Different Modes Of Action Research Articles

Eficacy of Certain Insecticides against Olive Psyllid <i>Euphyllura straminea</i> (Loginova)

A field study was conducted to assess the effectiveness of six insecticides (with different modes of action) viz, imidacloprid, spirotetramat, sulfoxaflor, buprofezin, pyriproxyfen, and mineral oil, against the olive psyllid Euphyllura straminea (Loginova) (Homoptera: Aphalaridae) on olive trees (Olea europea L.) in Giza Governorate during the 2022 season. The results indicated that all tested insecticidesa significantly reduced the olive psyllids (both nymph and adult stages). Particularly, imidacloprid, sulfoxaflor, and spirotetramat were superior in reducing nymphs (91.37, 89.80, and 89.34% reduction, respectively). Mineral oil was the least effective (only 81.39% reduction). The same order of efficiency was observed with the adults, except for spirotetramat. Buprofezin and pyriproxyfen as insect growth regulators (IGR) displayed good efficacy.

Antibacterial efficacy interference of the photocatalytic TiO2 nanoparticle and the lytic bacteriophage vb_EcoS_bov25_1D on the Enterohaemorragic Escherichia coli strain Sakai

Post-antibiotic era requires the use of alternative pesticides against bacterial infections. One potential application field is agriculture, where pesticides are routinely applied in combinations. In this study we tested the interference of antibacterial effects of two alternative antimicrobials with basically different mode of actions if applied together in vitro by using the Enterohemorrhagic E. coli strain Sakai as a modelorganism, one strain of a pathotype that is frequently associated with meat and plant derived infections. TiO2 is a photocatalytically active nanomaterial, which can generate reactive oxygen species (ROS), exerting destructive effects on macromolecules, while the vb_EcoS_bov25_1D bacteriophage has a specific lytic action. Both, bacteriophages and Sakai were sensitive against ROS if tested separately, during that PFUs of bacteriophages dropped from 5 × 105 to 0 in 4 h, while in case of Sakai CFUs decreased with 5 and 2 logs of magnitude in the presence of 0,05 % and 0,025 % of TiO2 respectively. In Sakai by the sixth minute of ROS exposition the expressions of superoxide dismutases and catalases were boosted, as revealed by whole transcriptomic analyses, but the elevated levels rclC and bshA support some roles of these genes under this stress situation. Combined application of phages and TiO2 under UV-A exposure have revealed that beside the inner enzymatic defence mechanisms presenting phage particles served as shields and spoiled the antimicrobial effect of TiO2 (0,0125 %). As a consequence, phages became sacrificed as during exposition a 3-log drop (5 × 105→5 × 102) in their PFUs was revealed. Survived bacteriophages however in the system remained active and under the subsequent dark phase the 3-log drop in the PFU was compensated in 24 h. Our results show that joint application of the two alternative antimicrobial agents TiO2 and a bacteriophage can have two consequences depending on the circumstances they were used. From one side they complement each other's effects in that TiO2 can exert its effect on UV-A or sunlight exposed areas, whereas the bacteriophage on non-exposed surfaces. On the other hand, they also can spoil each others effect as phages can bind generated ROS and by that protect target bacteria, but bacteria themselves can serve as shields and by that protect phages from the destroying effect of ROS, phages however can exert their antibacterial effects on bacteria.

Effects of vaccination against COVID-19 on overactive bladder symptoms on young population.

The vaccines developed against COVID-19 have different modes of action, with a primary focus on the spike protein of the virus. Adverse effects following vaccination have been reported, including local and systemic symptoms. Understanding the potential side effects on the urinary tract after vaccination is of importance. Actively investigating and comprehending the potential impact on the urinary tract, we can enhance public health strategies and pave the way for safer and more effective vaccination programs. The study was based on an online survey that included the Spanish Version of the Overactive Bladder Symptom Score (OABSS-S); 2,362 men and women replied to the survey. After the application of the exclusion criteria, 1,563 participants were insured. In the context of COVID-19, individuals were questioned regarding several key factors related to their vaccination status and medical history. These factors included the number of vaccine doses received, the specific type of vaccine administered, whether they had previously contracted COVID-19, and the frequency of prior infections, if applicable. A total of 1,563 (74.7% women and 27.3% men) subjects between the ages of 18 and 45 completed the survey and were included in the final analyses. The most frequently administered vaccine type was Pfizer-BioNTech (42.2%), and most subjects received three doses. The proportion of females who received the AstraZeneca vaccine and do not require to urinate during the night is significantly higher compared to males (59.1% vs. 33.3%; p<0.05). The proportion of individuals who urinate five or more times during the night is higher in those who have received a single vaccine dose than in those who have received three doses (2.2% vs. 0.1%; p<0.05). COVID-19 vaccination has been found to impact the lower urinary tract (LUT) and overactive bladder (OAB). Initially, LUT symptoms worsened, and OABSS-S scores increased after the first vaccine dose in individuals under 45 years old. However, symptoms improved after receiving the third and fourth doses. Gender differences were observed in the vaccination effects. Men vaccinated with AstraZeneca reported a higher number of nighttime voids, while women vaccinated with Moderna reported more daytime voids.

The Potential of Cold Atmospheric Pressure Plasmas for the Direct Degradation of Organic Pollutants Derived from the Food Production Industry.

Specialized chemicals are used for intensifying food production, including boosting meat and crop yields. Among the applied formulations, antibiotics and pesticides pose a severe threat to the natural balance of the ecosystem, as they either contribute to the development of multidrug resistance among pathogens or exhibit ecotoxic and mutagenic actions of a persistent character. Recently, cold atmospheric pressure plasmas (CAPPs) have emerged as promising technologies for degradation of these organic pollutants. CAPP-based technologies show eco-friendliness and potency for the removal of organic pollutants of diverse chemical formulas and different modes of action. For this reason, various types of CAPP-based systems are presented in this review and assessed in terms of their constructions, types of discharges, operating parameters, and efficiencies in the degradation of antibiotics and persistent organic pollutants. Additionally, the key role of reactive oxygen and nitrogen species (RONS) is highlighted. Moreover, optimization of the CAPP operating parameters seems crucial to effectively remove contaminants. Finally, the CAPP-related paths and technologies are further considered in terms of biological and environmental effects associated with the treatments, including changes in antibacterial properties and toxicity of the exposed solutions, as well as the potential of the CAPP-based strategies for limiting the spread of multidrug resistance.

Monitoring and tracking changes in sensitivity to zoxamide fungicide in Plasmopara viticola in Italy

Plasmopara viticola is controlled by fungicides with different modes of action, which include zoxamide. Zoxamide was developed in 1998 by Dow AgroSciences LIC (Indianapolis, IN) and has been commercialized since 2001 by Rohm and Haas Company. This fungicide is highly effective against oomycetes, used for foliar application in vine crops, potato, and other vegetables to control oomycete-induced diseases. Zoxamide acts by causing mitotic arrest by binding to β-tubulin, inhibiting tubulin polymerization and cell division of the pathogen. In the past three decades, the management of fungicide resistance has emerged as a significant concern for both growers and regulatory authorities; this is primarily due to the substantial increase in resistance, in terms of occurrence and spread, towards most fungicide groups. The monitoring of the effectiveness of fungicides is the only way to accurately identify as soon as possible the onset of resistance. In this study, we were interested in tracking the changes in the sensitivity of zoxamide to P. viticola populations collected during a 6-year monitoring (2017–2022) in two Italian locations: the autonomous province of Trento and the autonomous region of Friuli-Venezia Giulia. Bioassays on leaf discs were carried out, and EC50 and MIC values were elaborated. From our results, zoxamide showed for a long period of time high sensitivity, but over the last years we observed a change, as in 2022 most of the samples tested in these two regions showed MIC > 100 mg L−1.

Temperature-dependent intracellular crystallization of firefly luciferase in mammalian cells is suppressed by D-luciferin and stabilizing inhibitors

Firefly luciferase (Fluc) from Photinus pyralis is one of the most widely used reporter proteins in biomedical research. Despite its widespread use, Fluc's protein phase transition behaviors and phase separation characteristics have not received much attention. Current research uncovers Fluc's intrinsic property to phase separate in mammalian cells upon a simple cell culture temperature change. Specifically, Fluc spontaneously produced needle-shaped crystal-like inclusion bodies upon temperature shift to the hypothermic temperatures ranging from 25 °C to 31 °C. The crystal-like inclusion bodies were not associated with or surrounded by membranous organelles and were likely built from the cytosolic pool of Fluc. Furthermore, the crystal-like inclusion formation was suppressed when cells were cultured in the presence of D-luciferin and its synthetic analog, as well as the benzothiazole family of so-called stabilizing inhibitors. These two classes of compounds inhibited intracellular Fluc crystallization by different modes of action as they had contrasting effects on steady-state luciferase protein accumulation levels. This study suggests that, under substrate insufficient conditions, the excess Fluc phase separates into a crystal-like state that can modulate intracellular soluble enzyme availability and protein turnover rate.

Hormesis in Pathogenic and Biocontrol Fungi: From Inhibition to Stimulation

Hormesis, a biphasic response where low doses of stressors stimulate growth and high doses inhibit it, has significant implications for agricultural chemical use. This review explores the impact of low-dose fungicides or pesticides on pathogenic and biocontrol fungi. This study highlights how sublethal dose exposure can enhance growth and virulence of fungal pathogens, while also potentially increasing their stress tolerance at higher doses. This phenomenon complicates fungicide resistance management strategies. The review focuses on specific fungicides such as dimethachlone, prochloraz, carbendazim, and others, and their hormetic effects on fungal pathogens. Furthermore, the effects of low-dose pesticides and fungicides on beneficial fungi like entomopathogenic and arbuscular mycorrhizal fungi (AMF) are discussed. Here, low-dose exposure can stimulate the germination of entomopathogenic fungal conidia and enhance AMF root colonization and phosphorus uptake. However, hormesis can have trade-offs, potentially leading to unforeseen consequences for the organism. A thorough understanding of hormesis and dose-dependent fungicide effects is crucial for optimizing disease management and agricultural practices. This knowledge can inform strategies to minimize pathogen resistance and promote sustainable approaches. Implementing integrated disease management that combines fungicides with different modes of action alongside other control methods can be effective. Careful consideration of fungicide doses and potential hormesis effects is paramount for ensuring sustainable plant disease control and food security.

Comparative assessment of microplastics and microalgae as vectors of mercury and chlorpyrifos in the copepod Acartia tonsa

Microplastics (MPs) raise concerns not only as pollutants themselves, but also due to their ability to act as vectors of pollutants adsorbed from seawater, transferring them to marine organisms. However, the relevance of MPs as carriers of pollutants compared to microalgae needs further exploration. This study compared the role of MPs (2–10 μm non-oxidized and 10–15 μm oxidized high-density polyethylene) and natural organic particles (Rhodomonas lens microalgae, MA) as carriers of mercury (Hg, 2.3 μg Hg/L) and chlorpyrifos (CPF, 1.0 μg CPF/L) to adult Acartia tonsa copepods, after 24–48 h exposure. Dose-response experiments were first performed with adult female copepods exposed to oxidized MPs (0.25–4.0 mg/L), waterborne Hg (0.01–10.0 μg/L) and Ox MPs + Hg (0.25–4.0 mg oxidized MPs/L + 0.50–8.0 μg Hg/L) for 48 h, to complement previous studies that focused on the pesticide CPF. Effects were evaluated with four replicates for physiological and reproductive responses (6 females/replicate), biochemical techniques (40 individuals/replicate) and Hg/CPF bioaccumulation measurements (1000 individuals/replicate). Copepods accumulated Hg/CPF similarly from dissolved pollutants (6204 ± 2265 ng Hg/g and 1251 ± 646 ng CPF/g) and loaded MPs (3125 ± 1389 ng Hg/g and 1156 ± 266 ng CPF/g), but significantly less from loaded MA (21 ± 8 ng Hg/g and 173 ± 80 ng CPF/g). After 24–48 h, copepods exposed to MPs + Hg/CPF showed generally greater biological effects than those exposed to dissolved Hg/CPF or to MA + Hg/CPF, although differences were not statistically significant. MA + CPF had significantly lower AChE inhibition (1073.4 nmol min−1 mg−1) and MA + Hg lower GRx induction (48.8 nmol min−1 mg−1) compared to MPs + Hg/CPF and dissolved Hg/CPF (182.8–236.4 nmol min−1 mg−1 of AChE and 74.1–101.7 nmol min−1 mg−1 of GRx). Principal component analysis suggested different modes of action for Hg and CPF.

Macroinvertebrate communities respond strongly but non-specifically to a toxicity gradient derived by effect-based methods

Chemical pollution is one of the most important threats to freshwater ecosystems. The plethora of potentially occurring chemicals and their effects in complex mixtures challenge standard monitoring methods. Effect-based methods (EBMs) are proposed as complementary tools for the assessment of chemical pollution and toxic effects. To investigate the effects of chemical pollution, the ecological relevance of EBMs and the potential of macroinvertebrates as toxicity-specific bioindicators, ecological and ecotoxicological data were linked. Baseline toxicity, mutagenicity, dioxin-like and estrogenic activity of water and sediment samples from 30 river sites in central Germany were quantified with four in vitro bioassays. The responses of macroinvertebrate communities at these sites were assessed by calculating 16 taxonomic and functional metrics and by investigating changes in the taxonomic and trait composition. Principal component analysis revealed an increase in toxicity along a joint gradient of chemicals with different modes of action. This toxicity gradient was associated with a decrease in biodiversity and ecological quality, as well as significant changes in taxonomic and functional composition. The strength of the effects suggested a strong impact of chemical pollution and underlined the suitability of EBMs in detecting ecological relevant effects. However, the metrics, taxa, and traits associated with vulnerability or tolerance to toxicity were found to also respond to other stressors in previous studies and thus may have only a low potential as toxicity-specific bioindicators. Because macroinvertebrates respond integratively to all present stressors, linking both ecological and environmental monitoring is necessary to investigate the overall effects but also isolate individual stressors. EBMs have a high potential to separate the toxicity of chemical mixtures from other stressors in a multiple stressor scenario, as well as identifying the presence of chemical groups with specific modes of action.

A dynamic energy budget (DEB) model to assess the sublethal effects of imidacloprid toward Gammarus pulex at different temperatures

Environmental ambient temperature significantly impacts the metabolic activities of aquatic ectotherm organisms and influences the fate of various chemicals. Although numerous studies have shown that the acute lethal toxicity of most chemicals increases with increasing temperature, the impact of temperature on chronic effects — encompassing both lethal and sublethal endpoints — has received limited attention. Furthermore, the mechanisms linking temperature and toxicity, potentially unveiled by toxicokinetic-toxicodynamic models (TKTD), remains inadequately explored. This study investigated the effects of environmentally relevant concentrations of the insecticide imidacloprid (IMI) on the growth and survival of the freshwater amphipod Gammarus pulex at two different temperatures. Our experimental design was tailored to fit a TKTD model, specifically the Dynamic Energy Budget (DEB) model. We conducted experiments spanning three and six months, utilizing small G. pulex juveniles. We observed effects endpoints at least five times, employing both destructive and non-destructive methods, crucial for accurate model fittings. Our findings reveal that IMI at environmental concentrations (up to 0.3 μg/L) affects the growth and survival of G. pulex, albeit with limited effects, showing a 10% inhibition compared to the control group. These limited effects, observed in both lethal and sublethal aspects, suggest a different mode of action at low, environmentally-relevant concentrations in long-term exposure (3 months), in contrast to previous studies which applied higher concentrations and found that sublethal effects occurred at significantly lower levels than lethal effects in an acute test setting (4 days). Moreover, after parameterizing the DEB model for various temperatures, we identified a lower threshold for both lethal and sublethal effects at higher temperatures, indicating increased intrinsic sensitivity. Overall, this study contributes to future risk assessments considering temperature as a crucial factor and exemplifies the integration of the DEB model into experimental design for comprehensive toxicity evaluations.

Efficacy of sequential application of herbicide mixture for management of multiple herbicide resistant in Phalaris minor in wheat (Triticum aestivum)

The emergence of multiple herbicide resistance in Phalaris minor is a major threat to wheat (Triticum aestivum L.) production in north-western Indo-Gangetic Plains of India. The present study was carried out during winter (rabi) seasons of 2020–21 and 2021–22 at research farm of Chaudhary Charan Singh Haryana Agricultural University, Hisar, Haryana for management of herbicide resistance in Phalaris minor Retz. in wheat using pre and post-emergence herbicide mixtures with different mode of action. The experiment was laid out in randomized block design (RBD) with 15 treatments, replicated thrice. Sequential application of flumioxazin 125 g/ha with pendimethalin (tank mix) 1500 g/ha fb clodinafop + metribuzin 174 g/ha resulted in significantly lowest weed density, dry matter of P. minor and broad-leaf weeds, and it was statistically comparable to application of flumioxazin alone or as mixture with pendimethalin as pre-emergence; pyraxosulfone + pendimethalin 127.5 + 1500 g/ha fb PoE (post-emergence) application of either mesosulfuron + iodosulfuron 14.4 g/ha; sulfosulfuron + metsulfuron, pinoxaden + metsulfuron 50 + 4 g/ha, clodinafop + metribuzin 174 g/ha, respectively. Phytotoxicity of flumioxazin was observed on wheat after 2–3 days of 1st irrigation i.e. 25 DAS (days after sowing). Application of pyroxasulfone + pendimethalin pre fb PoE mesosulfuron + iodosulfuron resulted in significantly higher grain yield (5847 and 5369 kg/ha, during 2021 and 2022, respectively) as compared to other herbicides.

Lipid-derived electrophiles inhibit the function of membrane channels during ferroptosis

The therapeutic targeting of ferroptosis requires full understanding of the molecular mechanism of this regulated cell death pathway. While lipid-derived electrophiles (LDEs), including 4-hydroxy-2-nonenal (4-HNE), are important biomarkers of ferroptosis, a functional role for these highly reactive species in ferroptotic cell death execution has not been established. Here, through mechanistic characterization of LDE-detoxification impairment, we demonstrate that LDEs mediate altered protein function during ferroptosis. Applying live cell fluorescence imaging, we first identified that export of glutathione-LDE-adducts through multidrug resistance-associated protein (MRP) channels is inhibited following exposure to a panel of ferroptosis inducers (FINs) with different modes of action (type I-IV FINs erastin, RSL3, FIN56, and FINO2). This channel inhibition was recreated by both initiation of lipid peroxidation and treatment with 4-HNE. Importantly, treatment with radical-trapping antioxidants prevented impaired LDE-adduct export when working with both FINs and lipid peroxidation initiators but not 4-HNE, pinpointing LDEs as the cause of this inhibited MRP activity observed during ferroptosis. Our findings, when combined with reports of widespread LDE alkylation of key proteins following ferroptosis induction, including MRP1, set a precedent for LDEs as critical mediators of ferroptotic cell damage. Lipid hydroperoxide breakdown to form truncated phospholipids and LDEs may fully explain membrane permeabilization and modified protein function downstream of lipid peroxidation, offering a unified explanation of the molecular cell death mechanism of ferroptosis.

Evaluation of fungicides for management of Botryosphaeriaceae associated with dieback in Australian walnut orchards

Dieback of fruiting spurs, stems and branches of walnut trees (Juglans regia L.), caused by Botryosphaeriaceae, is widespread in walnut orchards in Australia. Five species of Botryosphaeriaceae (Diplodia seriata, Dothiorella omnivora, Neofusicoccum macroclavatum, N. parvum, and Spencermartinsia viticola) were recovered from the Australian walnut orchards in a previous study, with D. seriata and N. parvum being the most prevalent. The present study evaluated inhibitory effects of ten fungicides on mycelium growth of those five species and on conidium germination of D. seriata and N. parvum. It investigated the preventative and curative efficacy of selected fungicides on disease incidence in glasshouse and field trials. In vitro experiments showed that nine of the fungicides reduced mycelium growth, and all ten inhibited conidium germination, but to varying extents. Tebuconazole, prochloraz manganese chloride, fluazinam, fludioxonil and pyraclostrobin were the most effective for inhibiting mycelium growth (EC50 &lt; 0.14 µg a.i. mL-1), whereas pyraclostrobin, fluxapyroxad, fluopyram, penthiopyrad and tebuconazole were the most effective for inhibiting conidium germination (EC50 &lt; 2.2 µg a.i. mL-1). In planta experiments with five fungicides confirmed that preventative treatments had greater efficacy than curative treatments. A field trial with four commercial fungicide formulations demonstrated that tebuconazole and tebuconazole + fluopyram provided protection of walnut trees for the longest period. The field trial also confirmed the efficacy of pyraclostrobin and the inhibitory effect of fluazinam. This study is the first in Australia to evaluate fungicides in different classes and with different modes of action for efficacy against Botryosphaeriaceae recovered from walnut orchards in Australia, and provides a wider selection of active ingredients for a fungicide rotation programme than that which is currently available to the Australian walnut industry.

Does the Invasive Heracleum mantegazzianum Influence Other Species by Allelopathy?

Heracleum mantegazzianum is an invasive species in middle Europe. The mode of action of its invasiveness is still not known. Our study focuses on observation of potential allelopathic influence by the production and release of phytochemicals into its environment. Plant material was collected four times within one season (April, May, June, July 2019) at locality Lekárovce (eastern Slovakia) for comparison of differences in composition and potential allelopathy. Water extracts from collected samples were used for different biological assays. The total phenols and flavonoids were determined spectrophotometrically. The profile and content of phenolic components, including coumarins, were determined by two techniques of liquid chromatography along with in vitro evaluation of the free radical scavenging activity of extracts (DPPH, Hydroxyl, Superoxide, and FRAP). The changes in composition in extracts in different seasonal periods were evident as well as potential phytotoxic activity in some concentrations on specific model plants. The slight antioxidant activity was noted. The invasiveness of the current species could be supported by the excretion of its phytochemicals into its surroundings and by different modes of action influencing living organisms in its environment.

Resistance of Phyllocoptruta oleivora (Acari: Eriophyidae) to acaricides in Turkey

Phyllocoptruta oleivora (Ashmead) (Acari: Eriophyidae) is a significant pest. The use of pesticides is the main strategy for its control and it has increased year by year. However, citrus growers stated that the effects of the acaricides have decreased in recent years. In order to determine whether this is due to resistance, P. oleivora populations were collected from Erdemli (Mersin), Karataş, Kozan, Yüreğir (Adana), and Balcalı (as a susceptible) in Turkey. Adults were bioassayed with abamectin, sulfur, spirodiclofen, and pyridaben, which are widely used and have different modes of action. Based on the bioassay experiments, the most resistant population to abamectin was found to be that from Kozan with 25.31-fold, and the population with the lowest resistance was determined to be that from Yüreğir with 8.13-fold both compared to susceptible population. All populations showed low resistance against sulfur, the highest resistance ratio to sulfur was found in Yüreğir with 2.53-fold. The highest resistance population against spirodiclofen was detected in Erdemli with 24.00-fold, followed by Karataş, Yüreğir, and Kozan populations with 15.39, 14.05, and 9.21-fold, respectively. The resistance ratios of P. oleivora populations against pyridaben were found to be 30.30, 15.85, 10.10, and 7.55-fold in Erdemli, Kozan, Yüreğir, and Karataş, respectively. The detected status of acaricide resistance indicates that this phenomenon takes place and should be a concern in the Eastern Mediterranean Region of Turkish populations of P. oleivora requiring monitoring and planning of resistance management strategies. The use of acaricides with different modes of action in sequential spraying is essential to prevent the development of resistance.

Safety of Janus kinase inhibitors compared to biological DMARDs in patients with rheumatoid arthritis and renal impairment: the ANSWER cohort study

Data on the safety of Janus kinase inhibitors (JAKis) in patients with renal impairment are lacking. This study aimed to investigate the safety of JAKis compared to biological (b) DMARDs in patients with rheumatoid arthritis (RA) and renal impairment. We used a multi-centre observational registry of patients with RA in Japan (the ANSWER cohort). We assessed the drug retention rates of b/targeted synthetic DMARDs with different modes of action (tumour necrosis factor inhibitors (TNFis), immunoglobulins fused with cytotoxic T-lymphocyte antigen (CTLA-4-Ig), interleukin-6 receptor inhibitors (IL-6Ris), and JAKis) in patients with RA stratified by pre-treatment estimated glomerular filtration rate (eGFR) levels. The time to discontinuation of bDMARDs or JAKis was analysed using a multivariate Cox proportional hazards model This study included 3775 patients, who were classified into three groups (the normal group (eGFR ≥ 60 mL/min/1.73 m2): 2893 patients; CKDa group (eGFR 45–60 mL/min/1.73 m2): 551; and CKDb group (eGFR < 45 mL/min/1.73 m2): 331). In the CKDb group, the 12-month drug retention rate due to adverse events (AE) was the lowest in patients treated with JAKi (TNFi: 93.1%; IL-6Ri: 94.1%; CTLA-4-Ig: 92.3%; JAKi: 75.1%). In the normal and CKDa groups, drug retention rates due to AE were similar among patients treated with bDMARDs and JAKi. In contrast, drug retention rates due to inefficacy were similar between bDMARDs and JAKis in all groups. In the Cox-proportional model, in the CKDb group, TNFi, IL-6Ri, and CTLA-4-Ig showed lower incidence of drug discontinuation due to AE than JAKis (TNFi: hazard ratio = 0.23 (95% confidence interval 0.09–0.61), IL-6Ri: 0.34 (0.14–0.81), CTLA-4-Ig: 0.36 (0.15–0.89)). JAKis showed the lowest drug retention due to AE in patients with moderate-to-severe and severe renal impairment (eGFR < 45 mL/min/1.73 m2). Physicians should pay more attention to renal function when using JAKis than when using bDMARDs.

The unusual mode of action of the polyketide glycoside antibiotic cervimycin C.

Cervimycins A-D are bis-glycosylated polyketide antibiotics produced by Streptomyces tendae HKI 0179 with bactericidal activity against Gram-positive bacteria. In this study, cervimycin C (CmC) treatment caused a spaghetti-like phenotype in Bacillus subtilis 168, with elongated curved cells, which stayed joined after cell division, and exhibited a chromosome segregation defect, resulting in ghost cells without DNA. Electron microscopy of CmC-treated Staphylococcus aureus (3 × MIC) revealed swollen cells, misshapen septa, cell wall thickening, and a rough cell wall surface. Incorporation tests in B. subtilis indicated an effect on DNA biosynthesis at high cervimycin concentrations. Indeed, artificial downregulation of the DNA gyrase subunit B gene (gyrB) increased the activity of cervimycin in agar diffusion tests, and, in high concentrations (starting at 62.5 × MIC), the antibiotic inhibited S. aureus DNA gyrase supercoiling activity in vitro. To obtain a more global view on the mode of action of CmC, transcriptomics and proteomics of cervimycin treated versus untreated S. aureus cells were performed. Interestingly, 3 × MIC of cervimycin did not induce characteristic responses, which would indicate disturbance of the DNA gyrase activity in vivo. Instead, cervimycin induced the expression of the CtsR/HrcA heat shock operon and the expression of autolysins, exhibiting similarity to the ribosome-targeting antibiotic gentamicin. In summary, we identified the DNA gyrase as a target, but at low concentrations, electron microscopy and omics data revealed a more complex mode of action of cervimycin, which comprised induction of the heat shock response, indicating protein stress in the cell.IMPORTANCEAntibiotic resistance of Gram-positive bacteria is an emerging problem in modern medicine, and new antibiotics with novel modes of action are urgently needed. Secondary metabolites from Streptomyces species are an important source of antibiotics, like the cervimycin complex produced by Streptomyces tendae HKI 0179. The phenotypic response of Bacillus subtilis and Staphylococcus aureus toward cervimycin C indicated a chromosome segregation and septum formation defect. This effect was at first attributed to an interaction between cervimycin C and the DNA gyrase. However, omics data of cervimycin treated versus untreated S. aureus cells indicated a different mode of action, because the stress response did not include the SOS response but resembled the response toward antibiotics that induce mistranslation or premature chain termination and cause protein stress. In summary, these results point toward a possibly novel mechanism that generates protein stress in the cells and subsequently leads to defects in cell and chromosome segregation.

Temperature dependence of the mutation rate towards antibiotic resistance

Abstract Objectives Environmental conditions can influence mutation rates in bacteria. Fever is a common response to infection that alters the growth conditions of infecting bacteria. Here we examine how a temperature change, such as is associated with fever, affects the mutation rate towards antibiotic resistance. Methods We used a fluctuation test to assess the mutation rate towards antibiotic resistance in Escherichia coli at two different temperatures: 37°C (normal temperature) and 40°C (fever temperature). We performed this measurement for three different antibiotics with different modes of action: ciprofloxacin, rifampicin and ampicillin. Results In all cases, the mutation rate towards antibiotic resistance turned out to be temperature dependent, but in different ways. Fever temperatures led to a reduced mutation rate towards ampicillin resistance and an elevated mutation rate towards ciprofloxacin and rifampicin resistance. Conclusions This study shows that the mutation rate towards antibiotic resistance is impacted by a small change in temperature, such as associated with fever. This opens a new avenue to mitigate the emergence of antibiotic resistance by coordinating the choice of an antibiotic with the decision of whether or not to suppress fever when treating a patient. Hence, optimized combinations of antibiotics and fever suppression strategies may be a new weapon in the battle against antibiotic resistance.

Combined effects of three insecticides with different modes of action on biochemical responses of the solitary bee Osmia bicornis

Bees are simultaneously exposed to a variety of pesticides, which are often applied in mixtures and can cause lethal and sublethal effects. The combined effects of pesticides, however, are not measured in the current risk assessment schemes. Additionally, the sublethal effects of pesticides on a variety of physiological processes are poorly recognized in bees, especially in non-Apis solitary bees. In this study, we used a full-factorial design to examine the main and interactive effects of three insecticide formulations with different modes of action (Mospilan 20 SP, Sherpa 100 EC, and Dursban 480 EC) on bee biochemical processes. We measured acetylcholinesterase (AChE), glutathione S-transferase (GST) and esterase (EST) activities, as well as a nonenzymatic biomarker associated with energy metabolism, i.e., ATP level. All studied endpoints were affected by Sherpa 100 EC, and the activities of AChE and EST as well as ATP levels were affected by Dursban 480 EC. Moreover, complex interactions between all three insecticides affected ATP levels, showing outcomes that cannot be predicted when testing each insecticide separately. The results indicate that even if interactive effects are sometimes difficult to interpret, there is a need to study such interactions if laboratory-generated toxicity data are to be extrapolated to field conditions.

Comparing Transcriptomic Points of Departure to Apical Effect Concentrations For Larval Fathead Minnow Exposed to Chemicals with Four Different Modes Of Action.

It is postulated that below a transcriptomic-based point of departure, adverse effects are unlikely to occur, thereby providing a chemical concentration to use in screening level hazard assessment. The present study extends previous work describing a high-throughput fathead minnow assay that can provide full transcriptomic data after exposure to a test chemical. One-day post-hatch fathead minnows were exposed to ten concentrations of three representatives of four chemical modes of action: organophosphates, ecdysone receptor agonists, plant photosystem II inhibitors, and estrogen receptor agonists for 24 h. Concentration response modeling was performed on whole body gene expression data from each exposure, using measured chemical concentrations when available. Transcriptomic points of departure in larval fathead minnow were lower than apical effect concentrations across fish species but not always lower than toxic effect concentrations in other aquatic taxa like crustaceans and insects. The point of departure was highly dependent on measured chemical concentration which were often lower than the nominal concentration. Differentially expressed genes between chemicals within modes of action were compared and often showed statistically significant overlap. In addition, reproducibility between identical exposures using a positive control chemical (CuSO4) and variability associated with the transcriptomic point of departure using in silico sampling were considered. Results extend a transcriptomic-compatible fathead minnow high-throughput assay for possible use in ecological hazard screening.