Mode of inheritance for pesticide resistance, importance and prevalence: A review.

Pesticides remain a cornerstone in pest control, yet their extensive and irrational use also fuel the evolution of resistance. This review analyzes globally published experimental data spanning from the 1970s to 2023 to focus on how phenotypic and underlying genotypic variations are shaped during the selective response. The discussion commences with an examination of sex-linked/maternal resistance. Observations related to maternal inheritance have enriched our understanding of pesticide mode of action, notably exemplified by bifenazate. However, the predominant control of the resistant phenotype is attributed to autosomal traits, with a high prevalence of dominance and monogenic inheritance observed, also evident in field strains. This observation raises concerns regarding resistance management strategies due to their potential to accelerate the spread of resistance. The interplay between dominance levels and monogenic inheritance is further explored, with dominant traits being significantly more prevalent in polygenic inheritance. This observation may be attributed to the accumulation of enhanced metabolism. Notably, further analysis indicated that field strains exhibit a higher incidence of monogenic inheritance compared to other selected strains, aligning with established theoretical frameworks. In conclusion, the genetic architecture of resistance warrants increased research focus for its pivotal role in guiding resistance management strategies and advancing fundamental research.

Contrasting roles of cytochrome P450s in amitraz and chlorfenapyr resistance in the crop pest Tetranychus urticae.

The molecular mechanisms of amitraz and chlorfenapyr resistance remain only poorly understood for major agricultural pests and vectors of human diseases. This study focusses on a multi-resistant field strain of the crop pest Tetranychus urticae, which could be readily selected in the laboratory to high levels of amitraz and chlorfenapyr resistance. Toxicity experiments using tralopyril, the active toxophore of chlorfenapyr, suggested decreased activation as a likely mechanism underlying resistance. Starting from the same parental strain, transcriptome profiling revealed that a cluster of detoxifying genes was upregulated after amitraz selection, but unexpectedly downregulated after chlorfenapyr selection. Further functional validation associated the upregulation of CYP392A16 with amitraz metabolism and the downregulation of CYP392D8 with reduced activation of chlorfenapyr to tralopyril. Genetic mapping (QTL analysis by BSA) was conducted in an attempt to unravel the genetic mechanisms of expression variation and resistance. This revealed that chlorfenapyr resistance was associated with a single QTL, while 3 QTLs were uncovered for amitraz resistance. Together with the observed contrasting gene expression patterns, we argue that transcriptional regulators most likely underly the distinct expression profiles associated with resistance, but these await further functional validation.

BGB-A445, a novel non-ligand-blocking agonistic anti-OX40 antibody, exhibits superior immune activation and antitumor effects in preclinical models.

OX40 is a costimulatory receptor that is expressed primarily on activated CD4+, CD8+, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.

Recombinant expression and characterization of GSTd3 from a resistant population of Anopheles arabiensis and comparison of DDTase activity with GSTe2.

The development of insecticide resistance in malaria vectors is a challenge for the global effort to control and eradicate malaria. Glutathione S-transferases (GSTs) are multifunctional enzymes involved in the detoxification of many classes of insecticides. For mosquitoes, it is known that overexpression of an epsilon GST, GSTe2, confers resistance towards DDT and pyrethroids. In addition to GSTe2, consistent overexpression of a delta class GST, GSTd3, has been observed in insecticide resistant populations of different malaria vector species. However, the functional role of GSTd3 towards DDT resistance has not yet been investigated. Here, we recombinantly expressed both GSTe2 and GSTd3 from Anopheles arabiensis and compared their metabolic activities against DDT. Both AaGSTd3 and AaGSTe2 exhibited CDNB-conjugating and glutathione peroxidase activity and DDT metabolism was observed for both GSTs. However, the DDT dehydrochlorinase activity exhibited by AaGSTe2 was much higher than for AaGSTd3, and AaGSTe2 was also able to eliminate DDE although the metabolite could not be identified. Molecular modeling revealed subtle differences in the binding pocket of both enzymes and a better fit of DDT within the H-site of AaGSTe2. The overexpression but much lower DDT metabolic activity of AaGSTd3, might suggest that AaGSTd3 sequesters DDT. These findings highlight the complexity of insecticide resistance in the major malaria vectors and the difficulties associated with control of the vectors using DDT, which is still used for indoor residual spraying.

Increased metabolism in combination with the novel cytochrome b target-site mutation L258F confers cross-resistance between the Qo inhibitors acequinocyl and bifenazate in Tetranychus urticae.

Acequinocyl and bifenazate are potent acaricides acting at the Qo site of complex III of the electron transport chain, but frequent applications of these acaricides have led to the development of resistance in spider mites. Target-site resistance caused by mutations in the conserved cd1- and ef-helices of the Qo pocket of cytochrome b has been elucidated as the main resistance mechanism. We therefore monitored Qo pocket mutations in European field populations of Tetranychus urticae and uncovered a new mutation, L258F. The role of this mutation was validated by revealing patterns of maternal inheritance and by the independently replicated introgression in an unrelated susceptible genetic background. However, the parental strain exhibited higher resistance levels than conferred by the mutation alone in isogenic lines, especially for acequinocyl, implying the involvement of strong additional resistance mechanisms. This was confirmed by revealing a polygenic inheritance pattern with classical genetic crosses and via synergism experiments. Therefore, a genome-wide expression analysis was conducted that identified a number of highly overexpressed detoxification genes, including many P450s. Functional expression revealed that the P450 CYP392A11 can metabolize bifenazate by hydroxylation of the ring structure. In conclusion, the novel cytochrome b target-site mutation L258F was uncovered in a recently collected field strain and its role in acequinocyl and bifenazate resistance was validated. However, the high level of resistance in this strain is most likely caused by a combination of target-site resistance and P450-based increased detoxification, potentially acting in synergism.

Processing High-Performance Thermoelectric Materials in a Green Way: A Proof of Concept in Cold Sintered PbTe0.94Se0.06.

For years, most of the advanced polycrystalline thermoelectric (TE) materials are fabricated by spark plasma sintering (SPS) in the research field, mainly because of its high processing efficiency. However, issues like high energy consumption and an expensive apparatus have prevented the application of this strategy in industry. Herein, taking PbTe0.94Se0.06 (PTS) as a typical n-type mid-temperature material, we demonstrate that the cold sintering process (CSP) can serve as a green and cost-effective technology for preparing advanced TE materials. By selecting the solvothermal precursors as liquid sintering aids, the CSP-densified PTS shows a maximum figure of merit of 0.96 at 700 K, which is on par with, if not better than, the reported similar materials prepared by SPS. This remarkable performance is ascribed to the distinct densification procedure in the CSP: (1) the ultralow temperature alleviates the precipitation of Pb, which preserves the high carrier concentration of PTS; (2) the transient liquid phase forms intimate grain boundaries comparable to the high-temperature sintered one, leading to a high carrier mobility; (3) the dissolution-precipitation process greatly restrains the coarsening of precipitates, which effectively suppresses the bipolar effect and lattice thermal conductivity due to enhanced scattering. We believe that these results can greatly encourage the application of CSP in the future development of TE materials.

Chemical Reaction and Bonding Mechanism at the Polymer-Metal Interface.

Polymer-metal hybrid structures have attracted significant attention recently due to their advantage of great weight reduction and excellent integrated physical/chemical properties. However, due to great physicochemical differences between polymers and metals, obtaining an interface with high bonding strength is a challenge, which makes it critically important to clarify the underlying bonding mechanisms. In the present research, we focused on revealing the underlying bonding mechanisms of a laminated Cr-coated steel-ethylene acrylic acid (EAA) strip prepared by hot roll bonding from the microscale to the molecular scale with experimental evidence. The microscale mechanical interlocking was analyzed and proven by scanning white light interferometry and scanning electron microscopy (SEM) by means of observing the surface and cross-sectional morphologies. Additionally, interfacial phases and chemical compositions were analyzed by transmission electron microscopy (TEM) and energy-dispersive X-ray spectroscopy (EDX). More directly and effectively, the interface was successfully exposed for X-ray photoelectron spectroscopy (XPS) analysis. Combined with time-of-flight secondary ion mass spectroscopy (ToF-SIMS) and depth profiling analysis, the formation of -(O═)C-O-Cr and -C-(O-Cr)2 covalent bonds through chemical reactions at the interface between -COOH and Cr2O3 was verified. Based on these characterization results, interfacial bonding mechanisms for the laminated Cr-coated steel-EAA strip were clearly identified to be chemical bonding and micromechanical interlocking, along with hydrogen bonding, which were all demonstrated with solid experimental evidence. In addition, 3D-render view and cross-section images of typical ion fragments at the interface were used to reveal the interfacial structure more comprehensively. The contributions of hydrogen bonds and covalent bonds to the interface were evaluated and compared for the first time. This study provides both methodological and theoretical guidance for investigating and understanding interfacial bonding formation in polymer-metal hybrid structures.

The H92R substitution in PSST is a reliable diagnostic biomarker for predicting resistance to mitochondrial electron transport inhibitors of complex I in European populations of Tetranychus urticae.

BACKGROUND: Mitochondrial Electron Transport Inhibitors of complex I (METI-I), such as tebufenpyrad and fenpyroximate, are acaricides that have been used extensively to control Tetranychus urticae Koch (Acari: Tetranychidae) for more than 20 years. Because of the ability of this spider mite to rapidly develop acaricide resistance, field (cross-) resistance monitoring and elucidation of resistance mechanisms are extremely important for resistance management (RM). In the present study, 42 European T. urticae field populations were screened for tebufenpyrad and fenpyroximate resistance, and the correlation between resistance and the H92R substitution in PSST was investigated. RESULTS: According to the calculated lethal concentration values that kill 90% of the population (LC90 ), tebufenpyrad and fenpyroximate would fail to control many of the collected populations at recommended field rates. Six populations exhibited high to very high resistance levels (200- to over 1950-fold) to both METI-Is. Analysis based on the LC50 values displayed a clear correlation between tebufenpyrad and fenpyroximate resistance, further supporting cross-resistance, which is of great operational importance in acaricide RM. The previously uncovered METI-I target-site mutation H92R in the PSST homologue of complex I (NADH:ubiquinone oxidoreductase) was found with high allele frequencies in populations resistant to tebufenpyrad and fenpyroximate. Synergist assays showed this mutation is not the only factor involved in METI-I resistance and additive or synergistic effects of multiple mechanisms most likely determine the phenotypic strength. CONCLUSIONS: The predictive value of resistance by H92R is very high in European populations and offers great potential to be used as a molecular diagnostic marker for METI-I resistance. © 2022 Society of Chemical Industry.

Divergent molecular evolution in glutathione S-transferase conferring malathion resistance in the oriental fruit fly, Bactrocera dorsalis (Hendel).

Insect glutathione S-transferases (GSTs) are important in insecticide detoxification and Insect-specific GSTs, Epsilon and Delta, have largely expanded in insects. In this study, we functionally expressed and characterized an epsilon class GST gene (BdGSTe8), predominant in the adult Malpighian tubules of Bactrocera dorsalis. This gene may be associated with malathion resistance based on transcriptional studies of resistant and susceptible strains. RNA interference-mediated knockdown of this gene significantly recovered malathion susceptibility in the adults of a malathion-resistant strain, and overexpression of BdGSTe8 enhanced resistance in transgenic Drosophila. Analysis of BdGSTe8 polymorphism showed that several point mutations may be associated with metabolic resistance to malathion. A cytotoxicity assay in Escherichia coli indicated that both of the recombinant BdGSTe8 proteins may play a functional role in protecting cells from toxicity. The allele of BdGSTe8-B conferred higher levels of malathion detoxification capability. Liquid chromatography and ultra-performance liquid chromatography-tandem mass spectrometry analysis showed that the BdGSTe8-A allele did not metabolize malathion directly. However, the BdGSTe8-B allele was involved in the direct metabolism of malathion, which was caused by a mutation in V128A. Further analysis of the sequence suggests that BdGSTe8 evolved rapidly. It maybe play the role of a backup gene and could become a new gene in the future in order to retain the ability of detoxification of malathion, which was driven by positive selection. These results suggest that divergent molecular evolution in BdGSTe8 has played a role in metabolic resistance to malathion in B. dorsalis.

Hsp90 Inhibitor SNX-2112 Enhances TRAIL-Induced Apoptosis of Human Cervical Cancer Cells via the ROS-Mediated JNK-p53-Autophagy-DR5 Pathway.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent cancer cell apoptosis-inducing factor that can induce apoptosis in a variety of cancer cells. However, resistance to TRAIL in cancer cells is a huge obstacle in creating effective TRAIL-targeted clinical therapies. Thus, agents that can either enhance the effect of TRAIL or overcome its resistance are needed. In this study, we combined TRAIL with SNX-2112, an Hsp90 inhibitor we previously developed, to explore the effect and mechanism that SNX-2112 enhanced TRAIL-induced apoptosis in cervical cancer cells. Our results showed that SNX-2112 markedly enhanced TRAIL-induced cytotoxicity in HeLa cells, and this combination was found to be synergistic. Additionally, we found that SNX-2112 sensitized TRAIL-mediated apoptosis caspase-dependently in TRAIL-resistant HeLa cells. Mechanismly, SNX-2112 downregulated antiapoptosis proteins, including Bcl-2, Bcl-XL, and FLIP, promoted the accumulation of reactive oxygen species (ROS), and increased the expression levels of p-JNK and p53. ROS scavenger NAC rescued SNX-2112/TRAIL-induced apoptosis and suppressed SNX-2112-induced p-JNK and p53. Moreover, SNX-2112 induced the upregulation of death-receptor DR5 in HeLa cells. The silencing of DR5 by siRNA significantly decreased cell apoptosis by the combined effect of SNX-2112 and TRAIL. In addition, SNX-2112 inhibited the Akt/mTOR signaling pathway and induced autophagy in HeLa cells. The blockage of autophagy by bafilomycin A1 or Atg7 siRNA abolished SNX-2112-induced upregulation of DR5. Meanwhile, ROS scavenger NAC, JNK inhibitor SP600125, and p53 inhibitor PFTα were used to verify that autophagy-mediated upregulation of DR5 was regulated by the SNX-2112-stimulated activation of the ROS-JNK-p53 signaling pathway. Thus, the combination of SNX-2112 and TRAIL may provide a novel strategy for the treatment of human cervical cancer by overcoming cellular mechanisms of apoptosis resistance.