Resistance Management Research Articles

Fitness costs, realized heritability, and mechanism of resistance to tenvermectin B in Plutella xylostella.

Tenvermectin B (TVM-B) and five TVM-B analogs were produced by fermentation of a genetically engineered strain Streptomyces avermitilis HU02, and TVM-B is being developed as a new insecticide. Through 11 generations of resistance selection against TVM-B in the diamondback moth, Plutella xylostella, the median lethal concentration (LC50) was increased from 14.84 to 1213.73 mg L-1. The resistance to TVM-B in P. xylostella developed fast and its realized heritability was high (h2 = 0.2901 (F7), h2 = 0.4070 (F11)). However, the relative fitness was 0.6916 suggesting a fitness cost in the resistant strains. The fitness cost was partially explained by the upregulation of the detoxification enzyme activity by 2.15 folds in carboxylate esterase (CarE) and the gene expressions of ATP-binding cassette transporter gene (ABCC2) and the alpha subunit of the glutamate-gated chloride channel (GluCl) by 1.70- and 2.32 folds, respectively. The resistance was also explained by two points of mutations at the alpha subunit of the glutamate-gated chloride channel in the P. xylostella (PxGluClα) subunit in F11. However, there was little change in the binding affinity. These results provided helpful information for the mechanism study of TVM-B resistance and will be conducive to designing rational resistance management strategies in P. xylostella.

Targeting Acute Myeloid Leukemia Stem Cells through Perturbation of Mitochondrial Calcium.

Acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL-2, creating a therapeutic opportunity to target LSCs using the BCL-2 inhibitor venetoclax. Although venetoclax-based regimens have shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug-responsive and nonresponsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate an active metabolic (i.e., OXPHOS) status with relatively high levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter. We demonstrate that inhibition of calcium uptake reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in LSCs and provide an avenue for clinical management of venetoclax resistance. Significance: We identify increased utilization of mitochondrial calcium as a distinct metabolic requirement of venetoclax-resistant LSCs and demonstrate the potential of targeting mitochondrial calcium uptake as a therapeutic strategy.

A narrative review of wastewater surveillance: pathogens of concern, applications, detection methods, and challenges.

The emergence and resurgence of pathogens have led to significant global health challenges. Wastewater surveillance has historically been used to track water-borne or fecal-orally transmitted pathogens, providing a sensitive means of monitoring pathogens within a community. This technique offers a comprehensive, real-time, and cost-effective approach to disease surveillance, especially for diseases that are difficult to monitor through individual clinical screenings. This narrative review examines the current state of knowledge on wastewater surveillance, emphasizing important findings and techniques used to detect potential pathogens from wastewater. It includes a review of literature on the detection methods, the pathogens of concern, and the challenges faced in the surveillance process. Wastewater surveillance has proven to be a powerful tool for early warning and timely intervention of infectious diseases. It can detect pathogens shed by asymptomatic and pre-symptomatic individuals, providing an accurate population-level view of disease transmission. The review highlights the applications of wastewater surveillance in tracking key pathogens of concern, such as gastrointestinal pathogens, respiratory pathogens, and viruses like SARS-CoV-2. The review discusses the benefits of wastewater surveillance in public health, particularly its role in enhancing existing systems for infectious disease surveillance. It also addresses the challenges faced, such as the need for improved detection methods and the management of antimicrobial resistance. The potential for wastewater surveillance to inform public health mitigation strategies and outbreak response protocols is emphasized. Wastewater surveillance is a valuable tool in the fight against infectious diseases. It offers a unique perspective on the spread and evolution of pathogens, aiding in the prevention and control of disease epidemics. This review underscores the importance of continued research and development in this field to overcome current challenges and maximize the potential of wastewater surveillance in public health.

Bridging Diagnostic Gaps: Utilising HiCrome Agar and Tetrazolium Reduction Medium for the Rapid and Presumptive Identification and Speciation of Candida Species in Vulvovaginal Candidiasis in Low-Resource Environments.

Background Vulvovaginal candidiasis (VVC) is a common fungal infection caused by an overgrowth of Candida species, primarily Candida albicans (C. albicans). Using HiCrome agar and tetrazolium reduction medium offers cost-effectiveness in Candida detection by eliminating the need for additional tests, reducing equipment costs compared to automated systems, and simplifying workflow with direct species identification while maintaining high specificity. They expedite detection by directly identifying Candida species based on colony colour, bypassing the multiple steps of phenotypic methods. This efficiency saves time in the laboratory, providing rapid results without the extended processing times associated with automated systems and facilitating prompt diagnosis and treatment decisions. These diagnostic tools are especially valuable in low-resource environments where a quick and accurate diagnosis of VVC is crucial for effective treatment and management of antifungal resistance. Aims and objectives This study aims to evaluate the efficacy of HiCrome agar and tetrazolium reduction medium's efficacy in speciating Candida species in VVC cases. Materials and methods A cross-sectional observational study was conducted at Saveetha Medical College and Hospitals, Chennai, India, over six months. High vaginal swabs from 126 patients suspected of VVC were collected and plated on Sabouraud dextrose agar (SDA), HiCrome Candida differential agar (Himedia, Mumbai, India), and tetrazolium reduction medium. The results were compared with those obtained from the VITEK2 compact system (bioMérieux, Marcy-l'Étoile, France). Results Of the 126 samples, 74.6% showed single yeast infections, 7.9% displayed mixed yeast infections, and 17.5% showed no growth. A total of 114 Candida isolates were identified. Both HiCrome agar and tetrazolium reduction medium accurately identified all isolates, with complete concordance with the VITEK2 compact system. The most commonly isolated species were C. albicans (55.2%), Candida tropicalis (32.4%), Candida glabrata (8.8%), and Candida parapsilosis (3.6%). Both media provided rapid and accurate presumptive identification in low-resource settings. Conclusions HiCrome agar and tetrazolium reduction medium demonstrated high sensitivity and specificity in identifying Candida species. These methods are reliable for rapid and accurate diagnosis, particularly in resource-limited settings. However, they may require supplementary tests for definitive species identification. The adoption of these diagnostic tools represents a significant advancement in clinical microbiology, improving VVC management and addressing antifungal resistance.

In vitro selection and analysis of SARS-CoV-2 nirmatrelvir resistance mutations contributing to clinical virus resistance surveillance.

To facilitate the detection and management of potential clinical antiviral resistance, in vitro selection of drug-resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) against the virus Mpro inhibitor nirmatrelvir (Paxlovid active component) was conducted. Six Mpro mutation patterns containing T304I alone or in combination with T21I, L50F, T135I, S144A, or A173V emerged, with A173V+T304I and T21I+S144A+T304I mutations showing >20-fold resistance each. Biochemical analyses indicated inhibition constant shifts aligned to antiviral results, with S144A and A173V each markedly reducing nirmatrelvir inhibition and Mpro activity. SARS-CoV-2 surveillance revealed that in vitro resistance-associated mutations from our studies and those reported in the literature were rarely detected in the Global Initiative on Sharing All Influenza Data database. In the Paxlovid Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients trial, E166V was the only emergent resistance mutation, observed in three Paxlovid-treated patients, none of whom experienced COVID-19-related hospitalization or death.

Functional Validation of Endogenous Redox Partner Cytochrome P450 Reductase Reveals the Key P450s CYP6P9a/-b as Broad Substrate Metabolizers Conferring Cross-Resistance to Different Insecticide Classes in Anopheles funestus.

The versatility of cytochrome P450 reductase (CPR) in transferring electrons to P450s from other closely related species has been extensively exploited, e.g., by using An. gambiae CPR (AgCPR), as a homologous surrogate, to validate the role of An. funestus P450s in insecticide resistance. However, genomic variation between the AgCPR and An. funestus CPR (AfCPR) suggests that the full metabolism spectrum of An. funestus P450s might be missed when using AgCPR. To test this hypothesis, we expressed AgCPR and AfCPR side-by-side with CYP6P9a and CYP6P9b and functionally validated their role in the detoxification of insecticides from five different classes. Major variations were observed within the FAD- and NADP-binding domains of AgCPR and AfCPR, e.g., the coordinates of the second FAD stacking residue AfCPR-Y456 differ from that of AgCPR-His456. While no significant differences were observed in the cytochrome c reductase activities, when co-expressed with their endogenous AfCPR, the P450s significantly metabolized higher amounts of permethrin and deltamethrin, with CYP6P9b-AfCPR membrane metabolizing α-cypermethrin as well. Only the CYP6P9a-AfCPR membrane significantly metabolized DDT (producing dicofol), bendiocarb, clothianidin, and chlorfenapyr (bioactivation into tralopyril). This demonstrates the broad substrate specificity of An. funestus CYP6P9a/-b, capturing their role in conferring cross-resistance towards unrelated insecticide classes, which can complicate resistance management.

Longitudinal trials illustrate interactive effects between declining Bt efficacy against Helicoverpa zea (Lepidoptera: Noctuidae) and planting dates of corn.

Helicoverpa zea (Boddie) (Lepidoptera: Noctuidae) has evolved resistance to insecticidal toxins from Bacillus thuringiensis (Bt) Berliner (Bacillales: Bacillaceae) expressed in genetically engineered corn, Zea mays L. This study provides an overview of field trials from Georgia, North Carolina, and South Carolina evaluating Bt and non-Bt corn hybrids from 2009 to 2022 to show changes in susceptibility in H. zea to Bt corn. The reduction in kernel injury relative to a non-Bt hybrid averaged across planting dates generally declined over time for Cry1A.105 + Cry2Ab2 corn. In addition, there was a significant interaction with planting date used as a covariate. The reduction in kernel injury remained above 80% and did not vary with planting date from 2009 to 2014, whereas a significant decline with planting date was found in this reduction from 2015 to 2022. For Cry1Ab + Cry1F corn, the reduction in kernel injury relative to a non-Bt hybrid averaged across planting dates did not vary among years. The reduction in kernel injury significantly declined with planting date from 2012 to 2022. Kernel injury as a proxy for H. zea pressure was greater in late-planted trials in non-Bt corn hybrids. Our study showed that Bt hybrids expressing Cry1A.105 + Cry2Ab2 are now less effective in later planted trials in reducing H. zea injury; however, this was not the case during the earlier years of adoption of corn expressing these 2 toxins when resistance alleles were likely less frequent in H. zea populations. The implications for management of H. zea and for insect resistance management are discussed.

Expression and Functional Analysis of Two Cytochrome P450 Monooxygenase Genes and a UDP-Glycosyltransferase Gene Linked with Thiamethoxam Resistance in the Colorado Potato Beetle.

Cytochrome P450 monooxygenases (P450s) and UDP-glycosyltransferases (UGTs) are involved in the evolution of insecticide resistance. Leptinotarsa decemlineata (Say), the Colorado potato beetle (CPB), is a notorious insect that has developed resistance to various insecticides including neonicotinoids. This study investigated whether the differentially expressed P450 genes CYP9Z140 and CYP9AY1 and UGT gene UGT321AP1, found in our transcriptome results, conferred resistance to thiamethoxam in L. decemlineata. Resistance monitoring showed that the sampled field populations of L. decemlineata adults collected from Urumqi City and Qapqal, Jimsar, and Mulei Counties of Xinjiang in 2021-2023 developed low levels of resistance to thiamethoxam with resistance ratios ranging from 6.66- to 9.52-fold. Expression analyses indicated that CYP9Z140, CYP9AY1, and UGT321AP1 were significantly upregulated in thiamethoxam-resistant populations compared with susceptible populations. The expression of all three genes also increased significantly after thiamethoxam treatment compared with the control. Spatiotemporal expression patterns showed that the highest expression of CYP9Z140 and CYP9AY1 occurred in pupae and the midgut, whereas UGT321AP1 was highly expressed in adults and Malpighian tubules. Knocking down all three genes individually or simultaneously using RNA interference increased the sensitivity of adult L. decemlineata to thiamethoxam. These results suggest that overexpression of CYP9Z140, CYP9AY1, and UGT321AP1 contributes to the development of thiamethoxam resistance in L. decemlineata and provides a scientific basis for improving new resistance management of CPB.

A review of novel endothelin antagonists and overview of non-steroidal mineralocorticoid antagonists for treating resistant hypertension: An update

Several agents are emerging from five different novel classes of antihypertensive medications. We will focus on endothelin antagonists and non-steroidal mineralocorticoid receptor antagonists. While several agents exist in this later class, only a couple have demonstrated superior efficacy in resistant hypertension management. Endothelin receptor antagonists are effective therapy for primary and resistant hypertension, but they are not widely used. This is due to side effects demonstrated in large clinical trials, specifically increased peripheral edema and worsening heart failure in some cases, as well as the availability of many alternative agents to manage blood pressure effectively. However, the relationship between endothelin and its close ties to hypertension is evolving. Recent pre-clinical work explores new applications of more selective endothelin receptor antagonists. They suggest that specific subtypes of hypertension may benefit more from endothelin receptor blockade than simply those with primary hypertension. We review this topic and other related data. Lastly, we also provide a brief overview of non-steroidal mineralocorticoid receptor antagonists as some in the class show promise as antihypertensive agents.

The association between the triglyceride-glucose index and sarcopenia: data from the NHANES 2011–2018

BackgroundThe Triglyceride-glucose (TyG) index is a marker of insulin resistance, but its role in sarcopenia is controversial. The purpose of this study was to investigate the association of the TyG index with sarcopenia.Methods4030 participants aged 20 years and above were selected from National Health and Nutrition Examination Survey for cross sectional study. Weighted logistic regression model was used to estimate the association between TyG index and sarcopenia. Threshold effect analysis and restricted cubic spline were employed to describe nonlinear link, with interaction tests and subgroup analyses performed.ResultsIt was found in the fully adjusted model that the TyG index was positively associated with sarcopenia (per 1-unit increase in the TyG index: OR = 1.31, 95%CI: 1.07, 1.60). This association was further highlighted in groups characterized by the absence of MetS or diabetes, as well as the absence of vigorous or moderate work activity. Furthermore, analysis of the curve fitting and threshold effects indicated a nonlinear relationship, which exhibited a turning point at 9.14.ConclusionThe study results indicated that the TyG index was positively associated with sarcopenia. Enhancing the management of insulin resistance could help reduce the risk of developing sarcopenia.

A confirmation of the predictive utility of the Antibiotic Use Questionnaire

BackgroundThe change in the efficacy of antimicrobial agents due to their misuse is implicated in extensive health and mortality related concerns. The Antibiotics Use Questionnaire (AUQ) is a theory driven measure based on the Theory of Planned Behaviour (TpB) factors that is designed to investigate drivers of antibiotic use behaviour. The objective of this study is to replicate the factor structure from the pilot study within a similar Australian confirmation cohort, and to extend this through investigating if the factor structure holds in a Chinese-identifying cohort.MethodsThe AUQ was disseminated to two cohorts: a confirmation cohort similar to the original study, and a Chinese identifying cohort. Data analysis was completed on the two data sets independently, and on a combined data set. An orthogonal principal components analysis with varimax rotation was used to assess the factor structure, followed by general linear models to determine the influence of the TpB factors on reported antibiotic use.Results370 participant responses from the confirmation cohort, and 384 responses from the Chinese-identifying cohort were retained for analysis following review of the data. Results showed modest but acceptable levels of internal reliability across both cohorts. Social norms, and the interaction between attitudes and beliefs and knowledge were significant predictors of self-reported antibiotic use in both cohorts. In the confirmation cohort healthcare training was a significant predictor, and in the Chinese-identifying cohort education was a significant predictor. All other predictors tested produced a nonsignificant relationship with the outcome variable of self-reported antibiotic use.ConclusionsThis study successfully replicated the factor structure of the AUQ in a confirmation cohort, as well as a cohort that identified as culturally or legally Chinese, determining that the factor structure is retained when investigated across cultures. The research additionally highlights the need for a measure such as the AUQ, which can identify how differing social, cultural, and community factors can influence what predicts indiscriminate antibiotic use. Future research will be required to determine the full extent to which this tool can be used to guide bespoke community level interventions to assist in the management of antimicrobial resistance.

Combining Single-Gene-Resistant and Pyramided Cultivars of Perennial Crops in Agricultural Landscapes Compromises Pyramiding Benefits in Most Production Situations.

Although resistant cultivars are valuable in safeguarding crops against diseases, they can be rapidly overcome by pathogens. Numerous strategies have been proposed to delay pathogen adaptation (evolutionary control) while still ensuring effective protection (epidemiological control). For perennial crops, multiple resistance genes can be deployed (i) in the same cultivar (pyramiding strategy); in single-gene-resistant cultivars grown (ii) in the same field (mixture strategy) or (iii) in different fields (mosaic strategy); or (iv) in hybrid strategies that combine the three previous options. In addition, the spatial scale at which resistant cultivars are deployed can affect the plant-pathogen interaction: Small fields are thought to reduce pest density and disease transmission. Here, we used the spatially explicit stochastic model landsepi to compare the evolutionary and epidemiological control across spatial scales and deployment strategies relying on two major resistance genes. Our results, broadly focused on resistance to downy mildew of grapevine, show that the evolutionary control provided by the pyramiding strategy is at risk when single-gene-resistant cultivars are concurrently planted in the landscape (hybrid strategies), especially at low mutation probability. Moreover, the effectiveness of pyramiding compared with hybrid strategies is influenced by whether the adapted pathogen pays a fitness cost across all hosts or only for unnecessary virulence, particularly when the fitness cost is high rather than intermediate. Finally, field size did not affect model outputs for a wide range of mutation probabilities and associated fitness costs. The socioeconomic policies favoring the adoption of optimal resistant management strategies are discussed.

Realized heritability and fitness costs of flupyradifurone resistance in the cowpea aphid, Aphis craccivora Koch

The cowpea aphid, Aphis craccivora Koch (Homoptera: Aphididae) is a serious insect pest that infests legume crops. Flupyradifurone (FPF) is a butenolide insecticide that selectively targets sucking insects including aphids and whiteflies. However, the realized heritability (h2) and fitness costs associated with resistance to FPF have not yet been assessed with A. craccivora. In this study, A. craccivora showed the potential to develop resistance to FPF under continuous selection, with an overall mean estimated h2 of resistance of 0.21. Results of fitness costs showed no differences in the developmental time (except for N2 and N3), longevity, fecundity, adult pre-reproductive period (APRP), total pre-reproductive period (TPRP), and oviposition days (Od) of the FPF-R strain compared to the S-strain. In contrast, all population growth parameters, including the growth reproductive rate (GRR), net reproductive rate (R0), intrinsic rate of increase (r), finite rate of increase (λ), mean generation time (T), and doubling time (DT), were significantly lower in the FPF-R strain than in the S-strain. Fitness cost studies revealed that resistance to FPF decreased the relative fitness of the FPF-R strain to 0.76 compared with that of the S-strain. The estimation of realized heritable h2 and identification of resistance fitness costs provide a basis for designing insecticide resistance management (IRM) programs to sustain susceptibility in insect populations.

Evaluating foliar insecticides and economic thresholds for Tychius picirostris (Coleoptera: Curculionidae) management in Oregon white clover seed production.

The clover seed weevil, Tychius picirostris Fabricius (Coleoptera: Curculionidae), is a major pest in Oregon white clover seed crops. Reliance on synthetic pyrethroid insecticides and limited availability of diverse modes of action (MoAs) has increased insecticide resistance selection in regional T. picirostris populations, emphasizing the need to evaluate novel chemistries and rotational strategies for effective insecticide resistance management (IRM). The efficacy of 8 foliar insecticide formulations for managing T. picirostris adult and larval life stages was determined in small and large-plot field trials across 2 crop years. In both years, bifenthrin (Brigade 2EC), the grower's standard, showed negligible adult and larval suppression. Insecticide formulations with isocycloseram and cyantraniliprole active ingredients reduced adult and larval populations when applied at BBCH 59-60 (prebloom) and BBCH 65-66 (full bloom) growth stages, respectively. While differences in T. picirostris abundance were observed among insecticide treatments, seed yield differences were not detected in large-plot trials. Larval abundance was correlated with reduced seed yield, and an economic threshold of ≥3 larvae per 30 inflorescences was determined as a conservative larval threshold to justify foliar applications of diamide insecticides. Additional commercial white clover seed fields were surveyed to compare larval scouting techniques, including a standard Berlese funnel and a grower's do-it-yourself funnel. Both larval extraction techniques were correlated and provided similar estimates of larval abundance. These findings demonstrate new MoAs, optimal insecticide application timing, and larval monitoring methods that can be incorporated into an effective T. picirostris IRM program in white clover seed crops.

Resistance of Lepidopteran Pests to Bacillus thuringiensis Toxins: Evidence of Field and Laboratory Evolved Resistance and Cross-Resistance, Mode of Resistance Inheritance, Fitness Costs, Mechanisms Involved and Management Options.

Bacillus thuringiensis (Bt) toxins are potential alternatives to synthetic insecticides for the control of lepidopteran pests. However, the evolution of resistance in some insect pest populations is a threat and can reduce the effectiveness of Bt toxins. In this review, we summarize the results of 161 studies from 20 countries reporting field and laboratory-evolved resistance, cross-resistance, and inheritance, mechanisms, and fitness costs of resistance to different Bt toxins. The studies refer mainly to insects from the United States of America (70), followed by China (31), Brazil (19), India (12), Malaysia (9), Spain (3), and Australia (3). The majority of the studies revealed that most of the pest populations showed susceptibility and a lack of cross-resistance to Bt toxins. Factors that delay resistance include recessive inheritance of resistance, the low initial frequency of resistant alleles, increased fitness costs, abundant refuges of non-Bt, and pyramided Bt crops. The results of field and laboratory resistance, cross-resistance, and inheritance, mechanisms, and fitness cost of resistance are advantageous for predicting the threat of future resistance and making effective strategies to sustain the effectiveness of Bt crops.

Monitoring of the nAChRsα6 G275A spinetoram resistance allele in Drosophila melanogaster populations from New York vineyards.

Spinosyns are a group of naturally occurring and semi-synthetic insecticides with widespread utility in agriculture, including organic production systems. One example is spinetoram (Delegate), which is the only registered insecticide in New York State (for control of Drosophila melanogaster in vineyards) to which vinegar flies have not yet evolved high levels of resistance. However, low levels of resistance have been found in vineyard populations of D. melanogaster, and a highly resistant strain was obtained after only five selections (in the laboratory). We identified the nAChR α6 mutation (G275A) responsible for the resistance and developed a rapid, high-throughput assay for resistance. Surveys of collections made in 2023 show low levels of the resistance allele in four populations. A correlation was observed between vineyard use of spinetoram and frequency of the resistance allele, but not between county-wide use of spinosyns and frequency of the resistance allele. One of the sites we monitored was previously surveyed in 2019 and the frequency of the resistance allele detected in 2023 had increased. Implications of these findings to resistance management of D. melanogaster are discussed. © 2024 Society of Chemical Industry.

Effects of combining soil-applied insecticide and Bt corn for integrated pest management and resistance management of western corn rootworm (Coleoptera: Chrysomelidae).

The western corn rootworm, (Diabrotica virgifera virgifera LeConte, Coleoptera: Chrysomelidae), is a serious pest of corn (Zea mays Linnaeus, Cyperales: Poaceae) in the midwestern United States. Management practices for corn rootworm larvae include crop rotation, transgenic corn producing insecticidal toxins from the bacterium Bacillus thuringiensis Berliner (Bacillales: Bacillaceae) (Bt), and soil-applied insecticides. The extent to which combining soil-applied insecticide with Bt corn would be beneficial from the perspective of insect resistance management (IRM) or integrated pest management (IPM) remains uncertain. We conducted a 3-yr field study to characterize the implications of combining a soil-applied insecticide and Bt corn for IRM and IPM of western corn rootworm. Experimental treatments were Bt corn, a soil-applied insecticide, the combination of these factors, and an experimental control in which both factors were absent. Data were collected on root injury to corn by rootworm, survival to adulthood, adult size, and emergence time for western corn rootworm. We found that mortality caused by the soil-applied insecticide was insufficient to delay resistance to Bt corn. While combining Bt corn and a soil-applied insecticide may provide a short-term economic benefit, additional research is needed to determine appropriate economic thresholds for combining these tactics. Additionally, combining a soil-applied insecticide and Bt corn would not be sustainable over multiple growing seasons because of its potential to rapidly select for Bt resistance. In general, a more sustainable IRM strategy for rootworm management would include using crop rotation and alternating between non-Bt corn with soil-applied insecticide and Bt corn without soil-applied insecticide.

Continued decline in sublethal effects of Bt toxins on Helicoverpa zea (Lepidoptera: Noctuidae) in field corn.

The majority of field corn, Zea mays L., in the southeastern United States has been genetically engineered to express insecticidal toxins produced by the soil bacterium, Bacillus thuringiensis (Bt). Field corn is the most important mid-season host for corn earworm, Helicoverpa zea (Boddie) (Lepidoptera: Noctuidae), which has developed resistance to all Cry toxins in Bt corn. From 2020 to 2023, corn earworm pupae were collected from early- and late-planted pyramided hybrids expressing Bt toxins and non-Bt near-isolines in North and South Carolina (16 trials). A total of 5,856 pupae were collected across all trials, with 55 and 88% more pupae collected in later-planted trials relative to early plantings in North and South Carolina, respectively. Only 20 pupae were collected from hybrids expressing Cry1F + Cry1Ab + Vip3A20 across all trials. Averaged across trials, Cry1A.105 + Cry2Ab2 hybrids reduced pupal weight by 6 and 9% in North and South Carolina, respectively, relative to the non-Bt near-isoline. Cry1F + Cry1Ab hybrids reduced pupal weight on average by 3 and 8% in North and South Carolina, respectively, relative to the non-Bt near-isoline. The impact of the Bt toxins on pupal weight varied among trials. When combined with data from 2014 to 2019 from previous studies, a significant decline in the percent reduction in pupal weight over time was found in both states and hybrid families. This study demonstrates a continued decline in the sublethal impacts of Bt toxins on corn earworm, emphasizing the importance of insect resistance management practices.

Probing Dual Covalent Irreversible Inhibition of EGFR/FGFR4 by Electrophilic-Based Natural Compounds to Overcome Resistance and Enhance Combination Therapeutic Potentials and Management of Hepatocellular Carcinoma (HCC).

Hepatocellular carcinoma (HCC) is one of the most prevalent cancer types in the world and accounts for the majority of cases of primary liver cancer. A crucial part of the carcinogenesis of HCC involves aberrant stimulation of the FGF19-FGFR4 signaling pathway. Therefore, FGFR4 inhibition has become a strategic therapeutic approach for the treatment of HCC. However, the clinical treatment procedure is significantly hampered by the prevalence of kinase inhibitors resistance. It was recently established that the activation of EGFR signaling was found to be one of the primary mechanisms mediating the acquired resistance to FGFR4 inhibitors, moreover, sensitivity to FGFR4 inhibitors was effectively restored by inhibiting EGFR. These results provide compelling evidence that dual inhibition of EGFR and FGFR4 could represent a viable therapeutic approach to overcome resistance, hence enhanced management of HCC. To this end, we proposed a dual irreversible inhibition strategy through covalent binding by naturally occurring electrophilic warhead-bearing compounds (curcumin, deoxyelephantopin, eupalmerin acetate, syringolin A and andrographolide) to covalently target both EGFR and FGFR4 through cysteine residues, Cys797 and Cys552, respectively. Covalent docking and covalent molecular dynamics (MM/MDcov) simulations combined with thermodynamic binding free energy calculations were performed, and the results were compared against known potent and selective covalent EGFR and FGFR4 inhibitors with available X-ray crystal structures, Afatinib and BLU9931, respectively. Curcumin, deoxyelephantopin, eupalmerin acetate, syringolin A, and andrographolide showed relative binding free energies of -22.85, -17.14, -12.98, -21.81, and - 19.00kcal/mol against EGFR and - 41.06, -29.45, -24.76, -40.11, and - 37.55kcal/mol against FGFR4, respectively. The mechanisms of binding were emphasized by hydrogen bonding and binding forces analysis as well as active site physicochemical profiling. The findings of this study identified that curcumin, syringolin A and andrographolide-but not eupalmerin acetate or deoxyelephantopin -could be viable dual EGFR and FGFR4 covalent irreversible inhibitors and could be implemented in HCC combination therapy protocols alone or in conjunction with other chemotherapeutic agents. Investigations of this study conclusively indicate dual blockade of EGFR and FGFR4 may be a promising future therapeutic strategy for enhanced management of HCC.

Annual Review of Phytopathology, Volume 61

The Annual Review of Phytopathology, in publication since 1963, covers significant developments in the field of plant pathology, including plant disease diagnosis, pathogens, host-pathogen interactions, epidemiology and ecology, breeding for resistance and plant disease management, and includes a special section on the development of concepts. There are 18 articles.