Febrile seizures (FS) are the most prevalent seizures in children. Although FS are largely benign, complex FS increase the risk to develop temporal lobe epilepsy (TLE). Studies in rat models for FS have provided information about functional changes in the hippocampus after complex FS. However, our knowledge about the genes and pathways involved in the causes and consequences of FS is still limited. To enable molecular, genetic and knockout studies, we developed and characterized an FS model in mice and used it as a phenotypic screen to analyze FS susceptibility. Hyperthermia was induced by warm air in 10-to 14-day-old mice and induced FS in all animals. Under the conditions used, seizure-induced behavior in mice and rats was similar. In adulthood, treated mice showed increased hippocampal Ih current and seizure susceptibility, characteristics also seen after FS in rats. Of the seven genetically diverse mouse strains screened for FS susceptibility, C57BL/6J mice were among the most susceptible, whereas A/J mice were among the most resistant. Strains genetically similar to C57BL/6J also showed a susceptible phenotype. Our phenotypic data suggest that complex genetics underlie FS susceptibility and show that the C57BL/6J strain is highly susceptible to FS. As this strain has been described as resistant to convulsants, our data indicate that susceptibility genes for FS and convulsants are distinct. Insight into the mechanisms underlying seizure susceptibility and FS may help to identify markers for the early diagnosis of children at risk for complex FS and TLE and may provide new leads for treatment.
The Varroa destructor mite is a devastating parasite of Apis mellifera honeybees. They can cause colonies to collapse by spreading viruses and feeding on the fat reserves of adults and larvae. Amitraz is used to control mites due to its low toxicity to bees; however, the mechanism of bee resistance to amitraz remains unknown. In this study, we found that amitraz and its major metabolite potently activated all four mite octopamine receptors. Behavioral assays using Drosophila null mutants of octopamine receptors identified one receptor subtype Octβ2R as the sole target of amitraz in vivo. We found that thermogenetic activation of octβ2R-expressing neurons mimics amitraz poisoning symptoms in target pests. We next confirmed that the mite Octβ2R was more sensitive to amitraz and its metabolite than the bee Octβ2R in pharmacological assays and transgenic flies. Furthermore, replacement of three bee-specific residues with the counterparts in the mite receptor increased amitraz sensitivity of the bee Octβ2R, indicating that relative insensitivity of their receptor is the major mechanism for honeybees to resist amitraz. The present findings have important implications for resistance management and the design of safer insecticides that selectively target pests while maintaining low toxicity to non-target pollinators.
Insect nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels mainly expressed in the central nervous system of insects. They are the directed targets of many insecticides, including neonicotinoids, which are the most widely used insecticides in the world. However, the development of resistance in pests and the negative impacts on bee pollinators affect the application of insecticides and have created a demand for alternatives. Thus, it is very important to understand the mode of action of these insecticides, which is not fully understood at the molecular level. In this study, we systematically examined the susceptibility of ten Drosophila melanogaster nAChR subunit mutants to eleven insecticides acting on nAChRs. Our results showed that there are several subtypes of nAChRs with distinct subunit compositions that are responsible for the toxicity of different insecticides. At least three of them are the major molecular targets of seven structurally similar neonicotinoids in vivo. Moreover, spinosyns may act exclusively on the α6 homomeric pentamers but not any other nAChRs. Behavioral assays using thermogenetic tools further confirmed the bioassay results and supported the idea that receptor activation rather than inhibition leads to the insecticidal effects of neonicotinoids. The present findings reveal native nAChR subunit interactions with various insecticides and have important implications for the management of resistance and the development of novel insecticides targeting these important ion channels.
Abstract:Objective: To investigate the relationship between serum resistin level and acute coronary syndrome (ACS) or stable angina pectoris (SAP). Methods: Sixty-five patients, with coronary artery disease, were enrolled and divided into three subgroups: acute myocardial infarction (AMI), unstable angina pectoris (UAP) and SAP, and 26 healthy people were recruited as controls in the cross-sectional study. Serum resistin levels were determined by ELISA (enzyme-linked immunosorbent assay), and WBC (white blood cell count), hsCRP (high sensitive C-reaction protein), CK max (maximum of creatinkinase), CK-MB max (maximum of isozyme of creatinkinase) and cTnI max (maximum of troponin) were measured by standard laboratory methods. Results: The serum resistin levels were 4 folds higher in AMI patients, 2.43 folds in UAP patients and 1.12 folds in SAP patients than in the healthy controls (P<0.05). The resistin levels were also significantly different between AMI [(8.16±0.79) ng/ml], UAP [(5.59±0.75) ng/ml] and SAP [(3.45±0.56) ng/ml] groups (P<0.01); WBC, hsCRP, CK max , CK-MB max and cTnI max were significantly increased in AMI patients over UAP and SAP patients. Spearman analysis showed that serum resistin levels were positively correlated with WBC (r=0.412, P=0.046), hsCRP (r=0.427, P=0.037), CK max , CK-MB max and cTnI max (r=0.731, 0.678, 0.656; P<0.01). Conclusion: Serum resistin levels increased with inflammatory factors and myocardial impairment. The results suggest that human resistin might play an important role in the pathogenesis of atherosclerosis and AMI as an inflammatory factor.
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