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The editorial in "Frontiers in Plant Science" explores the molecular interactions between plants and insects, focusing on defense mechanisms and resistance genes. The research delves into the complex genetic and metabolic processes involved in plant-insect interactions, using advanced omics technologies. Specific studies highlighted in the editorial include the interaction between rice and the brown planthopper, as well as aphid-mediated tritrophic interactions and psyllid-pathogen interactions. The articles provide valuable insights into the molecular arms race between plants and insects, aiming to enhance pest control strategies and sustainable crop production. [Extracted from the article]

Tigecycline (TGC) is currently used to treat carbapenem-resistant Acinetobacter baumannii (CRAB) infections, while eravacycline (ERV), a new-generation tetracycline, holds promise as a novel therapeutic option for these infections. However, differences in resistance mechanism between ERV and TGC against A. baumannii remain unclear. This study sought to compare the characteristics and mechanisms of ERV and TGC resistance among clinical A. baumannii isolates. A total of 492 isolates, including 253 CRAB and 239 carbapenemsensitive A. baumannii (CSAB) isolates, were collected from hospitalized patients in China. The MICs of ERV and TGC against A. baumannii were determined by broth microdilution. Genetic mutations and expressions of adeB, adeG, adeJ, adeS, adeL, and adeN in resistant strains were examined by PCR and qPCR, respectively. The in vitro recombination experiments were used to verify the resistance mechanism of ERV and TGC in A. baumannii. The MIC90 of ERV in CRAB and CSAB isolates were lower than those of TGC. A total of 24 strains resistant to ERV and/or TGC were categorized into three groups: only ERVresistant (n = 2), both ERV- and TGC-resistant (n = 7), and only TGC-resistant (n = 15). ST208 (75%, n = 18) was a major clone that has disseminated in all three groups. The ISAba1 insertion in adeS was identified in 66.7% (6/9) of strains in the only ERV-resistant and both ERV- and TGC-resistant groups, while the ISAba1 insertion in adeN was found in 53.3% (8/15) of strains in the only TGC-resistant group. The adeABC and adeRS expressions were significantly increased in the only ERV-resistant and both ERV- and TGC-resistant groups, while the adeABC and adeIJK expressions were significantly increased and adeN was significantly decreased in the only TGC-resistant group. Expression of adeS with the ISAba1 insertion in ERV- and TGC-sensitive strains significantly increased the ERV and TGC MICs and upregulated adeABC and adeRS expressions. Complementation of the wildtype adeN in TGC-resistant strains with the ISAba1 insertion in adeN restored TGC sensitivity and significantly downregulated adeIJK expression. In conclusion, our data illustrates that ERV is more effective against A. baumannii clinical isolates than TGC. ERV resistance is correlated with the ISAba1 insertion in adeS, while TGC resistance is associated with the ISAba1 insertion in adeN or adeS in A. baumannii. [ABSTRACT FROM AUTHOR]

The editorial in "Frontiers in Plant Science" discusses the molecular interactions between plants and insects, focusing on defense mechanisms and strategies used by both organisms. The research topic explores the genetic, metabolic, and molecular interactions between herbivorous insects and host plants, using advanced omics technologies. Specific articles in the research topic delve into the interaction between rice and the brown planthopper, highlighting the molecular mechanisms of resistance genes such as Bph6, Bph14, Bph15, and Bph30. Additionally, the editorial covers studies on aphids as vectors in tritrophic interactions and psyllids as vectors in vector-pathogen interactions. [Extracted from the article]

BACKGROUND: Wheat crown rot (WCR), primarily caused by Fusarium pseudograminearum has become more and more prevalent in winter wheat areas in China. However, limited fungicides have been registered for the control of WCR in China so far. Pyraclostrobin is a representative quinone outside inhibitor (QoI) with excellent activity against Fusarium spp. There is currently limited research on the resistance risk and resistance mechanism of F. pseudograminearum to pyraclostrobin. RESULTS: Here, we determined the activity of pyraclostrobin against F. pseudograminearum. The EC50 values ranged from 0.022 to 0.172 μg mL−1 with an average EC50 value of 0.071 ± 0.030 μg mL−1. Four highly pyraclostrobin‐resistant mutants were obtained from two sensitive strains by ultraviolet (UV) mutagenesis in the laboratory. The mutants showed decreased mycelial growth rate and virulence as compared with the corresponding wild‐type strains, indicating that pyraclostrobin resistance suffered a fitness penalty in F. pseudograminearum. It was found that the high resistance of four mutants was caused by the G143S mutation in Cytb. Molecular docking analysis also further confirms that the G143S mutation in Cytb decreased the binding affinity between pyraclostrobin and Cytb. CONCLUSION: The resistance risk of F. pseudograminearum to pyraclostrobin could be low to medium. Although a mutation at the G143S position of Cytb could potentially occur, this mutation decreases the fitness of the mutant, which may reduce its survival in the environment. Therefore, the negative consequences of a possible mutation are lower. This makes pyraclostrobin a good candidate for controlling crown rot in wheat. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Introduction: Targeting the B-cell receptor pathway via ibrutinib, a specific inhibitor of Bruton's tyrosine kinase, has shown marked clinical efficacy in treatment of patients with chronic lymphocytic leukemia (CLL), thus becoming a preferred first line option independent of risk factors. However, acquired resistance to ibrutinib poses a major clinical problem and requires the development of novel treatment combinations to increase efficacy and counteract resistance development and clinical relapse rates. Case Presentation: In this study, we performed exome and transcriptome analyses of an ibrutinib resistant CLL patient in order to investigate genes and expression patterns associated with ibrutinib resistance. Here, we provide evidence that ibrutinib resistance can be attributed to aberrant mammalian target of rapamycin (MTOR) signaling. Conclusion: Thus, our study proposes that combined use of MTOR inhibitors with ibrutinib could be a possible option to overcome therapy resistance in ibrutinib treated patients. [ABSTRACT FROM AUTHOR]

Clubroot, a soil-borne disease caused by Plasmodiophora brassicae, is one of the most destructive diseases of Brassica oleracea all over the world. However, the mechanism of clubroot resistance remains unclear. In this research, transcriptome sequencing was conducted on root samples from both resistant (R) and susceptible (S) B. oleracea plants infected by P. brassicae. Then the comparative analysis was carried out between the R and S samples at different time points during the infection stages to reveal clubroot resistance related pathways and candidate genes. Compared with 0 days after inoculation, a total of 4991 differential expressed genes were detected from the S pool, while only 2133 were found from the R pool. Gene function enrichment analysis found that the effector-triggered immunity played a major role in the R pool, while the pathogen-associated molecular pattern triggered immune response was stronger in the S pool. Simultaneously, candidate genes were identified through weighted gene co-expression network analysis, with Bol010786 (CNGC13) and Bol017921 (SD2-5) showing potential for conferring resistance to clubroot. The findings of this research provide valuable insights into the molecular mechanisms underlying clubroot resistance and present new avenues for further research aimed at enhancing the clubroot resistance of B. oleracea through breeding. [ABSTRACT FROM AUTHOR]

The silkworm (Bombyx mori) is an important model lepidopteran insect and can be used to identify pesticide resistance‐related genes of great significance for biological control of pests. Uridine diphosphate glucosyltransferases (UGTs), found in all organisms, are the main secondary enzymes involved in the metabolism of heterologous substances. However, it remains uncertain if silkworm resistance to fenpropathrin involves UGT. This study observes significant variations in BmUGT expression among B. mori strains with variable fenpropathrin resistance post‐feeding, indicating BmUGT's role in fenpropathrin detoxification. Knockdown of BmUGT with RNA interference and overexpression of BmUGT significantly decreased and increased BmN cell activity, respectively, indicating that BmUGT plays an important role in the resistance of silkworms to fenpropathrin. In addition, fenpropathrin residues were significantly reduced after incubation for 12 h with different concentrations of a recombinant BmUGT fusion protein. Finally, we verified the conservation of UGT to detoxify fenpropathrin in Spodoptera exigua: Its resistance to fenpropathrin decreased significantly after knocking down SeUGT. In a word, UGT plays an important role in silkworm resistance to fenpropathrin by directly degrading the compound, a function seen across other insects. The results of this study are of great significance for breeding silkworm varieties with high resistance and for biological control of pests. [ABSTRACT FROM AUTHOR]

Zaifeng Si,1,2,&ast; Shengmei Zhao,3,&ast; Yingying Hao,3 Qian Wang,3 Yanfa Zhong,2 Yue Liu,3 Ran Chen,3 Yan Jin,3 Zhiming Lu1,3 1Department of Clinical Laboratory, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Clinical Laboratory, Dezhou Municipal Hospital of Traditional Chinese Medicine, Dezhou, Shandong, People’s Republic of China; 3Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Jin; Zhiming Lu, Email sdjinyan@163.com; luzhiming@sdu.edu.cnBackground: Enterobacter cloacae complex (ECC), which includes major nosocomial pathogens, causes urinary, respiratory, and bloodstream infections in humans, for which colistin is one of the last-line drugs.Objective: This study aimed to analyse the epidemiology and resistance mechanisms of colistin-resistant Enterobacter cloacae complex (ECC) strains isolated from Shandong, China.Methods: Two hundred non-repetitive ECC strains were collected from a tertiary hospital in Shandong Province, China, from June 2020 to June 2022. Whole-genome sequencing and bioinformatics analyses were performed to understand the molecular epidemiology of the colistin-resistant ECC strains. The nucleotide sequences of heat shock protein (hsp60) were analyzed by using BLAST search to classify ECC. The gene expression levels of ramA, soxS, acrA, acrB, phoP, and phoQ were assessed using RT-qPCR. MALDI-TOF MS was used to analyse the modification of lipid A.Results: Twenty-three colistin-resistant strains were detected among the 200 ECC clinical strains (11.5%). The hsp60 cluster analysis revealed that 20 of the 23 ECC strains belonged to heterogeneous resistance clusters. Variants of mgrB, phoPQ, and pmrAB, particularly phoQ and pmrB, were detected in the 23 ECC strains. The soxS and acrA genes were significantly overexpressed in all 23 colistin-resistant ECC strains (P < 0.05). Additionally, all 23 ECC strains contained modified lipid A related to colistin resistance, which showed five ion peaks at m/z 1876, 1920, 1955, 2114, and 2158. Among the 23 ECC strains, 6 strains possessed a phosphoethanolamine (pETN) moiety, 16 strains possessed a 4-amino-4-deoxy-L-arabinose (−L-Ara4N) moiety, and one strain had both pETN and −L-Ara4N moieties.Conclusion: This study suggests that diverse colistin resistance existed in ECC, including unknown resistance mechanisms, exist in ECC. Mechanistic investigations of colistin resistance are warranted to optimise colistin use in clinical settings and minimise the emergence of resistance.Keywords: Enterobacter cloacae complex, ECC, epidemiology, colistin, resistance mechanism

Simple Summary: RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1–2% of all NSCLCs. Chemotherapy and immunotherapy have a low impact on the prognosis of patients with RET fusions positive NSCLC. Multitargeted RET inhibitors have shown modest activity jeopardized by high toxicity. New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy in minimizing the known toxicities of the old drugs. This review will focus on the advent of new potent and selective RET-Is. We will describe their efficacy as well as the main mechanisms of resistance to them. We will further proceed to deal with new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events. RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1–2% of all NSCLCs. They share the same clinical features as the other fusion-driven NSCLC patients, as follows: younger age, adenocarcinoma histology, low exposure to tobacco, and high risk of spreading to the brain. Chemotherapy and immunotherapy have a low impact on the prognosis of these patients. Multitargeted RET inhibitors have shown modest activity jeopardized by high toxicity. New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy minimizing the known toxicities of the multitargeted agents. This review will describe the sensitivity of immune-checkpoint inhibitors (ICIs) in RET fusion + NSCLC patients, as well their experiences with the 'old' multi-targeted RET inhibitors. This review will focus on the advent of new potent and selective RET-Is. We will describe their efficacy as well as the main mechanisms of resistance to them. We will further proceed to deal with the new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events. [ABSTRACT FROM AUTHOR]

Background: Aminoglycoside-modifying enzymes (AMEs) play an essential role in bacterial resistance to aminoglycoside antimicrobials. With the development of sequencing techniques, more bacterial genomes have been sequenced, which has aided in the discovery of an increasing number of novel resistance mechanisms. Methods: The bacterial species was identified by 16S rRNA gene homology and average nucleotide identity (ANI) analyses. The minimum inhibitory concentration (MIC) of each antimicrobial was determined by the agar dilution method. The protein was expressed with the pCold I vector in E. coli BL21, and enzyme kinetic parameters were examined. The whole-genome sequence of the bacterium was obtained via the Illumina and PacBio sequencing platforms. Reconstruction of the phylogenetic tree, identification of conserved functional residues, and gene context analysis were performed using the corresponding bioinformatic techniques. Results: A novel aminoglycoside resistance gene, designated aph(3')-Ie, which confers resistance to ribostamycin, kanamycin, sisomicin and paromomycin, was identified in the chromosome of the animal bacterium Citrobacter gillenii DW61, which exhibited a multidrug resistance phenotype. APH(3')-Ie showed the highest amino acid identity of 74.90% with the functionally characterized enzyme APH(3')-Ia. Enzyme kinetics analysis demonstrated that it had phosphorylation activity toward four aminoglycoside substrates, exhibiting the highest affinity (Km, 4.22 ± 0.88 µM) and the highest catalytic efficiency [kcat/Km, (32.27 ± 8.14) × 104] for ribomycin. Similar to the other APH(3') proteins, APH(3')- Ie contained all the conserved functional sites of the APH family. The aph(3')-Ie homologous genes were present in C. gillenii isolates from different sources, including some of clinical significance. Conclusion: In this work, a novel chromosomal aminoglycoside resistance gene, designated aph(3')-Ie, conferring resistance to aminoglycoside antimicrobials, was identified in a rabbit isolate C. gillenii DW61. The elucidation of the novel resistance mechanism will aid in the effective treatment of infections caused by pathogens carrying such resistance genes. [ABSTRACT FROM AUTHOR]

One of the resistant mechanisms of EGFR‐TKIs is BRAF V600E mutation. Herein, we present the case of a 54‐year‐old Japanese female who underwent a right middle lobectomy for pathological stage IIB lung adenocarcinoma. One year and nine months after the surgery, she developed multiple intrapulmonary metastases. Osimertinib was administered due to EGFR exon 19 deletion. Although all intrapulmonary metastases had shrunk, the nodule at the superior segment of left lung enlarged after postoperative 4 years. The tumour was resected and BRAF V600E mutation and exon 19 deletion were detected. Three months after treatment with dabrafenib and trametinib instead of osimertinib, the remaining intrapulmonary metastases increased again. The continued growth of the metastatic foci even after EGFR‐TKI may indicate an acquired resistance. Thus, a repeat biopsy will aid in confirming the new gene expression. It should have been necessary to administer an additional dose of dabrafenib and trametinib without discontinuing osimertinib. [ABSTRACT FROM AUTHOR]

Tigecycline-non-susceptible Klebsiella pneumoniae (TNSKP) is increasing and has emerged as a global public health issue. However, the mechanism of tigecycline resistance remains unclear. The objective of this study was to investigate the potential role of efflux pump system in tigecycline resistance. 29 tigecycline-non-susceptible Klebsiella pneumoniae (TNSKP) strains were collected and their minimum inhibitory concentrations (MIC) were determined by the broth microdilution method. The ramR, acrR, rpsJ, tet(A), and tet(X) were amplified by polymerase chain reaction (PCR). The mRNA expression of different efflux pump genes and regulator genes were analyzed by real-time PCR. Additionally, KP14 was selected for genome sequencing. KP14 genes without acrB, oqxB, and TetA were modified using suicide plasmids and MIC of tigecycline of KP14 with target genes knocked out was investigated. It was found that MIC of tigecycline of 20 out of the 29 TNSKP strains decreased by over four folds once combined with phenyl-arginine-β-naphthylamide dihydrochloride (PaβN). Most strains exhibited upregulation of AcrAB and oqxAB efflux pumps. The strains with acrB, oqxB, and tetA genes knocked out were constructed, wherein the MIC of tigecycline of KP14∆acrB and KP14∆tetA was observed to be 2 µg/mL (decreased by 16 folds), the MIC of tigecycline of KP14ΔacrBΔTetA was 0.25 µg/mL (decreased by 128 folds), but the MIC of tigecycline of KP14∆oqxB remained unchanged at 32 µg/mL. The majority of TNSKP strains demonstrated increased expression of AcrAB-TolC and oqxAB, while certain strains showed mutations in other genes associated with tigecycline resistance. In KP14, both overexpression of AcrAB-TolC and tet(A) gene mutation contributed to the mechanism of tigecycline resistance. [ABSTRACT FROM AUTHOR]

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Background: Despite significant benefits from targeted therapy in patients with driver mutations, inevitable drug resistance usually occurred in non-small cell lung cancer, highlighting the necessity for sequential treatments to prolong overall survival. Unfortunately, durable drug response has not been reported in posterior-line therapy of cases with acquired EML4-ALK fusion after resistance to osimertinib, urging the need of referable decision-making in clinical management. Case presentation: We present a case of a 71-year-old Chinese female, never smoker, diagnosed with invasive adenocarcinoma in the left inferior lobe of her lung, with metastases in regional lymph nodes. She received erlotinib treatment after the detection of coexistent EGFR L858R/G719S and BRAF V600E via nextgeneration sequencing of resected tumor tissue. Routine imaging revealed disease progression approximately 14 months after starting erlotinib treatment, followed by the detection of EGFR L858R through non-invasive liquid biopsy. Subsequently, osimertinib was administered, showing clinical activities for nearly 19 months until the emergence of an EML4-ALK fusion. Given the EML4-ALK fusion, a relatively rare resistance mechanism to osimertinib, she received third-line ensartinib treatment. One month later, alleviated tumor lesions plus normal serum marker levels demonstrated the effectiveness of ensartinib in overcoming resistance to osimertinib. Of note, the clinical response to ensartinib persisted for more than 14 months, superior to the previously reported efficacy of aletinib and crizotinib in osimertinib-failure cases. As of the last follow-up in July 2022, the patient showed no signs of recurrence and maintained a good life quality. Conclusion: We reported a third-line ensartinib therapy in a patient with lung adenocarcinoma who developed an acquired EML4-ALK fusion after sequential treatment with erlotinib and osimertinib. Given the rarity of the EML4-ALK fusion as a resistance mechanism to osimertinib, ensartinib emerges as a promising treatment option for this specific clinical challenge, offering superior efficacy and good safety. [ABSTRACT FROM AUTHOR]

Microbial community adaptability to pH stress plays a crucial role in biofilm formation. This study aims to investigate the regulatory mechanisms of exogenous putrescine on pH stress, as well as enhance understanding and application for the technical measures and molecular mechanisms of biofilm regulation. Findings demonstrated that exogenous putrescine acted as a switch-like distributor affecting microorganism pH stress, thus promoting biofilm formation under acid conditions while inhibiting it under alkaline conditions. As pH decreases, the protonation degree of putrescine increases, making putrescine more readily adsorbed. Protonated exogenous putrescine could increase cell membrane permeability, facilitating its entry into the cell. Subsequently, putrescine consumed intracellular H+ by enhancing the glutamate-based acid resistance strategy and the γ-aminobutyric acid metabolic pathway to reduce acid stress on cells. Furthermore, putrescine stimulated ATPase expression, allowing for better utilization of energy in H+ transmembrane transport and enhancing oxidative phosphorylation activity. However, putrescine protonation was limited under alkaline conditions, and the intracellular H+ consumption further exacerbated alkali stress and inhibits cellular metabolic activity. Exogenous putrescine promoted the proportion of fungi and acidophilic bacteria under acidic stress and alkaliphilic bacteria under alkali stress while having a limited impact on fungi in alkaline biofilms. Increasing Bdellovibrio under alkali conditions with putrescine further aggravated the biofilm decomposition. This research shed light on the unclear relationship between exogenous putrescine, environmental pH, and pH stress adaptability of biofilm. By judiciously employing putrescine, biofilm formation could be controlled to meet the needs of engineering applications with different characteristics. [ABSTRACT FROM AUTHOR]

BACKGROUND: With the increasing incidence of pest resistance to transgenic crops producing Bacillus thuringiensis (Bt) proteins in the field, elucidating the molecular basis of resistance is important for monitoring, delaying and countering pest resistance. Previous work revealed that mutation or down‐regulated expression of the cadherin gene (PgCad1) is associated with pink bollworm (Pectinophora gossypiella) resistance to Cry1Ac, and 20 mutant PgCad1 alleles (r1‐r20) were characterized. Here, we tested the hypothesis that the ABC transporter PgABCC2 is a functional receptor for the Bt toxin Cry1Ac and that a mutation is associated with resistance. RESULTS: We identified and characterized the first resistance allele (rC2) of PgABCC2 in the laboratory‐selected Cry1Ac‐resistant strain AQ‐C2 of pink bollworm. The rC2 allele had a one‐base deletion in exon20, resulting in a frameshift and the introduction of a premature stop codon. This resulting PgABCC2 protein had a truncated C‐terminus, including the loss of the NBD2 domain. AQ‐C2 exhibited 20.2‐fold greater resistance to Cry1Ac than the susceptible strain, and its inheritance of Cry1Ac resistance was recessive and genetically linked to PgABCC2. When produced in cultured insect cells, recombinant wild‐type and rC2 mutant PgABCC2 proteins localized within the cell plasma membrane, although substantial cytoplasmic retention was also observed for the mutant protein, while the mutant PgABCC2 caused a 13.9‐fold decrease in Cry1Ac toxicity versus the wild‐type PgABCC2. CONCLUSIONS: PgABCC2 is a functional receptor of Cry1Ac and the loss of its carboxyl terminus (including its NBD2 domain) confers low‐level resistance to Cry1Ac in both larvae and in cultured cells. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Introduction: A neurotrophic tropomyosin receptor kinase (NTRK)‐tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene. However, almost all tumors eventually acquire resistance to NTRK‐TKIs. Method: To investigate the mechanism of resistance to NTRK‐TKIs, we established cells resistant to three types of NTRK‐TKIs (larotrectinib, entrectinib, and selitrectinib) using KM12 colon cancer cells with a TPM3‐NTRK1 rearrangement. Result: Overexpression of 3‐hydroxy‐3‐methylglutaryl‐CoA synthase 2 (HMGCS2) was observed in three resistant cells (KM12‐LR, KM12‐ER, and KM12‐SR) by microarray analysis. Lower expression of sterol regulatory element‐binding protein 2 (SREBP2) and peroxisome proliferator activated receptor α (PPARα) was found in two cells (KM12‐ER and KM12‐SR) in which HMGCS2 was overexpressed compared to the parental KM12 and KM12‐LR cells. In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK‐TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK‐TKI resistance. In addition, simvastatin and silibinin had a synergistic effect with NTRK‐TKIs in resistant cells, and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK‐TKI and simvastatin in KM12 cells. In xenograft mouse models, combination treatment with entrectinib and simvastatin reduced resistant tumor growth compared with entrectinib alone. Conclusion: These results suggest that HMGCS2 overexpression induces resistance to NTRK‐TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance. [ABSTRACT FROM AUTHOR]

Key message: Transgenic plants stably overexpressing ScOPR1 gene enhanced disease resistance by increasing the accumulation of JA, SA, and GST, as well as up-regulating the expression of genes related to signaling pathways. 12-Oxo-phytodienoate reductase (OPR) is an oxidoreductase that depends on flavin mononucleotide (FMN) and catalyzes the conversion of 12-oxophytodienoate (12-OPDA) into jasmonic acid (JA). It plays a key role in plant growth and development, and resistance to adverse stresses. In our previous study, we have obtained an OPR gene (ScOPR1, GenBank Accession Number: MG755745) from sugarcane. This gene showed positive responses to methyl jasmonate (MeJA), salicylic acid (SA), abscisic acid (ABA), and Sporisorium scitamineum, suggesting its potential for pathogen resistance. Here, in our study, we observed that Nicotiana benthamiana leaves transiently overexpressing ScOPR1 exhibited weaker disease symptoms, darker 3,3-diaminobenzidine (DAB) staining, higher accumulation of reactive oxygen species (ROS), and higher expression of hypersensitive response (HR) and SA pathway-related genes after inoculation with Ralstonia solanacearum and Fusarium solanacearum var. coeruleum. Furthermore, the transgenic N. benthamiana plants stably overexpressing the ScOPR1 gene showed enhanced resistance to pathogen infection by increasing the accumulation of JA, SA, and glutathione S-transferase (GST), as well as up-regulating genes related to HR, JA, SA, and ROS signaling pathways. Transcriptome analysis revealed that the specific differentially expressed genes (DEGs) in ScOPR1-OE were significantly enriched in hormone transduction signaling and plant–pathogen interaction pathways. Finally, a functional mechanism model of the ScOPR1 gene in response to pathogen infection was depicted. This study provides insights into the molecular mechanism of ScOPR1 and presents compelling evidence supporting its positive involvement in enhancing plant disease resistance. [ABSTRACT FROM AUTHOR]

Insecticide resistance in Aedes mosquitoes presents a major challenge to the control of arboviral diseases. However, resistance mechanisms for many of the insecticides remain unknown. A commonly used insecticide, deltamethrin, was used to select a resistance strain of the vector mosquito, Aedes albopictus, and we identified an F1534S substitution in the voltage-gated sodium channel (VGSC) gene product as the first event in generating resistance. Engineering an F1534S substitution using Cas9/gRNA technologies conferred deltamethrin resistance on a previously susceptible strain. Crosses that removed this mutation restored the susceptible phenotype. Predicted protein structural changes and differences in transcript accumulation levels were correlated with the resistance phenotype. Furthermore, F1534S mutations were detected in all resistant Ae. albopictus populations collected in the field. We conclude that the VGSC F1534S mutation is essential for resistance to deltamethrin in Ae. albopictus, and is a suitable molecular index for pyrethroid resistance detection and monitoring in this species.

Tigecycline, hailed as a pivotal agent in combating multidrug-resistant bacterial infections, confronts obstacles posed by the emergence of resistance mechanisms in Gram-negative bacilli. This study explores the complex mechanisms of tigecycline resistance in Gram-negative bacilli, with a particular focus on the role of efflux pumps and drug modification in resistance. By summarizing these mechanisms, our objective is to provide a comprehensive understanding of tigecycline resistance in Gram-negative bacilli, thereby illuminating the evolving landscape of antimicrobial resistance. This review contributes to the elucidation of current existing tigecycline resistance mechanisms and provides insights into the development of effective strategies to manage the control of antimicrobial resistance in the clinical setting, as well as potential new targets for the treatment of tigecycline-resistant bacterial infections.

Glioblastoma, the most malignant primary brain tumor among gliomas, is characterized by a low cure rate, high recurrence rate, and invasive growth. Without chemotherapy, the median survival of patients is only 12.1 months. The standard treatment for glioblastoma primarily involves surgical resection, complemented by radiotherapy. Temozolomide (TMZ), a new oral alkylating agent, is currently used as the first-line chemotherapy drug for glioma. However, TMZ treatment only improves median survival by 2 months, largely because of the tumor's ability to develop resistance to the drug. The main mechanism underlying this resistance involves DNA repair processes, such as the action of O6⁃methylguanine DNA methyltransferase (MGMT), which repairs the DNA damage caused by TMZ, and other DNA repair mechanisms including mismatch repair and base excision repair. These mechanisms can effectively repair the DNA damage caused by TMZ, thereby reducing the sensitivity of tumor cells to the drug. This study summarized the recent research progress of TMZ resistance mechanism in glioblastoma, aiming to provide a theoretical basis for the development of new therapies. The mechanisms of glioma resistance to TMZ mainly involves DNA damage repair (as mentioned above), abnormal cell signaling pathways (p53-mediated signaling, reactive oxygen species-mediated signaling, endoplasmic reticulum stress and autophagy-related signaling, receptor tyrosine kinase-related signaling, transforming growth factors, β-mediated signaling pathway, Wnt/β-Catenin signaling pathway), glioma stem cells, tumor microenvironment (hypoxic microenvironment, nano-drug delivery system), epidermal growth factor receptor, and microRNAs.

Helicoverpa zea is a major target pest of pyramided transgenic crops expressing Cry1, Cry2 and/or Vip3Aa proteins from Bacillus thuringiensis (Bt) in the United States. Laboratory-selected Cry1Ac/Cry2Ab cross resistance and field-evolved practical dual resistance of H. zea to these two toxins have been widely reported. Whether the widespread Cry1Ac/Cy2Ab dual resistance of H. zea has resulted from the selection of one shared or two independent resistance mechanisms by pyramided Bt crops remains unclear. Cadherin is a well-confirmed receptor of Cry1Ac and a suggested receptor of Cry2Ab in at least three Lepidopteran species. To test whether cadherin may serve as one shared mechanism for the cross and dual resistance of H. zea to Cry1Ac and Cry2Ab, we cloned H. zea cadherin (HzCadherin) cDNA and studied its functional roles in the mode of action of Cry1Ac and Cry2Ab by gain- and loss-of-function analyses. Heterologous expression of HzCadherin in H. zea midgut, H. zea fat body and Sf9 cells made all three of these cell lines more susceptible to activated Cry1Ac but not activated Cry2Ab, whereas silencing HzCadherin of H. zea midgut and fat body cells significantly reduced the susceptibility to Cry1Ac but not Cry2Ab. Likewise, suppressing HzCadherin with siRNA made H. zea larvae resistant to Cry1Ac. These results clearly demonstrate that HzCadherin is not a receptor for Cry2Ab, and thus it is unlikely to serve as one shared mechanism for the cross and dual resistance of H. zea to Cry1Ac and Cry2Ab.

Abstract Black rot, caused by Xanthomonas campestris pv. campestris (Xcc) significantly affects the production of cabbage and other cruciferous vegetables. Plant antioxidant system plays an important role in pathogen invasion and is one of the main mechanisms underlying resistance to biological stress. Therefore, it is important to study the resistance mechanisms of the cabbage antioxidant system during the early stages of Xcc. In this study, 108 CFU/mL (OD600 = 0.1) Xcc race1 was inoculated on “zhonggan 11” cabbage using the spraying method. The effects of Xcc infection on the antioxidant system before and after Xcc inoculation (0, 1, 3, and 5 d) were studied by physiological indexes determination, transcriptome and metabolome analyses. We concluded that early Xcc infection can destroy the balance of the active oxygen metabolism system, increase the generation of free radicals, and decrease the scavenging ability, leading to membrane lipid peroxidation, resulting in the destruction of the biofilm system and metabolic disorders. In response to Xcc infection, cabbage clears a series of reactive oxygen species (ROS) produced during Xcc infection via various antioxidant pathways. The activities of antioxidant enzymes such as superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) increased after Xcc infection, and the ROS scavenging rate increased. The biosynthesis of non-obligate antioxidants, such as ascorbic acid (AsA) and glutathione (GSH), is also enhanced after Xcc infection. Moreover, the alkaloid and vitamin contents increased significantly after Xcc infection. We concluded that cabbage could resist Xcc invasion by maintaining the stability of the cell membrane system and improving the biosynthesis of antioxidant substances and enzymes after infection by Xcc. Our results provide theoretical basis and data support for subsequent research on the cruciferous vegetables resistance mechanism and breeding to Xcc.

Mutations in influenza virus neuraminidase (NA) can lead to viral resistance to NA inhibitors (NAIs). To update global influenza NA mutations and resistance to NAIs, we investigated epidemic information from global regions for NAIs-resistant influenza strains and analyzed their NA mutations. Drug-resistant mutations in NA, especially new mutations occurred in 2016-2024, were updated. The H274Y mutation in N1, a major contributor to NAI resistance, peaked in 2008, significantly impacting public health in countries like Japan and the USA. Three main mechanisms of NAI resistance were identified: catalytic site mutations, structural hindrance, and monomer stability changes. Although global resistance rates of H1N1pdm09, H3N2, and influenza B have remained stable at around 1%, sporadic emergence of resistant strains highlights the need for continued vigilance. The evolution of drug-resistant, transmissible strains through compensatory mutations underscores the urgency of new antiviral strategies. Strengthening global surveillance and adjusting public health policies, such as improving vaccine coverage and prudent antiviral use, remain essential to mitigating future risks.

Copyright of Chinese Journal of Applied Entomology is the property of Chinese Journal of Applied Entomology, Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

To reduce the damage to crop from insects, some agricultural practices have been used such as spraying insecticides and planting Bt-transgenic insect-resistant plants. However, since insecticides are continuously sprayed and Bt-transgenic insect-resistant plants are continuously cultivated at large scales, target insects tend to evolve the resistance to insecticides and insect-resistant plants. This insectresistance evolution of target insects not only decrease the insect-control effectiveness of insecticides and transgenic plants but also affect the functional services in agricultural ecosystems. Here, we reviewed the molecular mechanisms of insect resistance to chemical and microbial insecticides and Bt-transgenic plants. Insects evolve resistance to chemical insecticides via decreasing the sensitivity of target sites and enhancing the activities of detoxifying enzymes in insects, resistance to microbial insecticides via activating immune systems and changing symbiotic flora in insects, and resistance to Bt-transgenic plants via downregulating midgut binding receptors and decreasing midgut protease activities in insects. To delay the resistance evolution of insects and increase the insect-control efficiency of insecticides, it is urgent to systematically control agricultural insects through reducing the use of chemical insecticides and to increasing the integrative use of broadspectrum and high-activity microbial insecticides as well as insect-resistant plants. [ABSTRACT FROM AUTHOR]

Transient receptor potential (TRP) channels are a class of important cation channels on the cell membrane that participate in the formation of sensory functions such as insect vision, olfaction, temperature perception, hearing, and mechanical sensation. The transient receptor potential vanilloid (TRPV) channels constitute a subfamily within the TRP family, with the protein complex encoded by the nanchung (Nan) and inactive (Iav) genes serving as molecular targets for insecticides such as pymetrozine, afidopyropen, and prifluquinazon. Studies have shown that the mechanism of action of TRPV channel modulators differs from traditional neuroactive insecticides, for example, pymetrozine and prifluquinazon inhibit the feeding behavior of Myzus persicae, pymetrozine induces unique poisoning symptoms in Locusta migratoria by acting on the chordotonal organs of insects, causing the hindlegs to lift and stretch, pymetrozine and prifluquinazon affect the gravity and auditory sensation of Drosophila melanogaster, disrupting its normal negative geotaxis behavior, pymetrozine interferes with the reproductive behavior of Nilaparvata lugens and Drosophila melanogaster, effectively inhibiting the population size of their offspring, thus exhibiting a prolonged efficacy. Field populations of N. lugens in China have developed moderate to high levels of resistance to pymetrozine, while resistance levels in Sogatella furcifera and Laodelphax striatellus are lower but increasing annually; Bemisia tabaci exhibits relatively low resistance levels to pymetrozine and afidopyropen Members of the cytochrome P450 family such as CYP6CS1, CYP6CM1 and CYP6CW1 were involved in metabolic resistance of current pests to pymetrozine. However, resistance to the targets of TRPV channel modulators in pests has not yet been identified. This paper systematically elaborates on the discovery, toxicological mechanism, resistance status, fitness costs, and resistance mechanism of TRPV channel modulators, this can provide reference for the in-depth research and scientific use of this class of compounds. [ABSTRACT FROM AUTHOR]

Introduction: The brown planthopper (BPH) poses a significant threat to rice production in Asia. The use of resistant rice varieties has been effective inmanaging this pest. However, the adaptability of BPH to resistant rice varieties has led to the emergence of virulent populations, such as biotype Y BPH. YHY15 rice, which carries the BPH resistance gene Bph15, exhibits notable resistance to biotype 1 BPH but is susceptible to biotype Y BPH. Limited information exists regarding how resistant rice plants defend against BPH populations with varying levels of virulence. Methods: In this study, we integrated miRNA and mRNA expression profiling analyses to study the differential responses of YHY15 rice to both avirulent (biotype 1) and virulent (biotype Y) BPH. Results: YHY15 rice demonstrated a rapid response to biotype Y BPH infestation, with significant transcriptional changes occurring within 6 hours. The biotype Yresponsive genes were notably enriched in photosynthetic processes. Accordingly, biotype Y BPH infestation induced more intense transcriptional responses, affecting miRNA expression, defenserelated metabolic pathways, phytohormone signaling, and multiple transcription factors. Additionally, callose deposition was enhanced in biotype Y BPH-infested rice seedlings. Discussion: These findings provide comprehensive insights into the defense mechanisms of resistant rice plants against virulent BPH, and may potentially guide the development of insect-resistant rice varieties. [ABSTRACT FROM AUTHOR]

The clover seed weevil, Tychius picirostris Fabricius, a serious pest of white clover, Trifolium repens L. grown for seed in western Oregon, causing feeding damage to flowers and developing seeds. Since 2017, white clover seed producers have anecdotally reported T. picirostris control failures using foliar pyrethroid insecticide applications. This mode of action (MoA) is an important chemical control option for T. picirostris management. To evaluate insecticide resistance selection to pyrethroids (bifenthrin) and other MoAs labeled for T. picirostris management (malathion and chlorantraniliprole), adult populations were collected from 8 commercial white clover grown for seed fields in the Willamette Valley, OR, in 2022 and 2023. Among collected Oregon populations, very high resistance ratios (RR50 = 178.00–725.67) were observed to technical grade bifenthrin and low to high resistance ratios (RR50 = 7.80–32.80) to malathion in surface contact assays compared to a susceptible Canadian field population. Moreover, >2.73 times the labeled rate of formulated product containing bifenthrin as the sole MoA was required to kill >50% of T. picirostris in topical assays. Synergistic assays with a mixed-function oxidase inhibitor, an esterase inhibitor, and a glutathione- S -transferase inhibitor revealed phase I and II detoxification enzymes are present in Oregon T. picirostris populations and confer metabolic resistance to bifenthrin. This is the first report of T. picirostris insecticide resistance selection to pyrethroid and organophosphate insecticides. Results will inform continued monitoring and insecticide resistance management strategies to slow the evolution of T. picirostris insecticide resistance selection in Oregon's white clover seed production. [ABSTRACT FROM AUTHOR]

BACKGROUND: SYP‐34773 is a low‐toxicity pyrimidine amine compound, which was synthesized by modifying the lead compound diflumetorim. Previous literature has shown that it can strongly inhibit the mycelial growth of several important plant pathogens, including Phytophthora litchii. However, the resistance risk of SYP‐34773 has not been reported for P. litchii. RESULTS: The mean effective concentration (EC50) value of SYP‐34773 against the mycelial growth of 111 P. litchii isolates was 0.108 ± 0.008 μg mL−1, which can be used as the baseline sensitivity for SYP‐34773 resistance detection in the future. Six mutants were obtained from two parental strain through fungicide induction, whose resistance factors fell between 194‐ and 687‐fold, with stability. Results regarding mycelial growth, sporangial production, sporangial germination, zoospore release, cystspore germination, and pathogenicity showed that the mutants' compound fitness index values were significantly lower than those of their parental isolate. Furthermore, there was no cross‐resistance between SYP‐34773 and diflumetorim in P. litchii. Significant inhibition of the mitochondrial complex I enzyme activity in two wild‐type P. litchii isolates, but not in mutants, was observed upon treatment with SYP‐34773. CONCLUSION: The resistance risk of SYP‐34773 in P. litchii is moderate, and resistance management strategies should be adopted in field use. SYP‐34773 is a mitochondrial complex I inhibitor, and SYP‐34773‐resistant P. litchii isolates did not show cross‐resistance against diflumetorim. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

BACKGROUND: Brown rot disease, caused by Monilinia fructicola, poses a significant challenge to peach production in China. The efficacy of mefentrifluconazole, a new triazole fungicide, in controlling brown rot in peaches has been remarkable. However, the resistance risk and mechanism associated with this fungicide remain unclear. This study was designed to assess the resistance risk of M. fructicola to mefentrifluconazole and reveal the potential resistance mechanism. RESULTS: The mean median effective concentration (EC50) of 101 M. fructicola isolates to mefentrifluconazole was 0.003 μg mL−1, and the sensitivity exhibited a unimodal distribution. Seven mefentrifluconazole‐resistant mutants were generated from three parental isolates in the laboratory through fungicide adaption. The biological characteristics of the resistant mutants revealed that three of them exhibited enhanced survival fitness compared to the parental isolates, whereas the remaining four mutants displayed reduced survival fitness. Mefentrifluconazole showed strong positive cross‐resistance with fenbuconazole, whereas no cross‐resistance was observed with pyrimethanil, procymidone or pydiflumetofen. No overexpression of MfCYP51 gene was detected in the resistant mutants. Multiple sequence alignment revealed that three resistant mutants (MXSB2‐2, Mf12‐1 and Mf12‐2) had a point mutation (G461S) in MfCYP51 protein. Molecular docking techniques confirmed the contribution of this point mutation to mefentrifluconazole resistance. CONCLUSION: The risk of M. fructicola developing resistance to mefentrifluconazole is relatively low‐to‐medium and point mutation G461S in MfCYP51 could confer mefentrifluconazole resistance in M. fructicola. This study provided essential data for monitoring the emergence of resistance and developing resistance management strategies for mefentrifluconazole. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Rice is cultivated and consumed worldwide. It belongs to genus 'Oryza' with about 21 wild relatives and eight identified genomes which makes it accessible to the huge pool of genetic resources. The rice crop can be distressed by various biotic and abiotic stressors that affect its productivity. Brown planthoppers (BPH) are major pests of different persistent biotypes in different regions. Several major and minor genes and quantitative trait loci (QTLs) regulate BPH resistance, a composite character. These genes/QTLs employ different resistance mechanisms and may be specific to each biotype. 22 of the 44 BPH genes are found in the wild cousins of rice. Several genes have been discovered, cloned, functionally assessed, and introduced into various lines. Most of the identified genes have not been functionally studied rendering their mechanisms to remain unknown. With the discovery that BPH-1 could not provide protection against Biotype 2, there were concerns about a major plant hopper outbreak. To avoid such a scenario, genes from various sources and different resistance mechanisms are being explored. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Modern Laboratory Medicine is the property of Journal of Modern Laboratory Medicine Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Antimicrobial peptides (AMPs) hold promise as alternatives to combat bacterial infections, addressing the urgent global threat of antibiotic resistance. COG1410, a synthetic peptide derived from apolipoprotein E, has exhibited potent antimicrobial properties against various bacterial strains, including Mycobacterium smegmatis. However, our study reveals a previously unknown resistance mechanism developed by M. smegmatis against COG1410 involving ClpC. Upon subjecting M. smegmatis to serial passages in the presence of sub-MIC COG1410, resistance emerged. The comparative genomic analysis identified a point mutation in ClpC (S437P), situated within its middle domain, which led to high resistance to COG1410 without compromising bacterial fitness. Complementation of ClpC in mutant restored bacterial sensitivity. In-depth analyses, including transcriptomic profiling and in vitro assays, uncovered that COG1410 interferes with ClpC at both transcriptional and functional levels. COG1410 not only stimulated the ATPase activity of ClpC but also enhanced the proteolytic activity of Clp protease. SPR analysis confirmed that COG1410 directly binds with ClpC. Surprisingly, the identified S437P mutation did not impact their binding affinity. This study sheds light on a unique resistance mechanism against AMPs in mycobacteria, highlighting the pivotal role of ClpC in this process. Unraveling the interplay between COG1410 and ClpC enriches our understanding of AMP-bacterial interactions, offering potential insights for developing innovative strategies to combat antibiotic resistance. [ABSTRACT FROM AUTHOR]

Previously, we reported that metronidazole MICs are not dependent on the expression levels of nim genes in B. fragilis strains and we compared the proteomes of metronidazole-resistant laboratory B. fragilis strains to those of their susceptible parent strains. Here, we used RT-qPCR to correlate the expression levels of 18 candidate genes in a panel of selected, clinical nim gene-positive and -negative B. fragilis strains to their metronidazole MICs. Metronidazole MICs were correlated with the expression of certain tested genes. Specifically, lactate dehydrogenase expression correlated positively, whereas cytochrome fumarate reductase/succinate dehydrogenase, malate dehydrogenase, phosphoglycerate kinase redox and gat (GCN5-like acetyltransferase), and relA (stringent response) regulatory gene expressions correlated negatively with metronidazole MICs. This result provides evidence for the involvement of carbohydrate catabolic enzymes in metronidazole resistance in B. fragilis. This result was supported by direct substrate utilization tests. However, the exact roles of these genes/proteins should be determined in deletion–complementation tests. Moreover, the exact redox cofactor(s) participating in metronidazole activation need to be identified. [ABSTRACT FROM AUTHOR]

Abstract One of the resistant mechanisms of EGFR‐TKIs is BRAF V600E mutation. Herein, we present the case of a 54‐year‐old Japanese female who underwent a right middle lobectomy for pathological stage IIB lung adenocarcinoma. One year and nine months after the surgery, she developed multiple intrapulmonary metastases. Osimertinib was administered due to EGFR exon 19 deletion. Although all intrapulmonary metastases had shrunk, the nodule at the superior segment of left lung enlarged after postoperative 4 years. The tumour was resected and BRAF V600E mutation and exon 19 deletion were detected. Three months after treatment with dabrafenib and trametinib instead of osimertinib, the remaining intrapulmonary metastases increased again. The continued growth of the metastatic foci even after EGFR‐TKI may indicate an acquired resistance. Thus, a repeat biopsy will aid in confirming the new gene expression. It should have been necessary to administer an additional dose of dabrafenib and trametinib without discontinuing osimertinib.

BackgroundAminoglycoside-modifying enzymes (AMEs) play an essential role in bacterial resistance to aminoglycoside antimicrobials. With the development of sequencing techniques, more bacterial genomes have been sequenced, which has aided in the discovery of an increasing number of novel resistance mechanisms.MethodsThe bacterial species was identified by 16S rRNA gene homology and average nucleotide identity (ANI) analyses. The minimum inhibitory concentration (MIC) of each antimicrobial was determined by the agar dilution method. The protein was expressed with the pCold I vector in E. coli BL21, and enzyme kinetic parameters were examined. The whole-genome sequence of the bacterium was obtained via the Illumina and PacBio sequencing platforms. Reconstruction of the phylogenetic tree, identification of conserved functional residues, and gene context analysis were performed using the corresponding bioinformatic techniques.ResultsA novel aminoglycoside resistance gene, designated aph(3’)-Ie, which confers resistance to ribostamycin, kanamycin, sisomicin and paromomycin, was identified in the chromosome of the animal bacterium Citrobacter gillenii DW61, which exhibited a multidrug resistance phenotype. APH(3’)-Ie showed the highest amino acid identity of 74.90% with the functionally characterized enzyme APH(3’)-Ia. Enzyme kinetics analysis demonstrated that it had phosphorylation activity toward four aminoglycoside substrates, exhibiting the highest affinity (Km, 4.22 ± 0.88 µM) and the highest catalytic efficiency [kcat/Km, (32.27 ± 8.14) × 104] for ribomycin. Similar to the other APH(3’) proteins, APH(3’)-Ie contained all the conserved functional sites of the APH family. The aph(3’)-Ie homologous genes were present in C. gillenii isolates from different sources, including some of clinical significance.ConclusionIn this work, a novel chromosomal aminoglycoside resistance gene, designated aph(3’)-Ie, conferring resistance to aminoglycoside antimicrobials, was identified in a rabbit isolate C. gillenii DW61. The elucidation of the novel resistance mechanism will aid in the effective treatment of infections caused by pathogens carrying such resistance genes.

Abstract Introduction A neurotrophic tropomyosin receptor kinase (NTRK)‐tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene. However, almost all tumors eventually acquire resistance to NTRK‐TKIs. Method To investigate the mechanism of resistance to NTRK‐TKIs, we established cells resistant to three types of NTRK‐TKIs (larotrectinib, entrectinib, and selitrectinib) using KM12 colon cancer cells with a TPM3‐NTRK1 rearrangement. Result Overexpression of 3‐hydroxy‐3‐methylglutaryl‐CoA synthase 2 (HMGCS2) was observed in three resistant cells (KM12‐LR, KM12‐ER, and KM12‐SR) by microarray analysis. Lower expression of sterol regulatory element‐binding protein 2 (SREBP2) and peroxisome proliferator activated receptor α (PPARα) was found in two cells (KM12‐ER and KM12‐SR) in which HMGCS2 was overexpressed compared to the parental KM12 and KM12‐LR cells. In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK‐TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK‐TKI resistance. In addition, simvastatin and silibinin had a synergistic effect with NTRK‐TKIs in resistant cells, and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK‐TKI and simvastatin in KM12 cells. In xenograft mouse models, combination treatment with entrectinib and simvastatin reduced resistant tumor growth compared with entrectinib alone. Conclusion These results suggest that HMGCS2 overexpression induces resistance to NTRK‐TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance.

Anaplastic lymphoma kinase (ALK) inhibitors are the recommended treatment of ALK-rearranged non-small cell lung cancer but are prone to eventual drug resistance.Herein we report a 45-year-old Asian woman diagnosed with EML4-ALK rearranged lung adenocarcinoma. Small cell lung cancer-like phenotypic transformation occurred when resistance to crizotinib treatment. Next-generation sequencing was performed and detected an ALK rearrangement co-existent with a TP53 gene mutation in the small cell specimens. The patient had a good response to alectinib with a progression-free survival >7 months. After disease progression, newly emerged ALK p.G1269A and p.L1196 M gene mutations co-existent with ALK rearrangement were detected. The patient had a good initial response to ceritinib treatment, which last for >12 months. After ceritinib failure, however, more complicated mutations within the ALK kinase domain (p.G1269A, p.L1196 M, newly emerged p.D1203 N, and p.L1122V) were detected. Ultimately, due to terminal rapid progression and resistance to lorlatinib, the overall survival was nearly 3 years.Our case showed that next-generation ALK-tyrosine kinase inhibitors (TKIs) may be an appropriate choice after transformation to small cell lung cancer and failure to one ALK-TKI. Sequential biopsies and gene mutation monitoring are important to arrange the sequence of different generation ALK-TKIs. Appropriate sequential therapies may yield a prolonged response with a satisfactory quality of life in patients with advanced ALK-rearranged non-small cell lung cancer.

Abstract Background Fusarium crown rot (FCR) is one of the most significant diseases limiting crop production in the Huanghuai wheat-growing region of China. Prothioconazole, a triazole sterol 14α-demethylation inhibitor (DMI) fungicide developed by the Bayer Crop Protection Company, is mainly registered for the prevention and control of wheat powdery mildew and stripe rust (China Pesticide Information Network). It is known to exhibit high activity against F. pseudograminearum, but further research, particularly regarding the potential for fungicide resistance, is required before it can be registered for the control of FCR in China. Results The current study found that the baseline sensitivity of 67 field isolates of F. pseudograminearum collected between 2019 and 2021 ranged between 0.016–2.974 μg/mL, with an average EC50 value of 1.191 ± 0.720 μg/mL (mean ± SD). Although none of the field isolates exhibited signs of resistance, three highly resistant mutants were produced by repeated exposure to prothioconazole under laboratory conditions. All of the mutants were found to exhibit significantly reduced growth rates on potato dextrose agar (PDA), as well as reduced levels of sporulation, which indicated that there was a fitness cost associated with the resistance. However, inoculation of wounded wheat coleoptiles revealed that the pathogenicity of the resistant mutants was little affected or actually increased. Molecular analysis of the genes corresponding to the prothioconazole target protein, FpCYP51 (FpCYP51A, FpCYP51B, and FpCYP51C), indicated that the resistant mutants contained three conserved substitutions (M63I, A205S, and I246V) that were present in the FpCYP51C sequence of all three mutants, as well as several non-conserved substations in their FpCYP51A and FpCYP51B sequences. Expression analysis revealed that the presence of prothioconazole (0.1 μg/mL) generally resulted in reduced expression of the three FpCYP51 genes, but that the three mutants exhibited more complex patterns of expression that differed in comparison to their parental isolates. The study found no evidence of cross-resistance between prothioconazole and any of the fungicides tested including three DMI fungicides tebuconazole, prochloraz, and flutriafol. Conclusions Taken together these results not only provide new insight into the resistant mechanism and biological characteristics associated with prothioconazole resistance in F. pseudograminearum, but also strong evidence that prothioconazole could provide effective and sustained control of FCR, especially when applied in combination with other fungicides.

Insecticides have been instrumental in the prevention and management of key agricultural insect pests, thereby contributing to increased food production. However, the effectiveness of insecticides diminishes when targeted pests develop resistance, a phenomenon linked to species evolution and survival instincts. The Arthropod Pesticide Resistance Database, maintained by Michigan State University, has documented 18,934 cases of resistance to insecticidal active ingredients worldwide from 1914 to the present. This special collection comprises eight original research articles that delve into the monitoring, mechanism and management of insecticide resistance. Two papers present multi‐year resistance monitoring results in Chilo suppressalis and Spodoptera litura. Two studies employ transcriptome data to examine the candidate genes implicated in solanine‐induced response in Phthorimaea operculella and chlorantraniliprole‐induced response in Galeruca daurica, respectively. Additionally, two papers describe the genetic and physiological impacts of insecticides, while others explore the potential mechanisms underlying chlorfenapyr resistance in Glyphodes pyloalis and pyrethroids resistance in Laodelphax striatellus. The new results, conclusions and suggestions presented in this collection are anticipated to contribute to the advancement of knowledge on insecticide resistance and facilitate the development of a sustainable approach to managing insect pests. [ABSTRACT FROM AUTHOR]

Bacillus biocontrol agent(s) BCA(s) such as Bacillus cereus, Bacillus thuringiensis and Bacillus subtilis have been widely applied to control insects' pests of plants and pathogenic microbes, improve plant growth, and facilitate their resistance to environmental stresses. In the last decade, researchers have shown that, the application of Bacillus biocontrol agent(s) BCA(s) optimized agricultural production yield, and reduced disease risks in some crops. However, these bacteria encountered various abiotic stresses, among which ultraviolet (UV) radiation severely decrease their efficiency. Researchers have identified several strategies by which Bacillus biocontrol agents resist the negative effects of UV radiation, including transcriptional response, UV mutagenesis, biochemical and artificial means (addition of protective agents). These strategies are governed by distinct pathways, triggered by UV radiation. Herein, the impact of UV radiation on Bacillus biocontrol agent(s) BCA(s) and their mechanisms of resistance were discussed. [ABSTRACT FROM AUTHOR]

Background: Fusarium crown rot (FCR) is one of the most significant diseases limiting crop production in the Huanghuai wheat-growing region of China. Prothioconazole, a triazole sterol 14α-demethylation inhibitor (DMI) fungicide developed by the Bayer Crop Protection Company, is mainly registered for the prevention and control of wheat powdery mildew and stripe rust (China Pesticide Information Network). It is known to exhibit high activity against F. pseudograminearum, but further research, particularly regarding the potential for fungicide resistance, is required before it can be registered for the control of FCR in China. Results: The current study found that the baseline sensitivity of 67 field isolates of F. pseudograminearum collected between 2019 and 2021 ranged between 0.016–2.974 μg/mL, with an average EC50 value of 1.191 ± 0.720 μg/mL (mean ± SD). Although none of the field isolates exhibited signs of resistance, three highly resistant mutants were produced by repeated exposure to prothioconazole under laboratory conditions. All of the mutants were found to exhibit significantly reduced growth rates on potato dextrose agar (PDA), as well as reduced levels of sporulation, which indicated that there was a fitness cost associated with the resistance. However, inoculation of wounded wheat coleoptiles revealed that the pathogenicity of the resistant mutants was little affected or actually increased. Molecular analysis of the genes corresponding to the prothioconazole target protein, FpCYP51 (FpCYP51A, FpCYP51B, and FpCYP51C), indicated that the resistant mutants contained three conserved substitutions (M63I, A205S, and I246V) that were present in the FpCYP51C sequence of all three mutants, as well as several non-conserved substations in their FpCYP51A and FpCYP51B sequences. Expression analysis revealed that the presence of prothioconazole (0.1 μg/mL) generally resulted in reduced expression of the three FpCYP51 genes, but that the three mutants exhibited more complex patterns of expression that differed in comparison to their parental isolates. The study found no evidence of cross-resistance between prothioconazole and any of the fungicides tested including three DMI fungicides tebuconazole, prochloraz, and flutriafol. Conclusions: Taken together these results not only provide new insight into the resistant mechanism and biological characteristics associated with prothioconazole resistance in F. pseudograminearum, but also strong evidence that prothioconazole could provide effective and sustained control of FCR, especially when applied in combination with other fungicides. [ABSTRACT FROM AUTHOR]

Renew interest and enthusiasm for anaerobes stem from both technological improvements (culture media, production of an adequate anaerobic atmosphere, identification methods) and greater awareness on the part of clinicians. Anaerobic infections were historically treated empirically, targeting the species known to be involved in each type of infection. Prevotella, fusobacteria, and Gram-positive cocci (GPAC) were considered responsible for infections above the diaphragm whereas for intra-abdominal infections, Bacteroides of the fragilis group (BFG), GPAC and clostridia were predominantly implicated. The antibiotic susceptibility of anaerobes was only taken into consideration by the clinician in the event of treatment failure or when faced with infections by multidrug-resistant bacteria (MDR). The evolution of antibiotic resistance together with clinical failures due to the absence of detection of hetero-resistant clones has resulted in a greater need for accessible antibiotic susceptibility testing (AST) and disc diffusion method. Improved isolation and identification of anaerobes, along with the availability of accessible and robust methods for performing AST, will ensure that treatment, whether empirical or guided by an antibiogram, will lead to better outcomes for anaerobic infections. [ABSTRACT FROM AUTHOR]

Simple Summary: Researchers in this study were looking at certain types of Salmonella bacteria from China that are resistant to many drugs, and have found something surprising. They discovered a new type of this bacteria called S1467 that does not have the usual elements that make it resistant. When they studied S1467's entire genetic makeup, they found that it has 54 genes that help it resist many different drugs. This shows how important it is to understand this bacterium better, especially how it becomes resistant to drugs. Furthermore, inside this S1467 bacterium, they found a unique section of DNA (about 51 kilobytes in size) that helps it resist drugs. This section also contains a special system called YeeVU, which is rare in this type of Salmonella bacteria. This new finding about S1467, a drug-resistant Salmonella type without the usual drug-resistance elements, is a big deal. It helps us understand more about the different types of Salmonella and how they become resistant to drugs. Knowing this helps scientists come up with better ways to fight Salmonella infections. The emergence of multi-drug resistant (MDR) Salmonella enterica serovar Indiana (S. Indiana) strains in China is commonly associated with the presence of one or more resistance plasmids harboring integrons pivotal in acquiring antimicrobial resistance (AMR). This study aims to elucidate the genetic makeup of this plasmid-free, highly drug-resistant S. Indiana S1467 strain. Genomic sequencing was performed using Illumina HiSeq 2500 sequencer and PacBio RS II System. Prodigal software predicted putative protein-coding sequences while BLASTP analysis was conducted. The S1467 genome comprises a circular 4,998,300 bp chromosome with an average GC content of 51.81%, encompassing 4709 open reading frames (ORFs). Fifty-four AMR genes were identified, conferring resistance across 16 AMR categories, aligning closely with the strain's antibiotic susceptibility profile. Genomic island prediction unveiled an approximately 51 kb genomic island housing a unique YeeVU toxin–antitoxin system (TAS), a rarity in Salmonella species. This suggests that the AMR gene cluster on the S1467 genomic island may stem from the integration of plasmids originating from other Enterobacteriaceae. This study contributes not only to the understanding of the genomic characteristics of a plasmid-free, highly drug-resistant S. Indiana strain but also sheds light on the intricate mechanisms underlying antimicrobial resistance. The implications of our findings extend to the broader context of horizontal gene transfer between bacterial species, emphasizing the need for continued surveillance and research to address the evolving challenges posed by drug-resistant pathogens. [ABSTRACT FROM AUTHOR]

Introduction: Carbapenem-resistant Acinetobacter baumannii (CRAB) is an important health problem for the treatment of infectious diseases. Carbapenems have historically been used as a last resort for treating MDR Gram-negative bacterial infections. There has been a recent surge in carbapenem resistance in A. baumannii. The majority of the carbapenem resistance mechanisms in A. baumannii are due to enzymatic degradation by -lactamases. Aim And Objectives: To study the Molecular Characterization of Invasive Carbapenem-Resistant Acinetobacter baumannii with special reference to blaVIM gene in ICU patients at a Tertiary care centre, Uttar Pradesh. Material And Methods: This was a Cross sectional study carried out in the Department of Microbiology for a period of 1 year i.e, August 2022 to August 2023 at a tertiary care centre, Uttar pradesh. A total of 210 non-duplicate, consecutive, carbapenem-resistant isolates recovered from Acinetobacter species were included in this study. The isolates were obtained from the clinical samples. The isolates were identified by the Standard biochemical tests and the Antimicrobial susceptibility testing was performed according to the CLSI guidelines 2022. Results: In the present study a total of 926 clinical samples were collected out of which 210 Acinetobacter species were isolated. The maximum number of isolates were from the ETA samples with 132 (62.8%), 70 (33.3%) from blood and 8 (3.8%) from the tissue. The ratio of Males 124 (59%) was more as compared to that of the Females 86(40%) with the maximum age of 31-40 being affected the most followed by 41-50 and least in the age group above 61 years of age. Antimicrobial susceptibility testing revealed that all the isolates were resistant to ceftazidime, cefepime, piperacillin/tazobactam, cefoperazone/sulbactam, aztreonam, imipenem, meropenem, amikacin, netilmycin, tetracycline, tobramycin, levofloxacin and co-trimoxazole. In the present study it was also observed that 208 (98.5%) of the study isolates were susceptible to polymyxin B (colistin). The Molecular characterization reveals that among 210 isolates tested for MBL, there were 11 isolates positive for the blaVIM gene (5.2%). Conclusion: There should be continuous further research necessary to monitor the spread of carbapenem-resistant OXA-type lactamase genes from A. baumannii in hospital settings since they are becoming a significant cause of carbapenem resistance.. Effective infection control practises and strict guidelines for the use of antibiotics should be in place. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) antibodies, have initiated a new era in the treatment of malignant melanoma. ICIs can be used in various settings, including first-line, adjuvant, and neo-adjuvant therapy. In the scope of this review, we examined clinical studies utilizing ICIs in the context of treating oral mucosal melanoma, a rare disease, albeit with an extremely poor prognosis, with a specific focus on unraveling the intricate web of resistance mechanisms. The absence of a comprehensive review focusing on ICIs in oral mucosal melanoma is notable. Therefore, this review seeks to address this deficiency by offering a novel and thorough analysis of the current status, potential resistance mechanisms, and future prospects of applying ICIs specifically to oral malignant melanoma. Clarifying and thoroughly understanding these mechanisms will facilitate the advancement of effective therapeutic approaches and enhance the prospects for patients suffering from oral mucosal melanoma. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium Tuberculosis (MTB). It is the second largest single cause of death besides novel coronavirus pneumonia. Along with the abuse of antibiotics and extensive use of anti-tuberculosis drugs, multidrug-resistant (MDR) TB, drug-resistant (XDR) TB and totally drug-resistant (TDR) TB became obstacles to the tuberculosis eradication worldwide. According to the World Health Organization (WHO) statistics, China is not only a high burden tuberculosis country in the world, but also a country with a serious epidemic of MDR. Traditional drugs fail to meet the needs of tuberculosis control. Therefore, it is urgent to find new targets of anti-tuberculosis drugs and develop new anti-tuberculosis drugs. Hence, this paper systematically summarizes the mechanism of traditional and newly developed anti-tuberculosis drugs, in which stressing the research progress of drug resistance mechanisms. This work provides us with new insights of new antituberculosis drug developments, and may contribute to a reduction in the harm that tuberculosis brings to society. [ABSTRACT FROM AUTHOR]

Uncouplers represented by fluazinam show low toxicity, broad-spectrum, and high-efficiency activity, and exhibit strong virulence against pathogenic fungi, oomycetes, and bacteria. However, pathogens have developed increasingly severe resistance to fungicides due to their frequent and extensive use. Investigating the resistance mechanism of plant pathogens to fungicides will contribute to effective delaying or managing resistance. The analysis method for the resistance mechanism of fungicides is usually based on the target protein, but this does not apply to uncouplers as their antifungal efficacy may not occur through target protein binding in pathogens. It is unable to seek the changed amino acid sites in the resistant mutants, making it extremely difficult for exploring resistance mechanisms to uncouplers. This review focuses on the fluazinam and self-developed fungicide SYP14288 in China and summarizes the research progress of their mode of action and resistance mechanism. The study could provide reference both for the scientific use of uncouplers in the field and for the disclosure of multidrug resistance mechanism, therefore enriching the research system of fungicide resistance and providing a basis for resistance management in practice. [ABSTRACT FROM AUTHOR]