resistance system
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2022 ◽  
Vol 12 (1) ◽  
pp. 61-70
Author(s):  
Wenfang Chen ◽  
Weiwei Qin

This study aimed to explore 6-mercaptopurine (MP)-induced children’s acute lymphoblastic leukemia (ALL) drug resistance system and leukemia hypoxanthine-guanine phosphoribosyl transferase 1 (HPRT1) protein. Based on metabonomics, drug resistance of 6MP-Reh cell line was established by increasing concentration administration method, and the degree of drug resistance of 6MP-Reh was verified by apoptosis test, western blotting (WB) test, and drug sensitivity test. The changes of tissue inhibitor of matrix metalloproteinase (TIMP) and thioguanosine monophosphate (TGMP) in drug-resistant cells were detected through liquid chromatograph (LC)/mass spectrometer (MS). The 6MP-Reh-wt cell line was established by lentivirus infection, so as to verify the correlation between HPRT1 and drug resistance mechanism. The results showed that the inhibition concentration (IC50) value, cell vitality (CV), apoptosis rate, and 6-MP content of 6MP-Reh were higher hugely than those of Reh (P < 0.05). The contents of HPRT1, TIMP, and TGMP in 6MP-Reh cells were lower sharply than the contents of Reh cells (P < 0.001). The IC50 value of 6MP-Reh-wt was also lower steeply than the value of 6MP-Reh (P < 0.001), and the concentrations of TIMP and TGMP increased obviously (P < 0.05). Therefore, it indicated that the mutation of HPRT1 in drugresistant cell lines could lead to a decrease in their viability and cause leukemia cells to develop resistance to 6-MP. In addition, HPRT1 gene could improve their resistance to 6-MP.


mBio ◽  
2021 ◽  
Author(s):  
Giovanni Gallo ◽  
Ioannis Mougiakos ◽  
Mauricio Bianco ◽  
Miriam Carbonaro ◽  
Andrea Carpentieri ◽  
...  

We here describe the discovery of an unknown protein by using a proteomic approach with a functionally related protein as bait. Remarkably, we successfully obtained a novel type of enzyme through the interaction with a transcription regulator controlling the expression of this enzyme.


2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Chunmei Du ◽  
Xiaoping Huo ◽  
Hanjie Gu ◽  
Dongmei Wu ◽  
Yonghua Hu

AbstractEdwardsiella tarda is a facultative intracellular pathogen in humans and animals. The Gram-negative bacterium is widely considered a potentially important bacterial pathogen. Adaptation to acid stress is important for the transmission of intestinal microbes, so the acid-resistance (AR) system is essential. However, the AR systems of E. tarda are totally unknown. In this study, a lysine-dependent acid resistance (LDAR) system in E. tarda, CadBA, was characterized and identified. CadB is a membrane protein and shares high homology with the lysine/cadaverine antiporter. CadA contains a PLP-binding core domain and a pyridoxal phosphate-binding motif. It shares high homology with lysine decarboxylase. cadB and cadA are co-transcribed under one operon. To study the function of the cadBA operon, isogenic cadA, cadB and cadBA deletion mutant strains TX01ΔcadA, TX01ΔcadB and TX01ΔcadBA were constructed. When cultured under normal conditions, the wild type strain and three mutants exhibited the same growth performance. However, when cultured under acid conditions, the growth of three mutants, especially TX01ΔcadA, were obviously retarded, compared to the wild strain TX01, which indicates the important involvement of the cadBA operon in acid resistance. The deletion of cadB or cadA, especially cadBA, significantly attenuated bacterial activity of lysine decarboxylase, suggesting the vital participation of cadBA operon in lysine metabolism, which is closely related to acid resistance. The mutations of cadBA operon enhanced bacterial biofilm formation, especially under acid conditions. The deletions of the cadBA operon reduced bacterial adhesion and invasion to Hela cells. Consistently, the deficiency of cadBA operon abated bacterial survival and replication in macrophages, and decreased bacterial dissemination in fish tissues. Our results also show that the expression of cadBA operon and regulator cadC were up-regulated upon acid stress, and CadC rigorously regulated the expression of cadBA operon, especially under acid conditions. These findings demonstrate that the AR CadBA system was a requisite for the resistance of E. tarda against acid stress, and played a critical role in bacterial infection of host cells and in host tissues. This is the first study about the acid resistance system of E. tarda and provides new insights into the acid-resistance mechanism and pathogenesis of E. tarda.


2021 ◽  
Author(s):  
Giovanni Gallo ◽  
Ioannis Mougiakos ◽  
Mauricio Bianco ◽  
Miriam Carbonaro ◽  
Andrea Carpentieri ◽  
...  

Arsenic detoxification systems can be found in a wide range of organisms, from bacteria to man. In a previous study, we discovered an arsenic-responsive transcriptional regulator in the thermophilic bacterium Thermus thermophilus HB27 (TtSmtB). Here, we characterize the arsenic resistance system of T. thermophilus in more detail. We employed TtSmtB-based pull-down assays with protein extracts from cultures treated with arsenate and arsenite to obtain an S-adenosylmethionine (SAM)-dependent arsenite methyltransferase (TtArsM). In vivo and in vitro analyses were performed to shed light on this new component of the arsenic resistance network and its peculiar catalytic mechanism. Heterologous expression of TtarsM in Escherichia coli resulted in arsenite detoxification at mesophilic temperatures. Although TtArsM does not contain a canonical arsenite binding site, the purified protein does catalyse SAM-dependent arsenite methylation. In addition, in vitro analyses confirmed the unique interaction between TtArsM and TtSmtB. Next, a highly efficient ThermoCas9-based genome-editing tool was developed to delete the TtArsM-encoding gene on the T. thermophilus genome, and to confirm its involvement in the arsenite detoxification system. Finally, the TtarsX efflux pump gene in the T. thermophilus ΔTtarsM genome was substituted by a gene, encoding a stabilised yellow fluorescent protein (sYFP), to create a sensitive genome-based bioreporter system for the detection of arsenic ions.


2021 ◽  
Vol 12 ◽  
Author(s):  
Andy Hesketh ◽  
Giselda Bucca ◽  
Colin P. Smith ◽  
Hee-Jeon Hong

Dalbavancin, vancomycin and chlorobiphenyl-vancomycin share a high degree of structural similarity and the same primary mode of drug action. All inhibit bacterial cell wall biosynthesis through complexation with intermediates in peptidoglycan biosynthesis mediated via interaction with peptidyl-d-alanyl–d-alanine (d-Ala–d-Ala) residues present at the termini of the intermediates. VanB-type glycopeptide resistance in bacteria encodes an inducible reprogramming of bacterial cell wall biosynthesis that generates precursors terminating with d-alanyl–d-lactate (d-Ala–d-Lac). This system in Streptomyces coelicolor confers protection against the natural product vancomycin but not dalbavancin or chlorobiphenyl-vancomycin, which are semi-synthetic derivatives and fail to sufficiently activate the inducible VanB-type sensory response. We used transcriptome profiling by RNAseq to identify the gene expression signatures elucidated in S. coelicolor in response to the three different glycopeptide compounds. An integrated comparison of the results defines both the contribution of the VanB resistance system to the control of changes in gene transcription and the impact at the transcriptional level of the structural diversity present in the glycopeptide antibiotics used. Dalbavancin induces markedly more extensive changes in the expression of genes required for transport processes, RNA methylation, haem biosynthesis and the biosynthesis of the amino acids arginine and glutamine. Chlorobiphenyl-vancomycin exhibits specific effects on tryptophan and calcium-dependent antibiotic biosynthesis and has a stronger repressive effect on translation. Vancomycin predictably has a uniquely strong effect on the genes controlled by the VanB resistance system and also impacts metal ion homeostasis and leucine biosynthesis. Leaderless gene transcription is disfavoured in the core transcriptional up- and down-regulation taking place in response to all the glycopeptide antibiotics, while HrdB-dependent transcripts are favoured in the down-regulated group. This study illustrates the biological impact of peripheral changes to glycopeptide antibiotic structure and could inform the design of future semi-synthetic glycopeptide derivatives.


2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaoying Wang ◽  
Wei Wei ◽  
Jing Zhao

Intracellular concentrations of essential mental ions must be tightly maintained to avoid metal deprivation and toxicity. However, their levels in cells are still difficult to monitor. In this report, the combination of a Co2+Ni2+-specific riboswitch and an engineered downstream mCherry fluorescent protein allowed a highly sensitive and selective whole-cell Co2+/Ni2+ detection process. The sensors were applied to examine the resistance system of Co2+/Ni2+in E. coli, and the sensors were able to monitor the effects of genetic deletions. These results indicate that riboswitch-based sensors can be employed in the study of related cellular processes.


2021 ◽  
Author(s):  
Jonathan Hu ◽  
Jonathan D Browne ◽  
Michael T Arnold ◽  
Anthony Robinson ◽  
Marin F Heacock ◽  
...  

BACKGROUND The intersection of games and exercise has sparked the growth of novel training systems with the potential to promote quality physical activity. Innovations in Immersive Virtual Reality (IVR) have propelled “exergaming” to the forefront of the fitness landscape. Researchers have yet to fully explore the physiological and metabolic efficacy and applications of the immersive environment and interactive programming. OBJECTIVE This study aimed to measure metabolic (i.e., energy expenditure (EE)) and physiological (i.e., heart rate (HR)) demands and subjective fatigue and enjoyment scores during a signature 30-minute IVR adaptive cable resistance exergaming session. METHODS Fourteen healthy, college-aged individuals (7 females) were initially acquainted with the equipment and acclimated to the virtual reality and gameplay dynamics. Participants then completed a signature 30-minute exergaming session using an IVR adaptive cable resistance system (Black Box VR ®) that incorporated chest press, squat, row, lat pulldown, overhead press, and stiff leg deadlift. During the session, a portable metabolic gas exchange analysis system assessed energy expenditure by indirect calorimetry and a chest-worn monitor captured heart rate. Immediately following the session, participants completed questionnaires including the Borg scale for Rating of Perceived Exertion (RPE), the Physical Activity Enjoyment Scale (PACES), and the Simulator Sickness Questionnaire (SSQ). RESULTS EE was greater in males compared to females in terms of kcal/min (P = 0.001), total kcal (P = 0.001), and metabolic equivalents (P = 0.029). Females demonstrated a higher average HR (P = 0.020) and HR as a percentage of theoretical HRmax (P = 0.018). The overall mean metabolic equivalent (MET) during the session was 12.9 (0.5). Men achieved greater volume of total weight lifted during the session (P < 0.001) and with chest press (P = 0.005), overhead press (P = 0.001), stiff-leg deadlift (P = 0.002), and squat (P = 0.015). For the questionnaires, the mean (SD) of RPE, PACES and SSQ was 14 (1), 4.31 (0.36) and 24.04 (24.13), respectively. CONCLUSIONS IVR exergaming with resistance cable training elicits substantial EE and very high physiological demand while attenuating perceived psychological and physical fatigue. Further investigations of IVR utility should explore nuanced muscle recruitment patterns during training and long-term regimen adherence.


The Analyst ◽  
2021 ◽  
Author(s):  
Jinhong Guo ◽  
Guopan Yang ◽  
Kunxue Cheng ◽  
Zhengkang Chu ◽  
Yusheng Fu ◽  
...  

Point-of-care testing (POCT) systems have been greatly developed in recent years. Among them, lateral flow immunochromatography (LFIA) based on magnetic nanoparticles (MNPs) is widely used in various fields due to...


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