Potential Resistance Mechanisms Research Articles

Potential Mechanisms of Hexaconazole Resistance in Fusarium graminearum.

Fusarium head blight (FHB) caused by Fusarium graminearum is a serious fungal disease that can dramatically impact wheat production. At present, disease control is mainly achieved by the use of chemical fungicides. Hexaconazole (IUPAC name: 2(2,4-dichlorophenyl)-1-(1,2,4-triazol-1-yl)hexan-2-ol) is a widely used triazole fungicide, but the sensitivity of F. graminearum to this compound has yet to be established. The current study found that the EC50 values of 83 field isolates of F. graminearum ranged between 0.06 and 4.33 μg/ml, with an average EC50 value of 0.78 μg/ml. Assessment of four hexaconazole-resistant laboratory mutants of F. graminearum revealed that their mycelial growth and pathogenicity were reduced compared with their parental isolates and that asexual reproduction was reduced by resistance to hexaconazole. Meanwhile, the mutants appeared to be more sensitive to abiotic stress associated with SDS and H2O2, while their tolerance to high concentrations of Congo red, and Na+ and K+ increased. Molecular analysis revealed numerous point mutations in the FgCYP51 target genes that resulted in amino acid substitutions, including L92P and N123S in FgCYP51A, as well as M331V, F62L, Q252R, A412V, and V488A in FgCYP51B, and S28L, S256A, V307A, D287G, and R515I in FgCYP51C, three of which (S28L, S256A, and V307A) were conserved in all of the resistant mutants. Furthermore, the expression of the FgCYP51 genes in resistant strains was found to be significantly (P < 0.05) reduced compared with their sensitive parental isolates. Positive cross-resistance was found between hexaconazole and metconazole and flutriafol, as well as with the diarylamine fungicide fluazinam, but not with propiconazole, and the phenylpyrrole fungicide fludioxonil, or with tebuconazole, which actually exhibited negative cross-resistance. These results provide valuable insight into resistant mechanisms to triazole fungicides in F. graminearum, as well as the appropriate selection of fungicide combinations for the control of FHB to ensure optimal wheat production.

Cellular liquid biopsy provides unique chances for disease monitoring, preclinical model generation and therapy adjustment in rare salivary gland cancer patients.

While cell-free liquid biopsy (cfLB) approaches provide simple and inexpensive disease monitoring, cell-based liquid biopsy (cLB) may enable additional molecular genetic assessment of systemic disease heterogeneity and preclinical model development. We investigated 71 blood samples of 62 patients with various advanced cancer types and subjected enriched circulating tumor cells (CTCs) to organoid culture conditions. CTC-derived tumoroid models were characterized by DNA/RNA sequencing and immunohistochemistry, as well as functional drug testing. Results were linked to molecular features of primary tumors, metastases, and CTCs; CTC enumeration was linked to disease progression. Of 52 samples with positive CTC counts (≥1) from eight different cancer types, only CTCs from two salivary gland cancer (SGC) patients formed tumoroid cultures (P = 0.0005). Longitudinal CTC enumeration of one SGC patient closely reflected disease progression during treatment and revealed metastatic relapse earlier than clinical imaging. Multiomics analysis and functional invitro drug testing identified potential resistance mechanisms and drug vulnerabilities. We conclude that cLB might add a functional dimension (to the genetic approaches) in the personalized management of rare, difficult-to-treat cancers such as SGC.

14K prolactin derived 14-mer antiangiogenic peptide targets bradykinin-/nitric oxide-cGMP-dependent angiogenesis.

Over the past few decades, VEGF-targeted antiangiogenic therapy for cancers has gained increasing attention. Nevertheless, there are still several limitations such as the potential resistance mechanisms arising in cancer cells against these therapies and their potential adverse effects. These limitations highlight the need for novel anti-angiogenesis molecules and better understanding of the mechanisms of tumor angiogenesis. In the present study, we investigated the antiangiogenic properties of a novel 14-mer antiangiogenic peptide (14-MAP) derived from N-terminal 14 kDa buffalo prolactin and characterized its mode of action. 14-MAP at the picomolar concentration inhibited VEGF- and bradykinin (an autacoid peptide expressed in vascular tissues in pathophysiology, BK)-stimulated endothelial nitric oxide (eNO) production, cell migration, and proliferation in endothelial cells and vessel development in the chick embryo. Although this peptide inhibited both VEGF- and BK-dependent angiogenic processes, its action was more pronounced in the latter. Moreover, the interference of 14-MAP with the eNO synthase (eNOS)-cyclic GMP pathway was also identified. A combination of a low dose of Avastin, a widely used drug targeting VEGF-dependent angiogenesis, and 14-MAP significantly reduced tumor size in an in vivo model of human colon cancer. Taken together, our results suggest that 14-MAP, a BK- and eNOS-dependent antiangiogenic peptide, might be useful for overcoming the limitation of VEGF-targeted antiangiogenic therapy in cancer patients. However, further studies will be required to further characterize its mode of action and therapeutic potential.

Investigation on the mechanisms of carbapenem resistance among the non-carbapenemase-producing carbapenem-resistant Klebsiella pneumoniae.

In Malaysia, an increase in non-carbapenemase-producing carbapenem-resistant Klebsiella pneumoniae (NC-CRKP) has been observed over the years. Previously, four NC-CRKP with increased susceptibility to ciprofloxacin in the presence of phenylalanine-arginine β-naphthylamide (PAβN) were identified. However, no contribution of the PAβN-inhibited efflux pump to carbapenem resistance was observed. All four NC-CRKP harboured non-carbapenemase β-lactamase, with two also exhibiting porin loss. In this study, we further investigated the genomic features and resistance mechanisms of these four isolates. All four NC-CRKP were subjected to whole-genome sequencing, followed by comparative genomic and phylogenetic analyses. Multi-locus sequence typing (MLST) analysis divided the four NC-CRKP into different sequence types: ST392, ST45, ST14, and ST5947. Neither major nor rare carbapenemase genes were detected. Given the presence of non-carbapenemase β-lactamase in all isolates, we further investigated the potential mechanisms of resistance by identifying related chromosomal mutations. Deletion mutation was detected in the cation efflux system protein CusF. Insertion mutation was identified in the nickel/cobalt efflux protein RcnA. Missense mutation of ompK36 porin was detected in two isolates, while the loss of ompK36 porin was observed in another two isolates. This study revealed that NC-CRKP may confer carbapenem resistance through a combination of non-carbapenemase β-lactamase and potential chromosomal mutations including missense mutation or loss of ompK36 porin and/or a frameshift missense mutation in efflux pump systems, such as cation efflux system protein CusF and nickel/cobalt efflux protein RcnA. Our findings highlighted the significance of implementing whole-genome sequencing into clinical practice to promote the surveillance of carbapenem resistance mechanisms among NC-CRKP.

Adaptation mechanisms of Clostridioides difficile to auranofin and its impact on human gut microbiota

Auranofin (AF), a former rheumatoid polyarthritis treatment, gained renewed interest for its use as an antimicrobial. AF is an inhibitor of thioredoxin reductase (TrxB), a thiol and protein repair enzyme, with an antibacterial activity against several bacteria including C. difficile, an enteropathogen causing post-antibiotic diarrhea. Several studies demonstrated the effect of AF on C. difficile physiology, but the crucial questions of resistance mechanisms and impact on microbiota remain unaddressed. We explored potential resistance mechanisms by studying the impact of TrxB multiplicity and by generating and characterizing adaptive mutations. We showed that if mutants inactivated for trxB genes have a lower MIC of AF, the number of TrxBs naturally present in clinical strains does not impact the MIC. All stable mutations isolated after AF long-term exposure were in the anti-sigma factor of σB and strongly affect physiology. Finally, we showed that AF has less impact on human gut microbiota than vancomycin.

Abstract C029: Window-of-opportunity trial of metastatic pancreatic cancer reveals potential mechanisms of response to targeting RAS/MEK signaling

Abstract KRAS is mutated in ∼85% of pancreatic ductal adenocarcinoma (PDAC) patient's tumors, suggesting that it is a key node of PDAC targeted therapy. RAF/MEK/ERK signaling is downstream of KRAS signaling. Preclinical studies targeting MEK showed promises but clinical trials failed to show the benefit compared to Standard-of-Care treatment chemotherapy. To elucidate the mechanism of action and resistance to several targeted therapies including MEK inhibition in human PDAC, we conducted a Window-Of-Opportunity trial for Metastatic pancreatic cancer (WOOM trial). In this trial, metastatic PDAC patients received 10 days of Cobimetinib, an FDA approved MEK inhibitor, therapy and specimens of pre- and post- treatment were obtained by biopsy to evaluate the response to targeted treatment using deep multi-omic analytics including DNA-seq, RNA-seq, multiplex IHC, cyclic IF and Digital Spatial Profiling (DSP). Four of 13 patient’s tumors were defined as Responsive tumors by using CA19- 9 and KI67 as a readout. Genomic sequence showed that KRAS amplifications were frequently seen in non-responsive tumors and KrasG12R mutations were seen with higher frequency in Responsive tumors. RNA-seq analysis showed that these Responsive tumors had lower KRAS activity and were more likely to be classical-like subtype compared to non-responsive tumors. DSP analysis confirmed the downregulation of ERK phosphorylation with paradoxical phospho- MEK activation after treatment in all examined cases which is consistent with effective target inhibition. Phospho-MYC protein expression and MYC transcriptomic activity were significantly decreased in responsive tumors, which suggest MYC downregulation could contribute to an active response to MEK inhibition. Single cell RNA-seq and spacial analysis showed tumor microenvironment changes after Cobimetinib treatment including the increase of CD8 T cell infiltration in responsive tumors. Furthermore, PDX from patient’s biopsy recapitulated patient's response to Cobimetinib and faithfully metastasized to the liver. Interestingly, Cobimetinib resistant PDX was also resistant to KRAS inhibitor. This model could be a great tool for testing new therapeutic strategies targeting the KRAS/MEK pathway. Here, we summarize the multi- omics data and discuss potential mechanisms of response and resistance to targeting KRAS signaling and related microenvironmental changes. Citation Format: Motoyuki Tsuda, Colin Daniel, Xiaoyan Wang, Carl Peltz, Hayley Zimmny, Alexander Smith, John Muschler, Xi Li, Tugba Yildiran Ozmen, Furkan Ozmen, Dove Keith, Christopher Corless, Koei Chin, Jonathan Brody, Charles Lopez, Gordon Mills, Rosalie Sears. Window-of-opportunity trial of metastatic pancreatic cancer reveals potential mechanisms of response to targeting RAS/MEK signaling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C029.

Translation stalling induced mitochondrial entrapment of ribosomal quality control related proteins offers cancer cell vulnerability.

Ribosome-associated quality control (RQC) monitors ribosomes for aberrant translation. While the role of RQC in neurodegenerative disease is beginning to be appreciated, its involvement in cancer is understudied. Here, we show a positive correlation between RQC proteins ABCE1 and ZNF598 and high-grade muscle-invasive bladder cancer. Translational stalling by the inhibitor emetine (EME) leads to increased mitochondrial localization of RQC factors including ABCE1, ZNF598, and NEMF, which are continuously imported into mitochondria facilitated by increased mitochondrial membrane potential caused by EME. This reduces the availability of these factors in the cytosol, compromising the effectiveness of RQC in handling stalled ribosomes in the cytosol and those associated with the mitochondrial outer membrane (MOM). Imported RQC factors form aggregates inside the mitochondria in a process we term stalling-induced mitochondrial stress (SIMS). ABCE1 plays a crucial role in maintaining mitochondrial health during SIMS. Notably, cancer stem cells (CSCs) exhibit increased expression of ABCE1 and consequently are more resistant to EME-induced mitochondrial dysfunction. This points to a potential mechanism of drug resistance by CSCs. Our study highlights the significance of mitochondrial entrapment of RQC factors such as ABCE1 in determining the fate of cancer cells versus CSCs. Targeting ABCE1 or other RQC factors in translational inhibition cancer therapy may help overcome drug resistance.

Pheno- and genotypic epidemiological characterization of Staphylococcus aureus isolated from bulk tank milk in Colombia

Staphylococcus aureus is recognized for causing contagious mastitis in cattle. Elimination of the organism in affected animals is challenging due to its potential antibiotic resistance mechanisms and virulence factors. The aim of the study was the pheno- and genotypic epidemiological characterization of S. aureus isolated from bulk tank milk samples obtained from three municipalities in the northern region of Antioquia. Twenty-one S. aureus isolates from 150 bulk tank milk samples were characterized by evaluating antimicrobial susceptibility to 17 antibiotics using the VITEK 2, and identifying several genes encoding for virulence factors, enterotoxins, and the agr groups by conventional PCR. The clonal relationship between the isolates was assessed using macrorestriction fragment analysis (MRFA) of chromosomal DNA by pulsed-field gel electrophoresis (PFGE). Most of the isolates showed susceptibility to the tested antibiotics; 19% exhibited resistance to tetracycline and all isolates showed beta-lactamases. Molecular typing revealed that 76% carried the agrI and cap5 genes. Seven isolates harbored genes coding for staphylococcal enterotoxins (SE), with seh being the most identified gene. Furthermore, MRFA demonstrated high heterogeneity among the isolates, resulting in the assignment of 18 different MRFA patterns. These results indicate phenotypic resistance to tetracycline and beta-lactams, the presence of genes encoding for staphylococcal enterotoxins, and high heterogeneity among S. aureus isolates from bulk tank milk.

Genome-centric metagenomes unveiling the hidden resistome in an anchialine cave

BackgroundAntibiotic resistance is a critical global concern, posing significant challenges to human health and medical treatments. Studying antibiotic resistance genes (ARGs) is essential not only in clinical settings but also in diverse environmental contexts. However, ARGs in unique environments such as anchialine caves, which connect both fresh and marine water, remain largely unexplored despite their intriguing ecological characteristics.ResultsWe present the first study that comprehensively explores the occurrence and distribution of ARGs and mobile genetic elements (MGEs) within an anchialine cave. Utilizing metagenomic sequencing we uncovered a wide array of ARGs with the bacitracin resistance gene, bacA and multidrug resistance genes, being the most dominant. The cave’s microbial community and associated resistome were significantly influenced by the salinity gradient. The discovery of novel β-lactamase variants revealed the cave’s potential as a reservoir for previously undetected resistance genes. ARGs in the cave demonstrated horizontal transfer potential via plasmids, unveiling ecological implications.ConclusionsThese findings highlight the need for further exploration of the resistome in unique environments like anchialine caves. The interconnected dynamics of ARGs and MGEs within anchialine caves offer valuable insights into potential reservoirs and mechanisms of antibiotic resistance in natural ecosystems. This study not only advances our fundamental understanding but also highlights the need for a comprehensive approach to address antibiotic resistance in diverse ecological settings.

P2X7 receptors from the perspective of NLRP3 inflammasome pathway in depression: Potential role of cannabidiol

Many patients with depressive disorder do not respond to conventional antidepressant treatment. There is an ongoing interest in investigating potential mechanisms of treatment resistance in depression to provide alternative treatment options involving inflammatory mechanisms. Increasing evidence implicates the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome as a critical factor in neuroinflammation. ATP-induced P2X7 receptor (P2X7R) activation is a major trigger for inflammation, activating the canonical NLRP3 inflammatory cascade. Psychosocial stress, the primary environmental risk factor for depression, is associated with changes in ATP-mediated P2X7R signaling. Depression and stress response can be alleviated by Cannabidiol (CBD). CBD has an anti-inflammatory activity related to the regulation of NLRP3 inflammasome activation. However, CBD's effects on the inflammasome pathway are poorly understood in central nervous system (CNS) cells, including microglia, astrocytes, and neurons. This review will emphasize some findings for neuroinflammation and NLRP3 inflammasome pathway involvement in depression, particularly addressing the ATP-induced P2X7R activation. Moreover, we will underline evidence for the effect of CBD on depression and address its potential impacts on neuroinflammation through the NLRP3 inflammasome cascade.

Overexpression of Two Odorant Binding Proteins Confers Chlorpyrifos Resistance in the Green Peach Aphid Myzus persicae.

The green peach aphid, Myzus persicae, is a worldwide agricultural pest. Chlorpyrifos has been widely used to control M. persicae for decades, thus leading to a high resistance to chlorpyrifos. Recent studies have found that insect odorant binding proteins (OBPs) play essential roles in insecticide resistance. However, the potential resistance mechanism underlying the cross-link between aphid OBPs and chlorpyrifos remains unclear. In this study, two OBPs (MperOBP3 and MperOBP7) were found overexpressed in M. persicae chlorpyrifos-resistant strains (CRR) compared to chlorpyrifos-sensitive strains (CSS); furthermore, chlorpyrifos can significantly induce the expression of both OBPs. An in vitro binding assay indicated that both OBPs strongly bind with chlorpyrifos; an in vivo RNAi and toxicity bioassay confirmed silencing either of the two OBPs can increase the susceptibility of aphids to chlorpyrifos, suggesting that overexpression of MperOBP3 and MperOBP7 contributes to the development of resistance of M. persicae to chlorpyrifos. Our findings provide novel insights into insect OBPs-mediated resistance mechanisms.

1462P A pilot study of hypoxia as a potential resistance mechanism to PD-1 checkpoint blockade therapy in neoadjuvant treatment of esophageal squamous cell carcinoma (HYPERION)

1462P A pilot study of hypoxia as a potential resistance mechanism to PD-1 checkpoint blockade therapy in neoadjuvant treatment of esophageal squamous cell carcinoma (HYPERION)

Alterations in Physiological Parameters and Secondary Metabolites of Astragalus adsurgens Infected by the Pathogen Alternaria gansuensis

Alternaria gansuensis, a seed-borne fungus of standing milkvetch (Astragalus adsurgens), is the most common pathogen of this plant species and causes yellow stunt and root rot. Although plant resistance to this disease has been identified, a better understanding of the nature of this resistance will help improve and optimize its implementation in standing milkvetch. The effects of A. gansuensis on the physiology of standing milkvetch were assessed in a 4-week study comparing a resistant plant variety, Shanxi, and a susceptible variety, Ningxia. In the first week, there was an obvious decrease in photosynthesis (P) in inoculated plants, especially in the susceptible variety, but there were no changes in stomatal conductance (Sc). From the second week on, P and Sc decreased progressively, and significant stem lesions were observed concomitantly. Water use efficiency (WUE) increased slightly in the second week but then decreased significantly from the third week. Physiological changes observed for the resistant variety of standing milkvetch were less dramatic than those of the susceptible variety. Hyphae were observed around inoculation lesions of the plants. Culture filtrate (CF) of A. gansuensis induced changes in extracellular pH and conductivity, especially in the susceptible variety samples. Tissue integrity changes in the plants correlated with the decrease in P. Secondary metabolite compounds were extracted from the plants and 21 types of compounds were identified. The composition and proportion of secondary metabolites were markedly altered by the pathogen, and these differences may indicate potential mechanisms of disease resistance to A. gansuensis in standing milkvetch.

Epigenetic regulation of noncanonical menin targets modulates menin inhibitor response in acute myeloid leukemia

AbstractMenin inhibitors that disrupt the menin-MLL interaction hold promise for treating specific acute myeloid leukemia (AML) subtypes, including those with KMT2A rearrangements (KMT2A-r), yet resistance remains a challenge. Here, through systematic chromatin-focused CRISPR screens, along with genetic, epigenetic, and pharmacologic studies in a variety of human and mouse KMT2A-r AML models, we uncovered a potential resistance mechanism independent of canonical menin-MLL targets. We show that a group of noncanonical menin targets, which are bivalently cooccupied by active menin and repressive H2AK119ub marks, are typically downregulated after menin inhibition. Loss of polycomb repressive complex 1.1 (PRC1.1) subunits, such as polycomb group ring finger 1 (PCGF1) or BCL6 corepressor (BCOR), leads to menin inhibitor resistance by epigenetic reactivation of these noncanonical targets, including MYC. Genetic and pharmacological inhibition of MYC can resensitize PRC1.1-deficient leukemia cells to menin inhibition. Moreover, we demonstrate that leukemia cells with the loss of PRC1.1 subunits exhibit reduced monocytic gene signatures and are susceptible to BCL2 inhibition, and that combinational treatment with venetoclax overcomes the resistance to menin inhibition in PRC1.1-deficient leukemia cells. These findings highlight the important roles of PRC1.1 and its regulated noncanonical menin targets in modulating the menin inhibitor response and provide potential strategies to treat leukemia with compromised PRC1.1 function.

Novel ERBB2 Variant Potentially Associated with Resistance against Anti-HER2 Monoclonal Antibody-Based Therapy in ERBB2-Amplified Metastatic Colorectal Cancer.

HER2-targeted therapies in ERBB2-amplified metastatic colorectal cancer (mCRC) are effective; however, a notable portion of patients do not respond to treatment, and secondary resistance occurs in most patients receiving these treatments. The purpose of this study was to investigate determinants of treatment efficacy and resistance in patients with ERBB2-amplified mCRC who received HER2-targeted therapy by analyzing multiomics data. We investigated genomic data from a nationwide large cancer genomic screening project, the SCRUM-Japan project. We analyzed paired genome and transcriptome data of tissue and genomic data of ctDNA collected pre- and postprogression in patients enrolled in the related trial, TRIUMPH, in ERBB2-amplified mCRC. In 155 patients with ERBB2-amplified solid tumors who received HER2-targeted therapy based on the SCRUM-Japan project, the objective response rate was 50%, 51%, and 35% in ERBB2 wild-type, variant of unknown significance, and pathogenic variant groups, respectively. In the paired genome and transcriptome data analyses in TRIUMPH, we identified the novel splicing-associated variant c.644-66_-2del in one of the 11 patients with paired whole-exome sequencing and whole-transcriptome sequencing data sets, which lacks the binding domain of pertuzumab, in progressed metastatic tumor as a variant with potential pathogenicity. The time-course ctDNA analysis detected c.644-66_-2del as an acquired variant. This study highlighted the importance of ERBB2 genomic status when evaluating the efficacy of HER2-targeted therapies in ERBB2-amplified mCRC. The identification of a novel splicing-associated variant may provide insights into potential mechanisms of treatment resistance. Furthermore, we demonstrated the utility of ctDNA to follow the acquired genomic status of mCRC tumors.

Insights into macrolide resistance in Arcobacter butzleri: potential resistance mechanisms and impact on bacterial fitness and virulence.

Macrolides are recommended for treating the emerging enteropathogen Arcobacter butzleri; nonetheless, this bacterium often exhibits highly variable resistance rates, and the mechanisms behind this resistance phenotype remain largely unexplored. To understand the phenotypic and genotypic consequences associated with the acquisition of erythromycin resistance in A. butzleri, as well as the effects on the fitness of this species. Resistant strains resulting from spontaneous mutations and adaptive laboratory evolution under increasing erythromycin concentrations were examined regarding their cross-resistance and collateral susceptibility profiles. Genetic causes of phenotypic antibiotic resistance were analysed by sequencing and bioinformatics, with functional correlation through ethidium bromide accumulation assays. Growth profiles in the presence and absence of erythromycin, motility and biofilm formation abilities were assessed to detect potential changes in fitness and virulence. Clones from spontaneous mutation rate evolution demonstrated decreased susceptibility to erythromycin and other classes of antibiotics, associated with mutations in the transcriptional repressor areR, causing overexpression of the AreABC efflux pump. In turn, WGS analysis of the evolved strain showed additional mutations in the ribosomal proteins L4 and L22 and in the areR gene. Furthermore, the acquisition of macrolide resistance altered A. butzleri virulence and entailed a high biological cost. The findings of this study have proved that efflux activity contributes synergistically with mutations in the ribosomal proteins L4 and L22 to A. butzleri's high-level macrolide resistance. The results further suggest an impact on the bacterial physiology and virulence, with the increased fitness cost justifying the low worldwide prevalence of high-level resistant circulating strains.

Resistance to Anti-HER2 Therapies in Gastrointestinal Malignancies.

Human epidermal growth factor 2 (HER2) is a tyrosine kinase receptor that interacts with multiple signaling pathways related to cellular growth and proliferation. Overexpression or amplification of HER2 is linked to various malignancies, and there have been decades of research dedicated to targeting HER2. Despite the landmark ToGA trial, progress in HER2-positive gastrointestinal malignancies has been hampered by drug resistance. This review examines current HER2 expression patterns and therapies for gastroesophageal, colorectal, biliary tract, and small bowel cancers, while dissecting potential resistance mechanisms that limit treatment effectiveness.

Unveiling the toxicological effects and risks of prometryn on red swamp crayfish (Procambarus clarkii): Health assessments, ecological, and molecular insights

Prometryn is commonly used in agricultural and non-agricultural settings. However, possible harm to aquatic organisms remains a persistent concern. Prometryn was also the only one of the 26 triazine herbicides detected in this study. Numerous studies have assessed the harmful effects of prometryn in teleost fish and shrimp. There is a lack of information regarding the ecological and human health risks, as well as the toxic mechanisms affecting crayfish. In this study, human health risk assessment (THQ) and ecological risk assessment (RQ) were conducted on P. clarkii in the rice-crayfish co-culture (IRCC) farming model. The 96 h of exposure to 0.286 mg/L and 1.43 mg/L prometryn was conducted to investigate the potential effects and molecular mechanisms of hepatopancreatic resistance to prometryn in P. clarkii. The original sample analysis revealed that the THQ calculated from the prometryn levels in the muscle and hepatopancreas was below 0.1, suggesting no threat to human health. However, the calculated RQ values were >0.1, indicating a risk to P. clarkii. Histological analysis and biochemical index detection of the experimental samples revealed that the hepatopancreatic injury and oxidative damage in P. clarkii were caused by prometryn. Moreover, transcriptome analysis identified 2512 differentially expressed genes (DEGs) after 96 h of prometryn exposure. Prometryn exposure caused significant changes in metabolic pathways, including oxoacid metabolic processes and cytochrome P450-associated drug metabolism. Further hub gene analysis via PPI indicated that exposure to prometryn may inhibit lipid synthesis, storage, and amino acid transport and affect glucose metabolic pathways and hormone synthesis. Additionally, we hypothesized that prometryn-triggered cell death could be linked to the PI3K-Akt signaling cascade. This study's findings have significant meaning for the efficient and logical application of herbicides in IRCC, ultimately aiding in advancing a highly productive agricultural system.

Honey bee populations surviving Varroa destructor parasitism in Latin America and their mechanisms of resistance

The honey bee (Apis mellifera) parasitic mite, Varroa destructor, is considered one of the main causes of colony losses in European honey bee (EHB) populations around the world. However, some EHB and Africanized honey bee (AHB) populations (derived from the African subspecies A. m. scutellata) that inhabit tropical and subtropical regions of the Americas, have survived varroa mite infestations in the absence of acaricide treatments. It is conceivable to expect that these honey bee populations, which have been subjected to natural selection over decades, would have developed resistance against V. destructor or possess pre-existing adaptations that allow them to survive mite parasitism. Here, we present a comprehensive literature review describing the spread of V. destructor and the honey bee populations occurring in Latin America (LA), and summarize the evidence of resistance of those populations to V. destructor. We also analyze reports describing the potential mechanisms of mite resistance and how they operate in those honey bee populations. Studies of a few EHB, as well as of numerous AHB populations exhibiting resistance to V. destructor in LA, unveil the existence of evolutionary adaptations that restrain V. destructor population growth and provide insight into the current host-parasite relationship. This review supports the notion that selective breeding of local honey bee populations from LA could be a viable strategy to manage varroa mite infestations in colonies.

A novel mutation Trp-2027-Gly in acetyl-CoA carboxylase confers resistance to cyhalofop-butyl in Chinese sprangletop (Leptochloa chinensis).

Chinese sprangletop [Leptochloa chinensis (L.) Nees] control is threatened by resistance to acetyl-CoA carboxylase (ACCase)-inhibiting herbicides. In this study, a L. chinensis population, HFLJ18, that survived cyhalofop-butyl [aryloxyphenoxypropionate (APP) herbicide, CyB] treatment was collected from a rice field in Lujiang County, Anhui Province, China. This study aimed to evaluate the susceptibility of HFLJ18 to herbicides with different modes-of-action and investigate the potential mechanisms of resistance to CyB. The HFLJ18 population exhibited high levels of resistance to CyB (10.92-fold) and showed resistance to the ACCase inhibitors metamifop (4.63-fold) and fenoxaprop-P-ethyl (8.39-fold), but was susceptible to clethodim, pinoxaden, florpyrauxifen-benzyl, oxadiazon and pretilachlor. Target gene sequencing revealed a novel Trp-to-Gly substitution at codon position 2027 of ACCase in the resistant plants. Molecular docking revealed that the spatial structure of ACCase changed significantly following the substitution, as indicated by reduced H-bonds. A newly derived cleaved amplified polymorphic sequence (dCAPS) marker was subsequently developed to detect the Trp-2027-Gly mutation in the ACCase of L. chinensis. Additionally, pretreatment with the cytochrome P450 (P450) inhibitor piperonyl butoxide (PBO) and the glutathione S-transferase (GST) inhibitor 4-chloro-7-nitrobenzoxadiazole (NBD-Cl) did not reverse resistance to CyB, suggesting that nontarget-site resistance mechanisms were not involved in CyB resistance in the HFLJ18 population. Overall, the resistance to CyB in the HFLJ18 population derived from the mutation of ACCase gene, and to the best of our knowledge, this is the first report of the ACCase Trp-2027-Gly mutation conferring resistance to ACCase-inhibiting herbicides in grass species. © 2024 Society of Chemical Industry.