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BACKGROUND Milbemectin and abamectin are frequently used to control the spider mite Tetranychus urticae. The development of abamectin resistance in this major pest has become an increasing problem worldwide, potentially compromising the use of milbemectin. In this study, a large collection of European field populations was screened for milbemectin and abamectin resistance, and both target‐site and metabolic (cross‐)resistance mechanisms were investigated. RESULTS: High to very high levels of abamectin resistance were found in one third of all populations, while milbemectin resistance levels were low for most populations. The occurrence of well‐known target‐site resistance mutations in glutamate‐gated chloride channels (G314D in GluCl1 and G326E in GluCl3) was documented in the most resistant populations. However, a new mutation, I321T in GluCl3, was also uncovered in three resistant populations, while a V327G and L329F mutation was found in GluCl3 of one resistant population. A differential gene‐expression analysis revealed the overexpression of detoxification genes, more specifically cytochrome P450 monooxygenase (P450) and UDP‐glycosyltransferase (UGT) genes. Multiple UGTs were functionally expressed, and their capability to glycosylate abamectin and milbemectin, was tested and confirmed. CONCLUSIONS: We found a clear correlation between abamectin and milbemectin resistance in European T. urticae populations, but as milbemectin resistance levels were low, the observed cross‐resistance is probably not of operational importance. The presence of target‐site resistance mutations in GluCl genes was confirmed in most but not all resistant populations. Gene‐expression analysis and functional characterization of P450s and UGTs suggests that also metabolic abamectin resistance mechanisms are common in European T. urticae populations. © 2020 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

BACKGROUND: In spider mites, mutations in the mitochondrial cytochrome b Qo pocket have been reported to confer resistance to the Qo inhibitors bifenazate and acequinocyl. In this study, we surveyed populations of the two‐spotted spider mite Tetranychus urticae for mutations in cytochrome b, linked newly discovered mutations with resistance and assessed potential pleiotropic fitness costs. RESULTS: We identified two novel mutations in the Qo site: G132A (equivalent to G143A in fungi resistant to strobilurins) and G126S + A133T (previously reported to cause bifenazate and acequinocyl resistance in Panonychus citri). Two T. urticae strains carrying G132A were highly resistant to bifenazate but not acequinocyl, whereas a strain with G126S + A133T displayed high levels of acequinocyl resistance, but only moderate levels of bifenazate resistance. Bifenazate and acequinocyl resistance were inherited maternally, providing strong evidence for the involvement of these mutations in the resistance phenotype. Near isogenic lines carrying G132A revealed several fitness penalties in T. urticae; a lower net reproductive rate (R0), intrinsic rate of increase (rm) and finite rate of increase (LM); a higher doubling time (DT); and a more male‐biased sex ratio. CONCLUSIONS: Several lines of evidence were provided to support the causal role of newly discovered cytochrome b mutations in bifenazate and acequinocyl resistance. Because of the fitness costs associated with the G132A mutation, resistant T. urticae populations might be less competitive in a bifenazate‐free environment, offering opportunities for resistance management. © 2019 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS) is the most common cause of death in cardiovascular diseases and poses severe challenges to human life and safety. Epigenetics plays a vital role in every single link of AS. Whereas, how epigenetics regulates its development and regression is still unknown. Sirt3, a recognized histone deacetylase, having been reported to be involved in other acylation processes in recent years, is broadening its role in epigenetic modifications. Sirt3 is an important factor in the normal physiology of blood vessels through deacetylation of mitochondrial proteins and participates in various metabolic activities. Besides, medical research targeting Sirt3 is in full swing as well. This review combining histone deacetylase Sirt3 with AS, aims to clarify the latest progress in the significant role of Sirt3 in the development and regression of AS and to provide a novel prospect for a new regulatory factor and potential intervention target for AS. [Display omitted] • Sirt3 is a recognized histone deacetylase, having been reported to be involved in other acylation processes. • Sirt3 potentially plays a protective role in atherosclerosis. • Therapeutic targeting of Sirt3 represents a highly promising strategy in atherosclerosis. [ABSTRACT FROM AUTHOR]

Introduction: The systematic review and network meta-analysis (NMA) consolidate all relevant randomized controlled trials (RCTs) related to initial immunotherapy treatments for advanced esophageal squamous cell carcinoma (ESCC). Our goal is to thoroughly assess the effectiveness and safety of various immunotherapy methods, focusing on overall survival (OS) and progression-free survival (PFS) among patients with advanced ESCC positive for PD-L1., Methods: We conducted a systematic search of the PubMed, Embase, Cochrane Library, and Web of Science databases, covering all records from their inception until January 22, 2024. The inclusion criteria targeted patients with advanced ESCC undergoing first-line immunotherapy or chemotherapy, limiting the study selection to randomized controlled trials (RCTs) exclusively. The study upholds the values of openness, originality, and dependability, as evidenced by its enrollment in the Prospective Register of Systematic Reviews (CRD42024504992)., Results: Our analysis encompasses 7 RCTs, totaling 4688 patients, and evaluates 8 distinct immunotherapy combinations. In advanced ESCC patients irrespective of PD-L1 expression, both sintilimab-chemotherapy and toripalimab-chemotherapy regimens demonstrated comparable OS benefits (HR=0.92, 95% CI: 0.64-1.33). The most pronounced PFS advantages were seen with sintilimab-chemotherapy and camrelizumab-chemotherapy as compared to standard chemotherapy (HR=0.56, 95% CI: 0.46-0.58). Notably, camrelizumab-chemotherapy (HR=0.83, 95% CI: 0.59-1.16) and nivolumab-ipilimumab (HR=0.84, 95% CI: 0.60-1.17) demonstrated significant safety profiles over chemotherapy alone. Subgroup analysis based on PD-L1 expression revealed nivolumab-chemotherapy to yield the highest OS benefit (HR=0.54, 95% CI: 0.37-0.79) in ESCC patients with PD-L1 expression ≥1%. Furthermore, camrelizumab-chemotherapy (HR=0.51, 95% CI: 0.39-0.67) exhibited superior PFS benefits. Among patients with PD-L1 expression ≥10%, camrelizumab-chemotherapy (HR=0.52, 95% CI: 0.35-0.78) emerged as the most efficacious in improving OS, while serplulimab-chemotherapy (HR=0.48, 95% CI: 0.34-0.68) was associated with the longest PFS benefit., Conclusion: The integration of immune checkpoint inhibitors (ICIs) with chemotherapy appears to significantly enhance survival outcomes in patients with advanced ESCC compared to chemotherapy alone. Sintilimab-chemotherapy is potentially the optimal regimen for patients without PD-L1 expression. In contrast, nivolumab-chemotherapy and camrelizumab-chemotherapy are likely to offer the best OS and PFS benefits, respectively, in patients with PD-L1 expression ≥1%. Among those with PD-L1 expression ≥10%, camrelizumab-chemotherapy is projected to provide the greatest OS advantage, whereas serplulimab-chemotherapy is anticipated to offer the most prolonged PFS benefit. Since most of the patients in this study originated from Asia, the above findings are more applicable to the Asian population., Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024504992., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Cao, Zhang, Zhao, Chen, Li, Shang, Sun, Jiang, Wang and Xue.)

Background: The cys-loop ligand-gated ion channels, including the glutamate-gated chloride channel (GluCl) and GABA-gated chloride channel (Rdl) are important targets for drugs and pesticides. The macrocyclic lactone abamectin primarily targets GluCl and is commonly used to control the spider mite Tetranychus urticae, an economically important crop pest. However, abamectin resistance has been reported for multiple T. urticae populations worldwide, and in several cases was associated with the mutations G314D in GluCl1 and G326E in GluCl3. Recently, an additional I321T mutation in GluCl3 was identified in several abamectin resistant T. urticae field populations. Here, we aim to functionally validate this mutation and determine its phenotypic strength., Results: The GluCl3 I321T mutation was introgressed into a T. urticae susceptible background by marker-assisted backcrossing, revealing contrasting results in phenotypic strength, ranging from almost none to 50-fold. Next, we used CRISPR-Cas9 to introduce I321T, G314D and G326E in the orthologous Drosophila GluCl. Genome modified flies expressing GluCl I321T were threefold less susceptible to abamectin, while CRISPRed GluCl G314D and G326E flies were lethal. Last, functional analysis in Xenopus oocytes revealed that the I321T mutation might reduce GluCl3 sensitivity to abamectin, but also suggested that all three T. urticae Rdls are affected by abamectin., Conclusion: Three different techniques were used to characterize the role of I321T in GluCl3 in abamectin resistance and, combining all results, our analysis suggests that the I321T mutation has a complex role in abamectin resistance. Given the reported subtle effect, additional synergistic factors in resistance warrant more investigation. © 2020 Society of Chemical Industry., (© 2020 Society of Chemical Industry.)