provide important and fresh evolutionary insights into the gene-regulatory-network underpinning flowering time diversity in Lamiales, and more generally, in angiosperms.

Exploring the neural correlates of fat taste perception and discrimination: Insights from electroencephalogram analysis.

Understanding neural pathways and cognitive processes involved in the transformation of dietary fats into sensory experiences has profound implications for nutritional well-being. This study presents an efficient approach to comprehending the neural perception of fat taste using electroencephalogram (EEG). Through the examination of neural responses to different types of fatty acids (FAs) in 45 participants, we discerned distinct neural activation patterns associated with saturated versus unsaturated fatty acids. The spectrum analysis of averaged EEG signals revealed notable variations in δ and α-frequency bands across FA types. The topographical distribution and source localization results suggested that the brain encodes fat taste with specific activation timings in primary and secondary gustatory cortices. Saturated FAs elicited higher activation in cortical associated with emotion and reward processing. This electrophysiological evidence enhances our understanding of fundamental mechanisms behind fat perception, which is helpful for guiding strategies to manage hedonic eating and promote balanced fat consumption.

Deficiency of neutral cholesterol ester hydrolase 1 (NCEH1) impairs endothelial function in diet-induced diabetic mice.

BACKGROUND: Neutral cholesterol ester hydrolase 1 (NCEH1) plays a critical role in the regulation of cholesterol ester metabolism. Deficiency of NCHE1 accelerated atherosclerotic lesion formation in mice. Nonetheless, the role of NCEH1 in endothelial dysfunction associated with diabetes has not been explored. The present study sought to investigate whether NCEH1 improved endothelial function in diabetes, and the underlying mechanisms were explored. METHODS: The expression and activity of NCEH1 were determined in obese mice with high-fat diet (HFD) feeding, high glucose (HG)-induced mouse aortae or primary endothelial cells (ECs). Endothelium-dependent relaxation (EDR) in aortae response to acetylcholine (Ach) was measured. RESULTS: Results showed that the expression and activity of NCEH1 were lower in HFD-induced mouse aortae, HG-exposed mouse aortae ex vivo, and HG-incubated primary ECs. HG exposure reduced EDR in mouse aortae, which was exaggerated by endothelial-specific deficiency of NCEH1, whereas NCEH1 overexpression restored the impaired EDR. Similar results were observed in HFD mice. Mechanically, NCEH1 ameliorated the disrupted EDR by dissociating endothelial nitric oxide synthase (eNOS) from caveolin-1 (Cav-1), leading to eNOS activation and nitric oxide (NO) release. Moreover, interaction of NCEH1 with the E3 ubiquitin-protein ligase ZNRF1 led to the degradation of Cav-1 through the ubiquitination pathway. Silencing Cav-1 and upregulating ZNRF1 were sufficient to improve EDR of diabetic aortas, while overexpression of Cav-1 and downregulation of ZNRF1 abolished the effects of NCEH1 on endothelial function in diabetes. Thus, NCEH1 preserves endothelial function through increasing NO bioavailability secondary to the disruption of the Cav-1/eNOS complex in the endothelium of diabetic mice, depending on ZNRF1-induced ubiquitination of Cav-1. CONCLUSIONS: NCEH1 may be a promising candidate for the prevention and treatment of vascular complications of diabetes.

Longitudinal validation of cognitive reserve proxy measures: a cohort study in a rural Chinese community.

BACKGROUND: While evidence supports cognitive reserve (CR) in preserving cognitive function, longitudinal validation of CR proxies, including later-life factors, remains scarce. This study aims to validate CR's stability over time and its relation to cognitive function in rural Chinese older adults. METHODS: Within the project on the health status of rural older adults (HSRO), the survey included baseline assessment (2019) and follow-up assessment (2022). 792 older adults (mean age: 70.23 years) were followed up. The confirmatory factor analysis (CFA) was constructed using cognitive reserve proxies that included years of formal education, social support, hobbies, and exercise. We examined the longitudinal validity of the CR factor using confirmatory factor analyses and measurement invariance and explored the association of CR with cognition using Spearman's correlation and Generalized Estimating Equations (GEE). RESULTS: The results showed that CR's CFA structure was stable over time (T0, χ2/df: 3.21/2; RMSEA: 0.02, and T1, χ2/df: 7.47/2; RMSEA: 0.05) and that it accepted both configural and metric invariance (Δχ2/df = 2.28/3, P = 0.52). In addition, it was found that CR had a stable positive relationship with cognitive function across time (T0, r = 0.54; T1, r = 0.49). Furthermore, longitudinal CR were associated with MMSE (ß = 2.25; 95%CI = 2.01 ~ 2.49). CONCLUSIONS: This study provided valuable evidence on the stability and validity of cognitive reserve proxy measures in rural Chinese older adults. Our findings suggested that cognitive reserve is associated with cognitive function over time and highlighted the importance of accumulating cognitive reserve in later life.

A novel fluorescence probe for simultaneous detection of mitochondrial viscosity in hepatic ischemia reperfusion injury models.

Acute liver failure caused by hepatic ischemia reperfusion injury (HIRI) poses a severe threat to life, emphasizing the urgent need for precise and timely early diagnosis. Viscosity, a key parameter reflecting active analyte levels at the cellular level, remains underexplored in relation to HIRI. To address this gap, we have developed a groundbreaking near-infrared molecule rotator, PN, exhibiting exceptional characteristics. PN demonstrates remarkable sensitivity, with a 32-fold change in response to viscosity, ranging from PBS to glycerol solution. PN's distinctive features include maximum emission wavelength 790 nm, as well as an impressive Stokes shift 190 nm. Moreover, PN exhibits the ability to sensitively and selectively differentiate nystatin-induced viscosity changes within living cells, and can be used for the detection of viscosity changes in the HIRI mouse model. This capability enhances our understanding of cellular responses, opening avenues for potential applications within disease models. The versatility of PN extends to its potential role in guiding timely monitoring and imaging of viscosity, offering valuable insights into disease progression.

Pathogenesis and management of low-pressure hydrocephalus: A narrative review.

Patients diagnosed with low-pressure hydrocephalus typically present with enlarged ventricles and unusually low intracranial pressure, often measuring below 5 cmH2O or even below atmospheric pressure. This atypical presentation often leads to low recognition and diagnostic rates. The development of low-pressure hydrocephalus is believed to be associated with a decrease in the viscoelasticity of brain tissue or separation between the ventricular and subarachnoid spaces. Risk factors for low-pressure hydrocephalus include subarachnoid hemorrhage, aqueduct stenosis, prior cranial radiotherapy， ventricular shunting, and cerebrospinal fluid leaks. For potential low-pressure hydrocephalus, diagnostic criteria include neurological symptoms related to hydrocephalus, an Evans index >0.3 on imaging, ICP ≤ 5 cm H2O, symptom improvement with negative pressure drainage, and exclusion of ventriculomegaly caused by neurodegenerative diseases. The pathogenesis and pathophysiological features of low-pressure hydrocephalus differ significantly from other types of hydrocephalus, making it challenging to restore normal ventricular morphology through conventional drainage methods. The primary treatment options for low-pressure hydrocephalus involve negative pressure drainage and third ventriculostomy. With appropriate treatment, most patients can regain their previous neurological function. However, in most cases, permanent shunt surgery is still necessary. Low-pressure hydrocephalus is a rare condition with a high rate of underdiagnosis and mortality. Early identification and appropriate intervention are crucial in reducing complications and improving prognosis.

Physiological and pathological effects of phase separation in the central nervous system.

Phase separation, also known as biomolecule condensate, participates in physiological processes such as transcriptional regulation, signal transduction, gene expression, and DNA damage repair by creating a membrane-free compartment. Phase separation is primarily caused by the interaction of multivalent non-covalent bonds between proteins and/or nucleic acids. The strength of molecular multivalent interaction can be modified by component concentration, the potential of hydrogen, posttranslational modification, and other factors. Notably, phase separation occurs frequently in the cytoplasm of mitochondria, the nucleus, and synapses. Phase separation in vivo is dynamic or stable in the normal physiological state, while abnormal phase separation will lead to the formation of biomolecule condensates, speeding up the disease progression. To provide candidate suggestions for the clinical treatment of nervous system diseases, this review, based on existing studies, carefully and systematically represents the physiological roles of phase separation in the central nervous system and its pathological mechanism in neurodegenerative diseases.

[Corrigendum] Induction of microRNA­let­7a inhibits lung adeno-carcinoma cell growth by regulating cyclin D1.

After the publication of the article, an interested reader drew to the authors' attention that, in the western blots shown in Fig. 5C and D, a pair of data panels were inadvertently duplicated comparing between panels (C) and (D); in addition, the cell migration data shown in Fig. 7F on p. 1852 were selected incorrectly. The authors have examined their original data, and realize that these errors arose inadvertently as a consequence of their mishandling of their data. The revised versions of Figs. 5 and 7, featuring the corrected data for the caspase-8 experiment in Fig. 5C and alternative data for the cell migration assay experiments in Fig. 7F, are shown on the next two pages. The revised data shown for these Figures do not affect the overall conclusions reported in the paper. All the authors agree to the publication of this corrigendum, and are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish this. Furthermore, the authors apologize to the readership for any inconvenience caused. [Oncology Reports 40: 1843-1854, 2018; DOI: 10.3892/or.2018.6593].

A Study of the Adsorption Properties of Individual Atoms on the Graphene Surface: Density Functional Theory Calculations Assisted by Machine Learning Techniques.

In this research, the adsorption performance of individual atoms on the surface of monolayer graphene surface was systematically investigated using machine learning methods to accelerate density functional theory. The adsorption behaviors of over thirty different atoms on the graphene surface were computationally analyzed. The adsorption energy and distance were extracted as the research targets, and the basic information of atoms (such as atomic radius, ionic radius, etc.) were used as the feature values to establish the dataset. Through feature engineering selection, the corresponding input feature values for the input-output relationship were determined. By comparing different models on the dataset using five-fold cross-validation, the mathematical model that best fits the dataset was identified. The optimal model was further fine-tuned by adjusting of the best mathematical ML model. Subsequently, we verified the accuracy of the established machine learning model. Finally, the precision of the machine learning model forecasts was verified by the method of comparing and contrasting machine learning results with density functional theory. The results suggest that elements such as Zr, Ti, Sc, and Si possess some potential in controlling the interfacial reaction of graphene/aluminum composites. By using machine learning to accelerate first-principles calculations, we have further expanded our choice of research methods and accelerated the pace of studying element-graphene interactions.

CO-Tolerant Hydrogen Oxidation Electrocatalysts for Low-Temperature Hydrogen Fuel Cells.

The severe performance degradation of low-temperature hydrogen fuel cells upon exposure to trace amounts of carbon monoxide (CO) impurities in reformate hydrogen fuels is one of the challenges that hinders their commercialization. Despite significant efforts that have been made, the CO-tolerance performance of electrocatalysts for the hydrogen oxidation reaction (HOR) is still unsatisfactory. This Perspective discusses the path forward for the rational design of CO-tolerant HOR electrocatalysts. The fundamentals of the CO-tolerant mechanisms on commercialized platinum group metal (PGM) electrocatalysts via either promoting CO electrooxidation or weakening CO adsorption are provided, and comprehensive discussions based on these strategies are presented with typical examples. Given the recent progress, some emerging strategies, including blocking CO diffusion with a barrier layer and developing non-PGM HOR catalysts, are also discussed. We conclude with a discussion of the strengths and limitations of these strategies along with the perspectives of the major challenges and opportunities for future research on CO-tolerant HOR electrocatalysts.

Infrared Photodissociation Spectroscopy of Mass-Selected Dinuclear Transition Metal Boride Carbonyl Cluster Cations.

The transition-metal-boron bonding interactions and geometric structures of heterodinuclear transition metal carbonyl cluster cations BM(CO)n+ (M = Co, Ni, and Cu) are studied by a combination of the infrared photodissociation spectroscopy and density functional theory calculations at the B3LYP/def2-TZVP level. The BCu(CO)5+ and BCo(CO)6+ cations are characterized as an (CO)2B-M(CO)3/4+ structure involving an σ-type (OC)2B → M(CO)3,4+ dative bonding with end-on carbonyls, while for BNi(CO)5,6+ complexes with a bridged carbonyl, a 3c-2e bond involving the 5σ electrons of the bridged carbonyl and an electron-sharing bond between the B(CO)2 fragment and the Ni(CO)2,3+ subunits were revealed. Moreover, the fundamental driving force of the exclusive existence of a bridged carbonyl group in the boron-nickel complexes has been demonstrated to stem from the desire of the B and Ni centers for the favorable 8- and 18-electron structures.

Genomes of Meniocus linifolius and Tetracme quadricornis reveal the ancestral karyotype and genomic features of core Brassicaceae.

Brassicaceae represents an important plant family from both a scientific and economic perspective. However, genomic features related to the early diversification of this family have not been fully characterized, especially upon the uplift of the Tibetan Plateau, which was followed by increasing aridity in the Asian interior, intensifying monsoons in Eastern Asia, and significantly fluctuating daily temperatures. Here, we reveal the genomic architecture that accompanied early Brassicaceae diversification by analyzing two high-quality chromosome-level genomes for Meniocus linifolius (Arabodae; clade D) and Tetracme quadricornis (Hesperodae; clade E), together with genomes representing all major Brassicaceae clades and the basal Aethionemeae. We reconstructed an ancestral core Brassicaceae karyotype (CBK) containing 9 pseudochromosomes with 65 conserved syntenic genomic blocks and identified 9702 conserved genes in Brassicaceae. We detected pervasive conflicting phylogenomic signals accompanied by widespread ancient hybridization events, which correlate well with the early divergence of core Brassicaceae. We identified a successive Brassicaceae-specific expansion of the class I TREHALOSE-6-PHOSPHATE SYNTHASE 1 (TPS1) gene family, which encodes enzymes with essential regulatory roles in flowering time and embryo development. The TPS1s were mainly randomly amplified, followed by expression divergence. Our results provide fresh insights into historical genomic features coupled with Brassicaceae evolution and offer a potential model for broad-scale studies of adaptive radiation under an ever-changing environment.

Graph theoretical analysis and independent component analysis of diabetic optic neuropathy: A resting-state functional magnetic resonance imaging study.

AIMS: This study aimed to investigate the resting-state functional connectivity and topologic characteristics of brain networks in patients with diabetic optic neuropathy (DON). METHODS: Resting-state functional magnetic resonance imaging scans were performed on 23 patients and 41 healthy control (HC) subjects. We used independent component analysis and graph theoretical analysis to determine the topologic characteristics of the brain and as well as functional network connectivity (FNC) and topologic properties of brain networks. RESULTS: Compared with HCs, patients with DON showed altered global characteristics. At the nodal level, the DON group had fewer nodal degrees in the thalamus and insula, and a greater number in the right rolandic operculum, right postcentral gyrus, and right superior temporal gyrus. In the internetwork comparison, DON patients showed significantly increased FNC between the left frontoparietal network (FPN-L) and ventral attention network (VAN). Additionally, in the intranetwork comparison, connectivity between the left medial superior frontal gyrus (MSFG) of the default network (DMN) and left putamen of auditory network was decreased in the DON group. CONCLUSION: DON patients altered node properties and connectivity in the DMN, auditory network, FPN-L, and VAN. These results provide evidence of the involvement of specific brain networks in the pathophysiology of DON.

Identification of Novel Bisamide-Decorated Benzotriazole Derivatives as Anti-Phytopathogenic Virus Agents: Bioactivity Evaluation and Computational Simulation.

As a notorious phytopathogenic virus, the tobacco mosaic virus (TMV) severely reduced the quality of crops worldwide and caused critical constraints on agricultural production. The development of novel virucides is a persuasive strategy to address this predicament. Herein, a series of novel bisamide-decorated benzotriazole derivatives were elaborately prepared and screened. Biological tests implied that the optimized compound 7d possessed the most brilliant antiviral inactive profile (EC50 = 157.6 µg/mL) and apparently surpassed that of commercial ribavirin (EC50 = 442.1 µg/mL) 2.8-fold. The preliminary antiviral mechanism was elaborately investigated via transmission electron microscopy, microscale thermophoresis (MST) determination, RT-qPCR, and Western blot analysis. The results showed that compound 7d blocked the assembly of TMV by binding with coat protein (Kd = 0.7 µM) and suppressed TMV coat protein gene expression and biosynthesis process. Computational simulations indicated that 7d displayed strong H-bonds and pi interactions with TMV coat protein, affording a lower binding energy (ΔGbind = -17.8 kcal/mol) compared with Ribavirin (ΔGbind = -10.7 kcal/mol). Overall, current results present a valuable perception of bisamide decorated benzotriazole derivatives with appreciably virustatic competence and should be profoundly developed as virucidal candidates in agrochemical.