Bumblebees are resilient to neonicotinoid-fungicide combinations.

Bumblebees are among the most important wild bees for pollination of crops and securing wildflower diversity. However, their abundance and diversity have been on a steady decrease in the last decades. One of the most important factors leading to their decline is the frequent use of plant protection products (PPPs) in agriculture, which spread into forests and natural reserves. Mixtures of different PPPs pose a particular threat because of possible synergistic effects. While there is a comparatively large body of studies on the effects of PPPs on honeybees, we still lack data on wild bees. We here investigated the influence of the frequent fungicide Cantus® Gold (boscalid/dimoxystrobin), the neonicotinoid insecticide Mospilan® (acetamiprid) and their combination on bumblebees. Cognitive performance and foraging flights of bumblebees were studied. They are essential for the provisioning and survival of the colony. We introduce a novel method for testing four treatments simultaneously on the same colony, minimizing inter-colony differences. For this, we successfully quartered the colony and moved the queen daily between compartments. Bumblebees appeared astonishingly resilient to the PPPs tested or they have developed mechanisms for detoxification. Neither learning capacity nor flight activity were inhibited by treatment with the single PPPs or their combination.

3-acetylpyridine induced behavioral dysfunction and neuronal loss in the striatum and hippocampus of adult male rats.

3-acetylpyridine (3-AP) is a neurotoxin that is known to mainly affect the inferior olivary nucleus (ION) in the brain stem. Although several studies have explored the effect of this neurotoxin, still further investigation is required to understand the impact of this toxin on different parts of the brain. In this research, two groups of rats were studied, the 3-AP-treated and the control groups. Behavioral, stereological, and immunohistochemical analyses were performed. The locomotor activity of the 3-AP-treated rats decreased whereas their anxiety levels were higher than in normal controls. Also, memory performance was impaired in animals in the 3-AP group. Microscopic observations showed a decline in the numerical density of neurons in the hippocampus and striatum along with gliosis. Although this toxin is used to affect the ION, it exerts a neurotoxic effect on different brain regions.

Effect of the extra-nuclear cation on the cytotoxicity and mechanism of action of pyridine-2,6-dicarboxylate Ga(III) complexes.

Two Ga(III) complexes (C1) and (C2) were prepared by the one-pot reaction of pyridine-2,6-dicarboxylic acid and aminopyridine derivatives with gallium(III) nitrate octahydrate. The compounds were characterized by single-crystal X-ray diffraction. The distorted octahedral geometry was confirmed by crystallographic data for both complexes. The study of the in vitro cytotoxicity of the compounds showed that the presence of different extra-nuclear cations can affect the cytotoxicity of the same anionic complexes. The most significant antiproliferative activity was observed for C1 (IC50 = 0.69 µM, MAE = 73.96%) and C2 (IC50 = 3.78 µM, MAE = 60.35%) (where MAE represents the maximal antiproliferative effect) against A431 cell line. The mechanistic study evidenced the same pathway for the death of A431 cells treated with the complexes, although the results for C2 were obtained at approximately five times the concentration of C1. According to the study, both complexes induced cell cycle arrest in G2/M phase in A431 cells by upregulating the levels of p21, p27, p-cdc25C, and p-cdc2 and downregulating the levels of cdc25C, cdc2, and cyclin B1. In addition, apoptosis via a caspase-dependent mitochondrial pathway was confirmed by a decrease in Bcl-2 family proteins and an increase in the expression of procaspase-9 and 3. Also, the complexes induced autophagic cell death by activating the RAGE /PI3KC3/Beclin 1 pathway in A431 cells. DATA AVAILABILITY: CCDC 874052 and 874055 contain the supplementary crystallographic data for C1 and C2, respectively. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/services/structures?pid=ccdc:874052,874055&sid=CCDCManual, or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.

Comparison of the effects of sublethal concentrations of biofoulants, copper pyrithione and zinc pyrithione on a marine mysid - A multigenerational study.

To determine the effect of copper pyrithione (CuPT) and zinc pyrithione (ZnPT), a set of acute (96 h-LC50) and chronic endpoints was studied in the marine mysid, Neomysis awatschensis. Based on the 1/10 NOECs and NOEC values calculated from 96 h-toxicity test, survival and growth, intermolt duration, feeding, and the number of newborn juveniles were measured by evaluating enzymatic activity of detoxification parameter glutathione S-transferase (GST) and cholinergic biomarker acetylcholinesterase (AChE) in the marine mysid exposed to 96 h-NOECs of CuPT and ZnPT for four weeks across three generations. Dose-dependent decreases in survival rate monitored for four weeks were observed with age-specific sensitivity in response to the 96 h-NOECs of both antifoulants. Higher growth retardation was observed with an increase in intermolt duration and inhibition of the feeding rate in CuPT-exposed mysid compared to ZnPT-exposed mysid across generations. The numbers of newborn juveniles significantly decreased at the third generation by exposure to the 96 h-NOECs of both antifoulants. GST activity was significantly inhibited in response to 96 h-NOECs of both antifoulants, whereas AChE activity was only reduced by the 96 h-NOECs of CuPT at the third generation. These results indicate that CuPT has a higher toxicity than ZnPT and even sublethal levels of CuPT and ZnPT would have detrimental effects on the maintenance of the mysid population. Finally, consistent exposure to environmentally relevant concentrations of CuPT and ZnPT can induce intergenerational toxicity in mysid.

Unicellular cyanobacteria degrade sulfoxaflor to its amide metabolite of potentially higher aquatic toxicity.

Sulfoxaflor (SFX) is a fourth-generation neonicotinoid used widely in modern agriculture. Due to its high water solubility and mobility in environment, it is expected to occur in water environment. Degradation of SFX leads to formation of corresponding amide (M474), which in the light of recent studies may be much more toxic to aquatic organisms than the parent molecule. Therefore, the aim of the study was to assess the potential of two common species of unicellular bloom-forming cyanobacteria (Synechocystis salina and Microcystis aeruginosa) to metabolize SFX in a 14-day-long experiment, using elevated (10 mg L-1) and predicted highest environmental (10 µg L-1) concentrations. The results obtained support the occurrence of SFX metabolism in cyanobacterial monocultures, leading to release of M474 into the water. Differential SFX decline in culture media, followed by the presence of M474, was observed for both species at different concentration levels. For S. salina, SFX concentration decreased by 7.6% at lower concentration and by 21.3% at higher concentration; the M474 concentrations were 436 ng L-1 and 514 µg L-1, respectively. Corresponding values for M. aeruginosa were 14.3% and 3.0% for SFX decline; 282 ng L-1 and 317 µg L-1 for M474 concentration. In the same time, abiotic degradation was almost non-existent. Metabolic fate of SFX was then studied for its elevated starting concentration. Uptake of SFX to cells and amounts of M474 released to water fully addressed the decrease in SFX concentration in M. aeruginosa culture, while in S. salina 15.5% of initial SFX was transformed to yet unknown metabolites. The degradation rate of SFX observed in the present study is sufficient to produce a concentration of M474 that is potentially toxic for aquatic invertebrates during cyanobacterial blooms. Therefore, there is a need for more reliable risk assessment for the presence of SFX in natural waters.

Sulfoxaflor influences the biochemical and histological changes on honeybees (Apis mellifera L.).

Pesticide application can have an adverse effect on pollinator honey bees, Apis mellifera L., ranging from mortality to sublethal effects. Therefore, it is necessary to understand any potential effects of pesticides. The present study reports the acute toxicity and adverse effects of sulfoxaflor insecticide on the biochemical activity and histological changes on A. mellifera. The results showed that after 48 h post-treatment, the LD25 and LD50 values were 0.078 and 0.162 µg/bee, respectively, of sulfoxaflor on A. mellifera. The detoxification enzyme activity shows an increase of glutathione-S-transferase (GST) enzyme on A. mellifera in response to sulfoxaflor at LD50 value. Conversely, no significant differences were found in mixed-function oxidation (MFO) activity. In addition, after 4 h of sulfoxaflor exposure, the brains of treated bees showed nuclear pyknosis and degeneration in some cells, which evolved to mushroom shaped tissue losses, mainly neurons replaced by vacuoles after 48 h. There was a slight effect on secretory vesicles in the hypopharyngeal gland after 4 h of exposure. After 48 h, the vacuolar cytoplasm and basophilic pyknotic nuclei were lost in the atrophied acini. After exposure to sulfoxaflor, the midgut of A. mellifera workers showed histological changes in epithelial cells. These findings of the present study showed that sulfoxaflor could have an adverse effect on A. mellifera.

Real-time monitoring of honeybee colony daily activity and bee loss rates can highlight the risk posed by a pesticide.

Information on honeybee foraging performance and especially bee loss rates at the colony level are crucial for evaluating the magnitude of effects due to pesticide exposure, thereby ensuring that protection goals for honeybee colonies are met (i.e. threshold of acceptable effects). However, current methods for monitoring honeybee foraging activity and mortality are very approximate (visual records) or are time-limited and mostly based on single cohort analysis. We therefore assess the potential of bee counters, that enable a colony-level and continuous monitoring of bee flight activity and mortality, in pesticide risk assessment. After assessing the background activity and bee loss rates, we exposed colonies to two concentrations of sulfoxaflor (a neurotoxic insecticide) in sugar syrup: a concentration that was considered to be field realistic (0.59 µg/ml) and a higher concentration (2.36 µg/ml) representing a worst-case exposure scenario. We did not find any effect of the field-realistic concentration on flight activity and bee loss rates. However, a two-fold decrease in daily flight activity and a 10-fold increase in daily bee losses were detected in colonies exposed to the highest sulfoxaflor concentration as compared to before exposure. When compared to the theoretical trigger values associated with the specific protection goal of 7 % colony-size reduction, the observed fold changes in daily bee losses were often found to be at risk for colonies. In conclusion, the real-time and colony-level monitoring of bee loss rates, combined with threshold values indicating at which levels bee loss rates threaten the colony, have great potential for improving regulatory pesticide risk assessments for honeybees under field conditions.

Multigenerational effects of the insecticide Pyriproxyfen and recovery in Daphnia magna.

In the present study, an ecotoxicological approach to the evaluation of the insecticide Pyriproxifen in the crustacean Daphnia magna was done. Acute toxicity tests (48 h), feeding behavior test (5 h) and chronic toxicity test (21 days) were carried out on a parental daphnid generation (F0). Pyriproxifen D. magna EC50 value in our experimental conditions was 336.47 µg/L. Based on this result, sublethal test concentrations were selected for the feeding study and the F0 chronic experiment. Filtration and ingestion rates of D. magna exposed animals did not show any significant difference respect to control daphnids. However, daphnids from the parental F0 generation when exposed to the insecticide during 21 days showed a decreased in all the reproductive parameters tested (mean total neonates per female, mean brood size, time to first brood, and mean number of broods per female) as well as in the population statistic growth rate (r), although survival was not affected. On the other hand, offspring from F0 females exposed to the highest Pyriproxifen concentration (14.02 µg/L) were separated in two F1 generation experiments. One group was transferred during 21 days to a medium free of toxicant (F1 generation-TC group) while the other group was exposed during 21 days to the same insecticide concentration as their mothers (14.02 µg/L) (F1 generation-TT group). Results from both experiments determined a decreased in most of the reproductive parameters which was higher in the F1-TT group, although some of them were recovered in the F1-TC group. On the other hand, the morphological analysis of the daphnids showed that the coloration pattern was altered in the daphnids exposed to the insecticide, together with a significant size decreased, and neonates from F0 progeny with the same morphological abnormality. Finally, we determined that the insecticide caused the appearance of males among the offspring generated by the F0.

Exposure to flupyradifurone affect health of biocontrol parasitoid Binodoxys communis (Hymenoptera: Braconidae) via disrupting detoxification metabolism and lipid synthesis.

Assessing the potential effects of insecticides on beneficial biological control agents is key to facilitating the success of integrated pest management (IPM) approaches. Flupyradifurone (FPF) is a novel neonicotinoid insecticide that is replacing traditional neonicotinoids over a large geographical range to control pests. Binodoxys communis, is the dominant parasitic natural enemy of aphids. To date, no reports have addressed sublethal effects of FPF on B. communis. In this study, the lethal and sublethal effects of FPF on B. communis were investigated by indirect exposure to larvae and direct exposure to adults. Results showed that the sublethal LC10 and LC25 of FPF had negative effects on the biological parameters of B. communis, including significantly reducing survival rate, adult longevity, parasitism rate, and emergence rate, and significantly prolonging the developmental stages from egg to cocoons. In addition, we observed a transgenerational effect of FPF on the next generation (F1). RNA-Seq transcriptomic analysis identified a total of 1429 differentially expressed genes (DEGs) that were significantly changed between FPF-treated and control groups. These DEGs are mainly enriched in metabolic pathways such as peroxisomes, glutamate metabolism, carbon metabolism, fatty acid metabolism, and amino acid metabolism. This report is the first comprehensive evaluation of how FPF effects B. communis, which adds to the methods of assessing pesticide exposure in parasitic natural enemies. We speculate that the significant changes in pathways, especially those related to lipid synthesis, may be the reason for weakened parasitoid biocontrol ability. The present study provides new evidence for the toxic effects and environmental residue risk of FPF.

Development of immunoassay based on a specific antibody for sensitive detection of nicosulfuron in environment.

Nicosulfuron, one of the most widely used selective herbicides in corn field, can effectively control annual and perennial grass weeds, sedges, and some broadleaf weeds. The residual phytotoxicity of nicosulfuron in soil and water has become increasingly prominent. Therefore, an efficient method for detection of nicosulfuron was critical to ensure the sustainable and healthy development of agriculture and the ecological environment. In this paper, five nicosulfuron haptens which contained carboxyl group or aldehyde groups were designed and synthesized, and an indirect competitive immunoassay was developed for the first time. The assay showed an IC50 of 8.42 ng/mL and had negligible cross reactivities toward other sulfonylurea herbicides. In the spike and recovery studies, the recovery rate from soil samples was 95 %-104 %, and that of wheat roots was 92 %-98 %, which showed a good correlation with LC-MS analysis for nicosulfuron. The immunoassay was then used to quantify nicosulfuron concentration which could cause the obvious phytotoxic symptoms to wheat. Obvious symptoms of nicosulfuron phytotoxicity in wheat root was observed at the concentration of 0.068 ± 0.006 mg/kg (ELISA result) which was consistent with 0.072 ± 0.007 mg/kg obtained by LC-MS. The developed immunoassay method is an effective tool for environment contamination monitoring.

Toxic Encephalopathy and Methemoglobinemia after 5-Amino-2-(trifluoromethyl)pyridine Poisoning.

The aromatic amino compound 5-amino-2-(trifluoromethyl)pyridine acts as an intermediate in the synthesis of pharmaceutical products. However, the toxicity profile of this compound is sparse and no related poisoning events have been reported. Here, we report the case of a 35-year-old man who inhaled 5-amino-2-(trifluoromethyl)pyridine at work. After inhalation, the patient rapidly developed symptoms such as dizziness, fatigue, nausea, vomiting, chest tightness, and loss of consciousness. After admission, methemoglobinemia, hemolytic anemia, acute renal failure, and toxic encephalopathy occurred. Symptoms improved significantly after intravenous treatment with a low dose of methylene blue. This revealed that 5-amino-2-(trifluoromethyl)pyridine is toxic to the human body and can be absorbed through the respiratory tract, resulting in methemoglobinemia and toxic encephalopathy; thus, caution should be taken in industrial production.

Validation of quantitative real-time PCR reference genes and spatial expression profiles of detoxication-related genes under pesticide induction in honey bee, Apis mellifera.

Recently, pesticides have been suggested to be one of the factors responsible for the large-scale decline in honey bee populations, including colony collapse disorder. The identification of the genes that respond to pesticide exposure based on their expression is essential for understanding the xenobiotic detoxification metabolism in honey bees. For the accurate determination of target gene expression by quantitative real-time PCR, the expression stability of reference genes should be validated in honey bees exposed to various pesticides. Therefore, in this study, to select the optimal reference genes, we analyzed the amplification efficiencies of five candidate reference genes (RPS5, RPS18, GAPDH, ARF1, and RAD1a) and their expression stability values using four programs (geNorm, NormFinder, BestKeeper, and RefFinder) across samples of five body parts (head, thorax, gut, fat body, and carcass) from honey bees exposed to seven pesticides (acetamiprid, imidacloprid, flupyradifurone, fenitrothion, carbaryl, amitraz, and bifenthrin). Among these five candidate genes, a combination of RAD1a and RPS18 was suggested for target gene normalization. Subsequently, expression levels of six genes (AChE1, CYP9Q1, CYP9Q2, CYP9Q3, CAT, and SOD1) were normalized with a combination of RAD1a and RPS18 in the different body parts from honey bees exposed to pesticides. Among the six genes in the five body parts, the expression of SOD1 in the head, fat body, and carcass was significantly induced by six pesticides. In addition, among seven pesticides, flupyradifurone statistically induced expression levels of five genes in the fat body.

Persistence, leaching and associated toxicity risks of insecticide pyriproxyfen in soil ecosystem.

Pyriproxyfen is a pyridine-based insecticide used for pest control in fruits and vegetables. It is a potent endocrine disruptor and hormone imitator. Considering its potential hazards to non-target organisms and the associated environment, a lab study was conducted for assessing persistence, mobility in sandy loam soil and associated risk to various non-target organisms and soil enzymes. Pyriproxyfen formulation was applied at 0.05 and 0.10 µg g-1 soil which was equivalent to recommended and double dose of 100 and 200 g a.i. ha-1, respectively. Three methods namely QuEChERS, liquid-solid extraction (LSE) and matrix solid phase dispersion (MSPD) were compared for achieving efficient sample preparation. MSPD was applied for final analysis as it gave better recoveries (94.2 to 104.3%) over other methods with limits of detection and quantification (LOD and LOQ) as 0.0001 and 0.0005 µg g-1, respectively. Dissipation followed first order kinetics with half-lives of 7.6 and 8.2 days in both doses but residues retained over 45 days in soil. Leaching studies conducted at 50 and 100 µg of pyriproxyfen showed extremely poor leaching potential. Retention of over 90% residues in top 5 cm soil surface indicated minimal threat of ground and surface water contamination. Toxicological study demonstrated very different behaviour toward different enzymatic activities. Pyriproxyfen was relatively toxic for alkaline phosphatase and fluorescein diacetate hydrolase enzymes. ß-glucosidase activity was triggered whereas arylsulfatase activity remained unaffected. Unacceptable risk to soil invertebrates at double dose application clearly indicated that its longer persistence in soil could be toxic to other non-target organisms and needs further investigations.

Transcriptomic response of Pseudomonas nicosulfuronedens LAM1902 to the sulfonylurea herbicide nicosulfuron.

The overuse of the herbicide nicosulfuron has become a global environmental concern. As a potential bioremediation technology, the microbial degradation of nicosulfuron shows much promise; however, the mechanism by which microorganisms respond to nicosulfuron exposure requires further study. An isolated soil-borne bacteria Pseudomonas nicosulfuronedens LAM1902 displaying nicosulfuron, chlorimuron-ethyl, and cinosulfuron degradabilities in the presence of glucose, was used to determine the transcriptional responses to nicosulfuron exposure. RNA-Seq results indicated that 1102 differentially expressed genes (DEGs) were up-regulated and 702 down-regulated under nicosulfuron stress. DEGs were significantly enriched in "ABC transporters", "sulfur metabolism", and "ribosome" pathways (p ≤ 0.05). Several pathways (glycolysis and pentose phosphate pathways, a two-component regulation system, as well as in bacterial chemotaxis metabolisms) were affected by nicosulfuron exposure. Surprisingly, nicosulfuron exposure showed positive effects on the production of oxalic acid that is synthesized by genes encoding glycolate oxidase through the glyoxylate cycle pathway. The results suggest that P. nicosulfuronedens LAM1902 adopt acid metabolites production strategies in response to nicosulfuron, with concomitant nicosulfuron degradation. Data indicates that glucose metabolism is required during the degradation and adaptation of strain LAM1902 to nicosulfuron stress. The present studies provide a glimpse at the molecular response of microorganisms to sulfonylurea pesticide toxicity and a potential framework for future mechanistic studies.

Flupyradifurone induces transgenerational hormesis effects in the cowpea aphid, Aphis craccivora.

With low-dose stimulation and high-dose inhibition, insecticide-induced hormesis, a biphasic phenomenon, can contribute to pest resurgence. The cowpea aphid, Aphis craccivora (Koch) (Homoptera: Aphididae), is a vital insect that infests legume crops. Its hormesis of flupyradifurone has not been previously established. Age-stage two-sex life analysis is used to investigate the sublethal and transgenerational effects of flupyradifurone on two successive generations of A. craccivora. A leaf-dip bioassay method revealed high toxicity of flupyradifurone against A. craccivora, with lethal concentration 50% value (LC50) of 1.82 mg L-1 after 48 h exposure. Treatment of parent generation (F0) with LC10 and LC25 of flupyradifurone significantly increased the longevity and fecundity of the directly exposed adults. The results of transgenerational effects showed that the treatment of (F0) with LC25 induced significant hormetic effects in progeny generation (F1). Furthermore, flupyradifurone at LC25 significantly enhanced the biological traits, such as intrinsic rate of increase (r), finite rate of increase (λ), and net reproductive rate (R0) compared with the control. Similarly, both LC10 and LC25 induced a significant increase in the mean generation time T (d). Conversely, both treatments caused a significant decrease in the doubling time (DT). Data in the present study demonstrate that the exposure of (F0) to flupyradifurone at LC10 and LC25 enhanced longevity and fecundity in the directly exposed adults of A. craccivora, and induced transgenerational hormesis across the subsequent (F1) generation. These results should be taken into consideration when using flupyradifurone for controlling cowpea aphid.

Hematotoxic, oxidative and genotoxic damage in rainbow trout (Oncorhynchus mykiss) after exposure to 3-benzoylpyridine.

Pyridine is a basic heterocyclic organic compound. The pyridine ring is present in many important compounds, including agricultural chemicals, medicines and vitamins. Due to their widespread industrial use, bioaccumulation and non-target toxic effects are being considered as a great risk to human and environmental health. In this study, we aimed to evaluate the hematological, oxidative and genotoxic damage potentials by different concentrations (1, 1.5, and 2 g/L) of the ketone 3-Benzoylpyridine (3BP) on rainbow trout (Oncorhynchus mykiss). Alterations in the biomarker levels of oxidative DNA damage (8-hydroxy-2'-deoxyguanosine (8-OHdG)), apoptosis (Caspase-3), malondialdehyde (MDA) as well as antioxidant enzyme activities including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), myeloperoxidase (MPO), paraoxonase (PON), and arylesterase (AR) were assessed in brain, liver, gill and blood tissues. Acetylcholinesterase (AChE) activity was also determined in brain tissue. In addition, we analyzed micronucleus (MN) rates and hematological indices of total erythrocyte count (RBC), total leukocyte count (WBC), hemoglobin (Hb), hematocrit (Hct), total platelet count (PLT), mean cell hemoglobin concentration (MCHC), mean cell hemoglobin (MCH), and mean cell volume (MCV) in blood. LC50-96h value of 3BP was calculated as 5.2 g/L from the data obtained. A significant decrease in brain AChE activity was determined in clear time and dose dependent manners. While SOD, CAT, GPx, PON, and AR levels were decreased, MDA, MPO, 8-OHdG and Caspase-3 levels were increased in all tissues (p < 0.05). Again, the 3BP led to increases of MN formation at all applied concentrations in the rates of between 45.4 and 72.7%. Significant differences (p < 0.05) were found out in between all studied hematology parameters between 3BP-exposed and the control fish. In conclusion, ours study firstly indicated that the treatment doses of 3BP induced distinct hematological and oxidative alterations as well as genotoxic damage in rainbow trout.

The HVEM-BTLA Immune Checkpoint Restrains Murine Chronic Cholestatic Liver Injury by Regulating the Gut Microbiota.

The herpes virus entry mediator (HVEM) is an immune checkpoint molecule regulating immune response, but its role in tissue repair remains unclear. Here, we reported that HVEM deficiency aggravated hepatobiliary damage and compromised liver repair after 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced injury. A similar phenotype was observed in B and T lymphocyte attenuator (BTLA)-deficient mice. These were correlated with impairment of neutrophil accumulation in the liver after injury. The hepatic neutrophil accumulation was regulated by microbial-derived secondary bile acids. HVEM-deficient mice had reduced ability to deconjugate bile acids during DDC-feeding, suggesting a gut microbiota defect. Consistently, both HVEM and BTLA deficiency had dysregulated intestinal IgA responses targeting the gut microbes. These results suggest that the HVEM-BTLA signaling may restrain liver injury by regulating the gut microbiota.

Discrimination of hand-foot skin reaction caused by tyrosine kinase inhibitors based on direct keratinocyte toxicity and vascular endothelial growth factor receptor-2 inhibition.

Tyrosine kinase inhibitors (TKIs) are molecular-targeted anticancer drugs. Their benefits are limited by dermal toxicities, including hand-foot skin reaction (HFSR), which is commonly found in skin areas subjected to friction. The present study aimed to explain the incidence of HFSR in patients treated with TKIs by focusing on keratinocyte toxicity and inhibition of vascular endothelial growth factor receptor (VEGFR), which plays an essential role in angiogenesis. Mice with gene knockout for the immunosuppressive cytokine interleukin-10 exhibited HFSR-like phenotypes, such as cytotoxicity in keratinocytes and increased number and size of blood vessels after repeated doses of regorafenib, sorafenib, and pazopanib, all of which cause high incidence of HFSR, in combination with tape-stripping mimicking skin damage at the friction site. Comprehensive examination of the direct cytotoxic effects of 21 TKIs on primary cultured human keratinocytes revealed that 18 of them reduced the cell viability dose-dependently. Importantly, the ratio of the trough concentration in patients (Ctrough) to the LC50 values of cell viability reduction was higher than unity for four HFSR-inducing TKIs, suggesting that these TKIs cause keratinocyte toxicity at clinically relevant concentrations. In addition, eight HFSR-inducing TKIs caused inhibition of VEGFR-2 kinase activity, which was validated by their ratios of Ctrough to the obtained IC50,VEGFR-2 of more than unity. All 12 TKIs with no reported incidence of HFSR exhibited less than unity values for both Ctrough/LC50,keratinocytes and Ctrough/IC50,VEGFR-2. These results suggested that a combination of keratinocyte toxicity and VEGFR-2 inhibition may explain the incidence of HFSR upon TKI usage in humans.

Enantioselective bioaccumulation and toxicity of rac-sulfoxaflor in zebrafish (Danio rerio).

Sulfoxaflor is a fourth-generation neonicotinoid insecticide mainly used to control sap-feeding pests. In this study, four stereoisomers of sulfoxaflor were separated using HPLC, and the absolute configurations of three stereoisomers were identified via single-crystal X-ray diffraction. First, the stability and isomerization of the four enantiomers and rac-sulfoxaflor in water and seven organic solvents were investigated. All enantiomers were extremely unstable in water with isomerization rates above 20%. The racemate did not isomerize in any of the solutions and was stable in water (degradation rate less than 7%). Therefore, we studied the acute toxicity, enantioselective behavior, and enzymatic activities of rac-sulfoxaflor in zebrafish. The bioaccumulation experiment demonstrated that the bioconcentration of sulfoxaflor in zebrafish was enantioselective, and the four enantiomers accumulated in zebrafish in the order (+)-2S,3S-sulfoxaflor > (-)-2R,3R-sulfoxaflor > (+)-2R,3S-sulfoxaflor > (-)-2S,3R-sulfoxaflor. The effect of rac-sulfoxaflor on the enzymatic activities of zebrafish showed that superoxide dismutase and glutathione-S-transferase activities and malondialdehyde content were significantly enhanced as compared to those in control, whereas acetylcholinesterase was significantly reduced in the sulfoxaflor exposure treatment (p < 0.05), indicating that sulfoxaflor caused oxidative lesions and induced enzymatic activity in zebrafish. This study provides important information on the enantioselective behavior and toxic effects of sulfoxaflor, which can help assess the potential ecological risk of chiral pesticides to aquatic organisms.

Meta-Analysis of the Field Efficacy of Seed- and Soil-Applied Nematicides on Meloidogyne incognita and Rotylenchulus reniformis Across the U.S. Cotton Belt.

Meta-analysis was used to compare yield protection and nematode suppression provided by two seed-applied and two soil-applied nematicides against Meloidogyne incognita and Rotylenchulus reniformis on cotton across 3 years and several trial locations in the U.S. Cotton Belt. Nematicides consisted of thiodicarb- and fluopyram-treated seed, aldicarb and fluopyram applied in furrow, and combinations of the seed treatments and soil-applied fluopyram. The nematicides had no effect on nematode reproduction or root infection but had a significant impact on seed cotton yield response ([Formula: see text]), with an average increase of 176 and 197 kg/ha relative to the nontreated control in M. incognita and R. reniformis infested fields, respectively. However, because of significant variation in yield protection and nematode suppression by nematicides, five or six moderator variables (cultivar resistance [M. incognita only], nematode infestation level, nematicide treatment, application method, trial location, and growing season) were used depending on nematode species. In M. incognita-infested fields, greater yield protection was observed with nematicides applied in furrow and with seed-applied + in-furrow than with solo seed-applied nematicide applications. Most notable of these in-furrow nematicides were aldicarb and fluopyram (>131 g/ha) with or without a seed-applied nematicide compared with thiodicarb. In R. reniformis-infested fields, moderator variables provided no further explanation of the variation in yield response produced by nematicides. Furthermore, moderator variables provided little explanation of the variation in nematode suppression by nematicides in M. incognita- and R. reniformis-infested fields. The limited explanation by the moderator variables on the field efficacy of nematicides in M. incognita- and R. reniformis-infested fields demonstrates the difficulty of managing these pathogens with nonfumigant nematicides across the U.S. Cotton Belt.