COVID-19 Drug Treatments Are Prone to Sequestration in Extracorporeal Membrane Oxygenation Circuits: An Ex Vivo Extracorporeal Membrane Oxygenation Study.

Drug treatments for coronavirus disease 2019 (COVID-19) dramatically improve patient outcomes, and although extracorporeal membrane oxygenation (ECMO) has significant use in these patients, it is unknown whether ECMO affects drug dosing. We used an ex vivo adult ECMO model to measure ECMO circuit effects on concentrations of specific COVID-19 drug treatments. Three identical ECMO circuits used in adult patients were set up. Circuits were primed with fresh human blood (temperature and pH maintained within normal limits). Three polystyrene jars with 75 ml fresh human blood were used as controls. Remdesivir, GS-441524, nafamostat, and tocilizumab were injected in the circuit and control jars at therapeutic concentrations. Samples were taken from circuit and control jars at predefined time points over 6 h and drug concentrations were measured using validated assays. Relative to baseline, mean (± standard deviation [SD]) study drug recoveries in both controls and circuits at 6 h were significantly lower for remdesivir (32.2% [±2.7] and 12.4% [±2.1], p < 0.001), nafamostat (21.4% [±5.0] and 0.0% [±0.0], p = 0.018). Reduced concentrations of COVID-19 drug treatments in ECMO circuits is a clinical concern. Remdesivir and nafamostat may need dose adjustments. Clinical pharmacokinetic studies are suggested to guide optimized COVID-19 drug treatment dosing during ECMO.

Neonicotinoid exposure increases Varroa destructor (Mesostigmata: Varroidae) mite parasitism severity in honey bee colonies and is not mitigated by increased colony genetic diversity.

Agrochemical exposure is a major contributor to ecological declines worldwide, including the loss of crucial pollinator species. In addition to direct toxicity, field-relevant doses of pesticides can increase species' vulnerabilities to other stressors, including parasites. Experimental field demonstrations of potential interactive effects of pesticides and additional stressors are rare, as are tests of mechanisms via which pollinators tolerate pesticides. Here, we controlled honey bee colony exposure to field-relevant concentrations of 2 neonicotinoid insecticides (clothianidin and thiamethoxam) in pollen and simultaneously manipulated intracolony genetic heterogeneity. We showed that exposure increased rates of Varroa destructor (Anderson and Trueman) parasitism and that while increased genetic heterogeneity overall improved survivability, it did not reduce the negative effect size of neonicotinoid exposure. This study is, to our knowledge, the first experimental field demonstration of how neonicotinoid exposure can increase V. destructor populations in honey bees and also demonstrates that colony genetic diversity cannot mitigate the effects of neonicotinoid pesticides.

Aptamer-based biosensors for the detection of neonicotinoid insecticides in environmental samples: A systematic review.

Neonicotinoids, sometimes abbreviated as neonics, represent a class of neuro-active insecticides with chemical similarities to nicotine. Neonicotinoids are the most widely adopted group of insecticides globally since their discovery in the late 1980s. Their physiochemical properties surpass those of previously established insecticides, contributing to their popularity in various sectors such as agriculture and wood treatment. The environmental impact of neonicotinoids, often overlooked, underscores the urgency to develop tools for their detection and understanding of their behavior. Conventional methods for pesticide detection have limitations. Chromatographic techniques are sensitive but expensive, generate waste, and require complex sample preparation. Bioassays lack specificity and accuracy, making them suitable as preliminary tests in conjunction with instrumental methods. Aptamer-based biosensor is recognized as an advantageous tool for neonicotinoids detection due to its rapid response, user-friendly nature, cost-effectiveness, and suitability for on-site detection. This comprehensive review represents the inaugural in-depth analysis of advancements in aptamer-based biosensors targeting neonicotinoids such as imidacloprid, thiamethoxam, clothianidin, acetamiprid, thiacloprid, nitenpyram, and dinotefuran. Additionally, the review offers valuable insights into the critical challenges requiring prompt attention for the successful transition from research to practical field applications.

Generation of a lethal mouse model expressing human ACE2 and TMPRSS2 for SARS-CoV-2 infection and pathogenesis.

Mouse models expressing human ACE2 for coronavirus disease 2019 have been frequently used to understand its pathogenesis and develop therapeutic strategies against SARS-CoV-2. Given that human TMPRSS2 supports viral entry, replication, and pathogenesis, we established a double-transgenic mouse model expressing both human ACE2 and TMPRSS2 for SARS-CoV-2 infection. Co-overexpression of both genes increased viral infectivity in vitro and in vivo. Double-transgenic mice showed significant body weight loss, clinical disease symptoms, acute lung injury, lung inflammation, and lethality in response to viral infection, indicating that they were highly susceptible to SARS-CoV-2. Pretreatment with the TMPRSS2 inhibitor, nafamostat, effectively reduced virus-induced weight loss, viral replication, and mortality in the double-transgenic mice. Moreover, the susceptibility and differential pathogenesis of SARS-CoV-2 variants were demonstrated in this animal model. Together, our results demonstrate that double-transgenic mice could provide a highly susceptible mouse model for viral infection to understand SARS-CoV-2 pathogenesis and evaluate antiviral therapeutics against coronavirus disease 2019.

Can neonicotinoid and pyrrole insecticides manage malaria vector resistance in high pyrethroid resistance areas in Côte d'Ivoire?

BACKGROUND: Anopheles mosquito resistance to insecticide remains a serious threat to malaria vector control affecting several sub-Sahara African countries, including Côte d'Ivoire, where high pyrethroid, carbamate and organophosphate resistance have been reported. Since 2017, new insecticides, namely neonicotinoids (e.g.; clothianidin) and pyrroles (e.g.; chlorfenapyr) have been pre-qualified by the World Health Organization (WHO) for use in public health to manage insecticide resistance for disease vector control. METHODS: Clothianidin and chlorfenapyr were tested against the field-collected Anopheles gambiae populations from Gagnoa, Daloa and Abengourou using the WHO standard insecticide susceptibility biossays. Anopheles gambiae larvae were collected from several larval habitats, pooled and reared to adulthood in each site in July 2020. Non-blood-fed adult female mosquitoes aged 2 to 5 days were exposed to diagnostic concentration deltamethrin, permethrin, alpha-cypermethrin, bendiocarb, and pirimiphos-methyl. Clothianidin 2% treated papers were locally made and tested using WHO tube bioassay while chlorfenapyr (100 µg/bottle) was evaluated using WHO bottle assays. Furthermore, subsamples of exposed mosquitoes were identified to species and genotyped for insecticide resistance markers including the knock-down resistance (kdr) west and east, and acetylcholinesterase (Ace-1) using molecular techniques. RESULTS: High pyrethroid resistance was recorded with diagnostic dose in Abengourou (1.1 to 3.4% mortality), in Daloa (15.5 to 33.8%) and in Gagnoa (10.3 to 41.6%). With bendiocarb, mortality rates ranged from 49.5 to 62.3%. Complete mortality (100% mortality) was recorded with clothianidin in Gagnoa, 94.9% in Daloa and 96.6% in Abengourou, while susceptibility (mortality > 98%) to chlorfenapyr 100 µg/bottle was recorded at all sites and to pirimiphos-methyl in Gagnoa and Abengourou. Kdr-west mutation was present at high frequency (0.58 to 0.73) in the three sites and Kdr-east mutation frequency was recorded at a very low frequency of 0.02 in both Abengourou and Daloa samples and absent in Gagnoa. The Ace-1 mutation was present at frequencies between 0.19 and 0.29 in these areas. Anopheles coluzzii represented 100% of mosquitoes collected in Daloa and Gagnoa, and 72% in Abengourou. CONCLUSIONS: This study showed that clothianidin and chlorfenapyr insecticides induce high mortality in the natural and pyrethroid-resistant An. gambiae populations in Côte d'Ivoire. These results could support a resistance management plan by proposing an insecticide rotation strategy for vector control interventions.

Cocatalytic Activity of the Furfuryl and Oxanorbornane-Substituted Guanidines in the Aldol Reaction Catalyzed by (S)-Proline.

This work investigated the cocatalytic activity of recently prepared guanidinium salts containing an oxanorbornane subunit in an (S)-proline-catalyzed aldol reaction. The activity was interpreted by the diastereoselectivity of the reaction (anti/syn ratio) and for the most interesting polycyclic guanidinium salt, the enantioselectivity of the reaction was determined. The results indicated a negative impact on the oxanorbornane unit if present as the flexible substituent. For most of the tested aldehydes, the best cocatalysts provided enantioselectivities above 90% and above 95% at room temperature and 0 °C, respectively, culminating in >99.5% for 4-chloro- and 2-nitrobenzaldehyde as the substrate. The barriers for forming four possible enantiomers were calculated and the results for two anti-enantiomers are qualitatively consistent with the experiment. Obtained results suggest that the representatives of furfurylguanidinium and rigid polycyclic oxanorbornane-substituted guanidinium salts are good lead structures for developing new cocatalysts by tuning the chemical space around the guanidine moiety.

New strategy to treat spinal cord injury: Nafamostat mesilate suppressed NLRP3-mediated pyroptosis during acute phase.

Spinal cord injury (SCI) is a devastating condition for which effective clinical treatment is currently lacking. During the acute phase of SCI, myriad pathological changes give rise to subsequent secondary injury. The results of our previous studies indicated that treating rats post-SCI with nafamostat mesilate (NM) protected the blood-spinal cord barrier (BSCB) and exerted an antiapoptotic effect. However, the optimal dosage for mice with SCI and the underlying mechanisms potentially contributing to recovery, especially during the acute phase of SCI, have not been determined. In this study, we first determined the optimal dosage of NM for mice post-SCI (5 mg/kg/day). Subsequently, our RNA-seq findings revealed that NM has the potential to inhibit pyroptosis after SCI. These findings were further substantiated by subsequent Western blot (WB) and Immunofluorescence (IF) analyses in vivo. These results indicate that NM can alleviate NLRP3 (NOD-like receptor thermal protein domain associated protein 3)-mediated pyroptosis by modulating the NF-κB signaling pathway and reducing the protein expression levels of NIMA-related kinase 7 (NEK7) and cathepsin B (CTSB). In vitro experimental results supported our in vivo findings, revealing the effectiveness of NM in suppressing pyroptosis induced by adenosine triphosphate (ATP) and lipopolysaccharide (LPS) in BV2 cells. These results underscore the potential of NM to regulate NLRP3-mediated pyroptosis following SCI. Notably, compared with other synthetic compounds, NM exhibits greater versatility, suggesting that it is a promising clinical treatment option for SCI.

Toxicity evaluation of neonicotinoids to earthworm (Eisenia fetida) behaviors by a novel locomotion tracking assay.

Pesticides are substances used for controlling, preventing, and repelling pests in agriculture. Among them, neonicotinoids have become the fastest-growing class of insecticides because of their efficiency in targeting pests. They work by strongly binding to nicotinic acetylcholine receptors (nAChRs) in the central nervous system of insects, leading to receptor blockage, paralysis, and death. Despite their selectivity for insects, these substances may be hazardous to non-target creatures, including earthworms. Although earthworms may be invasive in some regions like north America, they contribute to the development of soil structure, water management, nutrient cycling, pollution remediation, and cultural services, positively impacting the environment, particularly in the soil ecosystem. Thus, this study aimed to develop a novel earthworm behavior assay since behavior is a sensitive marker for toxicity assay, and demonstrated its application in evaluating the toxicity of various neonicotinoids. Here, we exposed Eisenia fetida to 1 and 10 ppb of eight neonicotinoids (acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram pestanal, thiacloprid, thiametoxam, and sulfoxaflor) for 3 days to observe their behavior toxicities. Overall, all of the neonicotinoids decreased their locomotion, showed by a reduction of average speed by 24.94-68.63% and increment in freezing time movement ratio by 1.51-4.25 times, and altered their movement orientation and complexity, indicated by the decrement in the fractal dimension value by 24-70%. Moreover, some of the neonicotinoids, which were acetamiprid, dinotefuran, imidacloprid, nitenpyram, and sulfoxaflor, could even alter their exploratory behaviors, which was shown by the increment in the time spent in the center area value by 6.94-12.99 times. Furthermore, based on the PCA and heatmap clustering results, thiametoxam was found as the neonicotinoid that possessed the least pronounced behavior toxicity effects among the tested pesticides since these neonicotinoid-treated groups in both concentrations were grouped in the same major cluster with the control group. Finally, molecular docking was also conducted to examine neonicotinoids' possible binding mechanism to Acetylcholine Binding Protein (AChBP), which is responsible for neurotransmission. The molecular docking result confirmed that each of the neonicotinoids has a relatively high binding energy with AChBP, with the lowest binding energy was possessed by thiametoxam, which consistent with its relatively low behavior toxicities. Thus, these molecular docking results might hint at the possible mechanism behind the observed behavior alterations. To sum up, the present study demonstrated that all of the neonicotinoids altered the earthworm behaviors which might be due to their ability to bind with some specific neurotransmitters and the current findings give insights into the toxicities of neonicotinoids to the environment, especially animals in a soil ecosystem.

TMPRSS13 promotes the cell entry of swine acute diarrhea syndrome coronavirus.

Swine acute diarrhea syndrome coronavirus (SADS-CoV) has caused severe intestinal diseases in pigs. It originates from bat coronaviruses HKU2 and has a potential risk of cross-species transmission, raising concerns about its zoonotic potential. Viral entry-related host factors are critical determinants of susceptibility to cells, tissues, or species, and remain to be elucidated for SADS-CoV. Type II transmembrane serine proteases (TTSPs) family is involved in many coronavirus infections and has trypsin-like catalytic activity. Here we examine all 18 members of the TTSPs family through CRISPR-based activation of endogenous protein expression in cells, and find that, in addition to TMPRSS2 and TMPRSS4, TMPRSS13 significantly facilitates SADS-CoV infection. This is confirmed by ectopic expression of TMPRSS13, and specific to trypsin-dependent SADS-CoV. Infection with pseudovirus bearing SADS-CoV spike protein indicates that TMPRSS13 acts at the entry step and is sensitive to serine protease inhibitor Camostat. Moreover, both human and pig TMPRSS13 are able to enhance the cell-cell membrane fusion and cleavage of spike protein. Overall, we demonstrate that TMPRSS13 is another host serine protease promoting the membrane-fusion entry of SADS-CoV, which may expand its host tropism by using diverse TTSPs.

Polyhexamethylene guanidine phosphate induces pyroptosis via reactive oxygen species-regulated mitochondrial dysfunction in bronchial epithelial cells.

Pyroptosis is a form of programmed cell death characterized by gasdermin (GSDM)-mediated pore formation in the cell membrane, resulting in the release of pro-inflammatory cytokines and cellular lysis. Increasing evidence has shown that pyroptosis is responsible for the progression of various pulmonary disorders. The inhalation of polyhexamethylene guanidine (PHMG) causes severe lung inflammation and pulmonary toxicity; however, the underlying mechanisms are unknown. Therefore, in this study, we investigate the role of pyroptosis in PHMG-induced pulmonary toxicity. We exposed bronchial epithelial cells, BEAS-2B, to PHMG phosphate (PHMG-p) and evaluated cell death type, reactive oxygen species (ROS) levels, and relative expression levels of pyroptosis-related proteins. Our data revealed that PHMG-p reduced viability and induced morphological alterations in BEAS-2B cells. Exposure to PHMG-p induced excessive accumulation of mitochondrial ROS (mtROS) in BEAS-2B cells. PHMG-p activated caspase-dependent apoptosis as well as NLRP3/caspase-1/GSDMD-mediated- and caspase-3/GSDME-mediated pyroptosis through mitochondrial oxidative stress in BEAS-2B cells. Notably, PHMG-p reduced mitochondrial respiratory function and induced the translocation of Bax and cleaved GSDM into the mitochondria, leading to mitochondrial dysfunction. Our results enhanced our understanding of PHMG-p-induced lung toxicity by demonstrating that PHMG-p induces pyroptosis via mtROS-induced mitochondrial dysfunction in bronchial epithelial cells.

Joint toxic mechanism of clothianidin and prochloraz in the earthworm (Eisenia fetida).

Pesticides are typically present as combinations within soil ecosystems and have detrimental effects on untamed surroundings. However, the collective impacts and fundamental mechanisms of pesticides on soil living beings are currently inadequately assessed. In our current work, we evaluated the interactive consequences of clothianidin (CLO) and prochloraz (PRO) on earthworms (Eisenia fetida) using several toxicological tests, such as acute adverse effects, biocatalytic activity, and alterations in transcriptional activity. The findings revealed that CLO (with a 14-day LC50 value of 6.08 mg kg-1) exhibited greater toxicity compared to PRO (with a 14-day LC50 value of 79.41 mg kg-1). Moreover, the combinations of CLO and PRO had synergistic acute effects on E. fetida. Additionally, the activities of POD, CAT, and GST were significantly varied in most instances of single and mixed treatments when compared to the control. Surprisingly, the transcriptional levels of four genes (gst, sod, crt, and ann), related to oxidative load, metabolic detoxification systems, endoplasmic reticulum, and oxytocin neuropeptide, respectively, were also altered in response to single and mixture exposures, as compared to the control. Alterations in enzyme activity and gene transcriptional level could serve as early indicators for detecting co-exposure to pesticides. The findings of this research offered valuable holistic understanding regarding the toxicity of pesticide combinations on earthworms. Further research should be conducted to investigate the persistent effects of pesticide mixtures on terrestrial invertebrates in order to draw definitive conclusions about the associated risks.

Ion-imprinted aminoguanidine-chitosan for selective recognition of lanthanum (III) from wastewater.

Developing a sorbent for the removal of La3+ ions from wastewater offers significant environmental and economic advantages. This study employed an ion-imprinting process to integrate La3+ ions into a newly developed derivative of aminoguanidine-chitosan (AGCS), synthesized via an innovative method. The process initiated with the modification of chitosan by attaching cyanoacetyl groups through amide bonds, yielding cyanoacetyl chitosan (CAC). This derivative underwent further modification with aminoguanidine to produce the chelating AGCS biopolymer. The binding of La3+ ions to AGCS occurred through imprinting and cross-linking with epichlorohydrin (ECH), followed by the extraction of La3+, resulting in the La3+ ion-imprinted sorbent (La-AGCS). Structural confirmation of these chitosan derivatives was established through elemental analysis, FTIR, and NMR. SEM analysis revealed that La-AGCS exhibited a more porous structure compared to the smoother non-imprinted polymer (NIP). La-AGCS demonstrated superior La3+ capture capability, with a maximum capacity of 286 ± 1 mg/g. The adsorption process, fitting the Langmuir and pseudo-second-order models, indicated a primary chemisorption mechanism. Moreover, La-AGCS displayed excellent selectivity for La3+, exhibiting selectivity coefficients ranging from 4 to 13 against other metals. This study underscores a strategic approach in designing advanced materials tailored for La3+ removal, capitalizing on specific chelator properties and ion-imprinting technology.

Validation and application of an online extraction and liquid chromatography tandem mass spectrometry assay for the analysis of delamanid and its DM-6705 metabolite in human breast milk.

We developed and validated a bioanalytical assay to quantify delamanid and its key metabolite (DM-6705) in breast milk and aimed to quantify the secretion of these compounds in breast milk. Due to the hydrophobic nature of the analytes, special care was taken during sample preparation to prevent the formation of fatty deposits during protein precipitation. This was followed by online solid phase extraction and liquid chromatography with tandem mass spectrometry for detection. A Restek Viva BiPh C18 column (1.0 mm×50 mm, 5 µm) was used for extraction while chromatographic separation was performed using a Waters Xterra MS C18 (2.1 mm×100 mm, 5 µm) analytical column with an isocratic mobile phase consisting of acetonitrile, methanol, and 5 mM ammonium carbonate. The mass spectrometric detection of the analytes was performed using an AB Sciex 3200 mass spectrometer employing electrospray ionisation in the positive mode with multiple reaction motoring of the relevant precursor and product ions. Delamanid-d4 and OPC-14714 were used as internal standards. A quadratic (weighted 1/x concentration) regression was used to fit calibration curves for delamanid and DM-6705 over the concentration range of 10.0 - 1000 ng/mL. The intra- and inter-day validation accuracies of the quality control samples were between 92.1% and 98.3% for delamanid, and 97.0% and 102.8% for DM-6705. The percentage coefficient of variation (precision) was less than 7.8%. To our knowledge, this is the first report describing the concentrations of delamanid and DM-6705 in the breast milk of patients treated for rifampicin-resistant tuberculosis.

Collection and transportation of SARS-CoV-2 and influenza A virus diagnostic samples: Optimizing the usage of guanidine-based chaotropic salts for enhanced biosafety and viral genome preservation.

Many virus lysis/transport buffers used in molecular diagnostics, including the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA, contain guanidine-based chaotropic salts, primarily guanidine hydrochloride (GuHCl) or guanidine isothiocyanate (GITC). Although the virucidal effects of GuHCl and GITC alone against some enveloped viruses have been established, standardized data on their optimum virucidal concentrations against SARS-CoV-2 and effects on viral RNA stability are scarce. Thus, we aimed to determine the optimum virucidal concentrations of GuHCl and GITC against SARS-CoV-2 compared to influenza A virus (IAV), another enveloped respiratory virus. We also evaluated the effectiveness of viral RNA stabilization at the determined optimum virucidal concentrations under high-temperature conditions (35°C) using virus-specific real-time reverse transcription polymerase chain reaction. Both viruses were potently inactivated by 1.0 M GITC and 2.5 M GuHCl, but the GuHCl concentration for efficient SARS-CoV-2 inactivation was slightly higher than that for IAV inactivation. GITC showed better viral RNA stability than GuHCl at the optimum virucidal concentrations. An increased concentration of GuHCl or GITC increased viral RNA degradation at 35°C. Our findings highlight the need to standardize GuHCl and GITC concentrations in virus lysis/transport buffers and the potential application of these guanidine-based salts alone as virus inactivation solutions in SARS-CoV-2 and IAV molecular diagnostics.

The chelation mechanism of neonicotinoid insecticides influencing cadmium transport and accumulation in rice at different growth stage.

The combined exposure of heavy metals and organic contaminates can influence the transport and accumulation of heavy metals within the soil-rice system. However, the underlying mechanisms of this process remain largely unknown. Herein, this study investigated the influence of three neonicotinoid insecticides (NIs), including imidacloprid (IMI), clothianidin (CLO), and thiamethoxam (THI), on the Cd transport and accumulation in rice (Oryza sativa) at different growth stages. Particular focus lied on their complex interaction and key genes expression involved in Cd transport. Results showed that the interaction between Cd and NIs was the dominant factor affecting Cd transport and accumulation in rice exposed to NIs. All three NIs chelated with Cd with nitrogen (N) on the IMI and THI nitro groups, and the N on the CLO nitro guanidine group. Interestingly, this chelation behavior varied between the tillering stage and the filling/ripening stages, resulting in diverse patterns of Cd accumulation in rice tissues. During the tillering stage, all three NIs considerably inhibited Cd bioavailability and transport to the above-ground part, lowering Cd content in the stem and leaf. The inhibition was increased with stronger chelation ability in the order of IMI (-0.46 eV) > CLO (-0.41 eV) > THI (-0.11 eV), with IMI exhibiting the highest binding energy for Cd and reducing Cd transfers from root to stem by an impressive 94.49 % during the tillering stage. Conversely, during the filling/ripening stages, NIs facilitated Cd accumulation in rice roots, stems, leaves, and grains. This was mainly attributed to the generation of nitrate ions and the release of Cd2+ during the chelation between Cd and NIs under drainage condition. These findings provide theoretical basis for the treatment of combined contamination in field and deep insights into understanding the interaction of organic contaminants with heavy metals in rice culture process.

Risk analysis for groundwater intakes based on the example of neonicotinoids.

Neonicotinoids are a class of broad-spectrum insecticides that are dominant in the world market. They are widely distributed in the environment. Understanding the sources, distribution, and fate of these contaminants is critical to mitigating their effects and maintaining the health of aquatic ecosystems. Contamination of surface and groundwater by neonicotinoids has become a widespread problem worldwide, requiring comprehensive action to accurately determine the mechanisms behind the migration of these pesticides, their properties, and their adverse effects on the environment. A new approach to risk analysis for groundwater intake contamination with emerging contaminants was proposed. It was conducted on the example of four neonicotinoids (acetamiprid, clothianidin, thiamethoxam, and imidacloprid) in relation to groundwater accessed by a hypothetical groundwater intake, based on data obtained in laboratory tests using a dynamic method (column experiments). The results of the risk analysis conducted have shown that in this case study the use of acetamiprid and thiamethoxam for agricultural purposes poses an acceptable risk, and does not pose a risk to the quality of groundwater extracted from the intake for food purposes. Consequently, it does not pose a risk to the health and life of humans and other organisms depending on that water. The opposite situation is observed for clothianidin and imidacloprid, which pose a higher risk of groundwater contamination. For higher maximum concentration of neonicotinoids used in the risk analysis, the concentration of clothianidin and imidacloprid in the groundwater intake significantly (from several to several hundred thousand times) exceeds the maximum permissible levels for drinking water (<0.1 µg/L). This risk exists even if the insecticides containing these pesticides are used according to the information sheet provided by the manufacturer (lower maximum concentration), which results in exceeding the maximum permissible levels for drinking water from several to several hundred times.

Elevated temperature magnifies the acute and chronic toxicity of clothianidin to Eisenia fetida.

Pesticide residue and thermal stress resulting from global climate change are parallel stressors for soil fauna. However, it remains ambiguous how elevated temperatures and pesticides can interact to threaten soil fauna. In the study, the acute and chronic clothianidin (CTD) toxicity to earthworms (Eisenia fetida) at different temperatures, and the effect of increasing temperature on antioxidant defense mechanisms in response to CTD were investigated. The acute toxicity of CTD was exacerbated by increased temperature in both filter paper contact tests (a decrease in the 48-h median lethal concentration (LC50) from 0.077 µg/cm2 at 20 °C to 0.009 µg/cm2 at 30 °C) and natural soil tests (a decrease in the 48-h LC50 from 0.774 mg/kg at 20 °C to 0.199 mg/kg at 30 °C). Exposure to CTD or high temperature (30 °C) triggered reactive oxygen species (ROS) overgeneration and increased antioxidant enzyme activities in earthworms; and the effect was particularly pronounced after exposure to both higher temperatures and CTD. At 20 and 25 °C, there was no significant change in the growth and reproduction of E. fetida after 56-d exposure to CTD-contaminated soil. However, the combined effect of CTD and high temperature (30 °C) significantly reduced the weight change rate, cocoon number, hatching rate, and number of juveniles on day 56. These results indicated that elevated temperature could aggravate acute and chronic CTD toxicity to earthworms. The findings emphasize that evaluating changes in pesticide toxicity under global warming is worth further investigation.

Novel Sulfoximine Derivatives Containing Cyanoguanidine and Nitroguanidine Moieties: Design, Synthesis, and Bioactivities.

A total of 32 novel sulfoximines bearing cyanoguanidine and nitroguanidine moieties were designed and synthesized by a rational molecule design strategy. The bioactivities of the title compounds were evaluated and the results revealed that some of the target compounds possessed excellent antifungal activities against six agricultural fungi, including Sclerotinia sclerotiorum, Fusarium graminearum, Phytophthora capsici, Botrytis cinerea, Rhizoctonia solani, and Pyricularia grisea. Among them, compounds 8e1 and 8e4 exhibited significant efficacy against P. grisea with EC50 values of 2.72 and 2.98 µg/mL, respectively, which were much higher than that of commercial fungicides boscalid (47.95 µg/mL). Interestingly, in vivo assays determined compound 8e1 possessed outstanding activity against S. sclerotiorum with protective and curative effectiveness of 98 and 95.6% at 50 µg/mL, which were comparable to those of boscalid (93.2, 91.9%). The further preliminary mechanism investigation disclosed that compound 8e1 could damage the structure of the cell membrane of S. sclerotiorum, increase its permeability, and suppress its growth. Overall, the findings enhanced that these novel sulfoximine derivatives could be potential lead compounds for the development of new fungicides.

Neonicotinoid insecticides in paddy fields: Dissipation dynamics, migration, and dietary risk.

Neonicotinoid insecticides (NNIs) have caused widespread contamination of multiple environmental media and posed a serious threat to ecosystem health by accidently injuring non-target species. This study collected samples of water, soil, and rice plant tissues in a water-soil-plant system of paddy fields after spaying imidacloprid (IMI), thiamethoxam (THM), and clothianidin (CLO) to analyze their distribution characteristics and migration procedures and to assess related dietary risks of rice consumption. In the paddy water, the concentrations of NNIs showed a dynamic change of increasing and then decreasing during about a month period, and the initial deposition of NNIs showed a trend of CLO (3.08 µg/L) > THM (2.74 µg/L) > IMI (0.97 µg/L). In paddy soil, the concentrations of the three NNIs ranged from 0.57 to 68.3 ng/g, with the highest residual concentration at 2 h after application, and the concentration trend was opposite to that in paddy water. The initial deposition amounts of IMI, THM, and CLO in the root system were 5.19, 3.02, and 5.24 µg/g, respectively, showing a gradual decrease over time. In the plant, the initial deposition amounts were 19.3, 9.36, and 52.6 µg/g for IMI, THM, and CLO, respectively, exhibiting concentration trends similar to those in the roots. Except for IMI in soil, the dissipation of the NNIs conformed to the first-order kinetic equation in paddy water, soil, and plant. The results of bioconcentration factors (BCFs) and translocation factor (TF) indicated that NNIs can be bi-directionally transported in plants through leaf absorption and root uptake. The risk of NNIs intake through rice consumption was low for all age groups, with a slightly higher risk of exposure in males than in females.

Evaluation of pharmacokinetics, safety, and efficacy of [211At] meta-astatobenzylguanidine ([211At] MABG) in patients with pheochromocytoma or paraganglioma (PPGL): A study protocol.

BACKGROUND: Pheochromocytoma, or paraganglioma (PPGL), is a tumor that arises from catecholamine-producing chromaffin cells of the adrenal medulla or paraganglion. Systemic therapy, such as the combination of cyclophosphamide, vincristine, and dacarbazine or therapeutic radiopharmaceuticals such as [131I] meta-iodobenzylguanidine (MIBG), may be administered in cases of locally advanced tumors or distant metastases. However, the current therapies are limited in terms of efficacy and implementation. [211At] meta-astatobenzylguanidine (MABG) is an alpha-emitting radionuclide-labeled ligand that has demonstrated remarkable tumor-reducing effects in preclinical studies, and is expected to have a high therapeutic effect on pheochromocytoma cells. METHODS: We are currently conducting an investigator-initiated first-in-human clinical trial to evaluate the pharmacokinetics, safety, and efficacy of [211At] MABG. Patients with locally unresectable or metastatic PPGL refractory to standard therapy and scintigraphically positive [123I] MIBG aggregation are being recruited, and a 3 + 3 dose escalation design was adopted. The initial dose of [211At] MABG is 0.65 MBq/kg, with a dose escalation in a 1:2:4 ratio in each cohort. Dose-limiting toxicity is observed for 6 weeks after a single bolus dose of [211At] MABG, and the patients are observed for 3 months to explore safety and efficacy profiles. The primary endpoint is dose-limiting toxicity to determine both maximum tolerated and recommended doses. The secondary endpoints include radiopharmacokinetics, urinary radioactive excretion rate, urinary catecholamine response rate, objective response rate, progression free survival, [123I] MIBG scintigraphy on reducing tumor accumulation, and quality of life. TRIALS REGISTRATION: jRCT2021220012 registered on 17 June 2022.