Early Access to First-Seizure Clinics, Subsequent Outcomes, and Factors Associated With Attendance.

Importance: First-seizure clinics (FSCs) aim to deliver prompt specialist care to patients with new-onset undifferentiated seizure events. Objective: To determine whether FSC attendance and time to FSC are associated with subsequent health care utilization and mortality and to investigate factors associated with FSC nonattendance. Design, Setting, and Participants: This was a record-linkage, retrospective, cohort study of patients who booked appointments at 2 FSCs between 2007 and 2018. Patients' records were linked to state-wide administrative databases between 2000 and 2021. The setting comprised the FSCs of 2 major metropolitan public hospitals in Melbourne, Australia, providing national inpatient and outpatient adult epilepsy services. Of patients who booked appointments at the FSCs, those who were successfully linked for analysis were included in the study. Patients who recorded only canceled appointments were excluded from analysis of outcomes. Study data were analyzed from January 2000 to December 2021. Exposure: FSC attendance. Main Outcomes and Measures: Subsequent all-cause and seizure-related emergency department (ED) presentations and hospital admissions. Results: Of 10 162 patients with appointments at FSCs, 9392 were linked for analysis, with mean (SD) follow-up time 6.9 (2.8) years after FSC referral. A total of 703 patients were excluded. Among 9392 linked patients, 5398 were male (57.5%; mean [SD] age, 59.7 [11.2] years). FSC attendance was associated with reduced subsequent all-cause emergency presentations (adjusted incidence rate ratio [aIRR], 0.72; 95% CI, 0.66-0.79) and all-cause hospitalization (aIRR, 0.81; 95% CI, 0.75-0.88). Those who attended at the first-scheduled appointment, compared with those who attended only a rescheduled, delayed appointment, had reduced subsequent all-cause emergency presentations (aIRR, 0.83; 95% CI, 0.76-0.91), all-cause hospitalization (aIRR, 0.71; 95% CI, 0.65-0.79), seizure-related presentations (aIRR, 0.40; 95% CI, 0.33-0.49), and mortality (hazard ratio, 0.82; 95% CI, 0.69-0.98). Male sex was associated with nonattendance (adjusted relative risk [aRR], 1.12; 95% CI, 1.03-1.22), as were injury at emergency presentation (aRR, 1.12; 95% CI, 1.01-1.24), psychiatric comorbidity (aRR, 1.68; 95% CI, 1.55-1.81), previous seizure-related presentations (aRR, 1.35; 95% CI, 1.22-1.49), and delays (>14 days) between FSC referral and appointment (aRR, 1.35; 95% CI, 1.18-1.54). Hospitalization at referral was associated with reduced nonattendance (aRR, 0.80; 95% CI, 0.72-0.90), as were non-English language preference (aRR, 0.81; 95% CI, 0.69-0.94), distance greater than 6 mi from home to clinic (aRR, 0.85; 95% CI, 0.76-0.95), and physical comorbidity (aRR, 0.80; 95% CI, 0.72-0.89). Conclusions and Relevance: Results of this cohort study suggest that FSC attendance, particularly early attendance, was associated with reduced rates of subsequent hospital utilization. This knowledge may support adequately resourcing FSCs to improve equitable, timely access. Future study directions include assessing interventions that may support FSC attendance for at-risk groups.

A flexible modulated pesticide release platform through poly(urethane-urea) microcapsules: effect of different crosslinkers compositions.

BACKGROUND: Polymeric microcapsules (MCs) have become an important issue and have attracted increasing attention because of their tunable physical and chemical properties. Diverse shell structures can confer multiple properties on MCs. RESULTS: Different polyols (1,4-butanediol and glycerin) and polyamines (triethylenetetramine and isophorondiamine) were selected as crosslinkers to obtain emamectin benzoate (EB)-loaded poly(urethane-urea) MCs (PU-MCs) by interfacial polymerization. The four obtained PU-MCs showed sphericity with different degrees of smoothness on their surfaces, and displayed a uniform size distribution ranging from 500 to 700 nm. Moreover, transmission electron microscopy showed that the shell thickness was roughly uniform, and was greatly influenced by the type and structure of the crosslinker. GI-MCs, prepared using glycerin and isophorondiamine, had the largest shell thickness. GT-MCs, obtained using glycerin and triethylenetetramine, had the highest encapsulation efficiency and drug-loading content, and BT-MCs, obtained using mixtures of 1,4-butanediol and triethylenetetramine, had the fastest release behavior. Thermogravimetric analysis revealed that the greater the degree of shell crosslinking, the higher decomposition temperature and the greater the thermal stability. A BT-MC suspension had the lowest viscosity and contact angle with the best wettability. Bioassay experiments showed that BT-MCs exhibited good insecticidal activity against Plutella xylostella larvae with a half-maximal lethal concentration of 4.19 mg/L. Furthermore, a BT-MC suspension showed good thermal and light stability, with potential applications in minimizing the toxicity of EB through sustained release. CONCLUSION: Various properties of EB-loaded PU-MCs were modulated through simple selection of different polyols and polyamines during fabrication, which might have an important role in constructing the pesticide delivery system and improving pesticide utilization. © 2024 Society of Chemical Industry.

A H2O2-specific fluorescent probe for evaluating oxidative stress in pesticides-treated cells, rice roots and zebrafish.

Hydrogen peroxide (H2O2) plays an irreplaceable role in the evaluation of the redox status in versatile circumstances. The levels of H2O2 can be affected by both internal and external stimuli, including environmental hazards. Abnormal production of H2O2 is a common characteristic of pesticide-caused damage. Therefore, H2O2 levels can intuitively and conveniently reflect the oxidative stress caused by various pesticides in cells and organisms. However, reliable and convenient monitoring of H2O2 in living cells is still limited by the lack of specific imaging probes. In this study, a fluorescent probe (HBTM-HP) was developed for in situ observation of H2O2 fluctuations caused by pesticide treatment over time in mammalian cells, rice roots and zebrafish. HBTM-HP showed high sensitivity and selectivity for H2O2. Fluorescence imaging results confirmed that HBTM-HP could be applied to reveal H2O2 production induced by multiple pesticides. This study revealed that HBTM-HP could serves as a versatile tool to monitor the redox status related to H2O2 both in vitro and in vivo upon exposure to pesticides, and also provides a basis for clarifying the mechanisms of pesticides in physiological and pathological processes.

Prevalence and influencing factors of PTSD symptoms among healthcare workers: A multicenter cross-sectional study during the surge period of the COVID-19 pandemic since December 2022 in the Chinese mainland.

BACKGROUND: China has experienced a surge period of COVID-19 pandemic since December 2022. Healthcare workers (HCWs) were exposed to huge workload under high risk of being infected, and significant levels of trauma, which might cause Post-traumatic Stress Disorders (PTSD) symptoms in HCWs. OBJECTIVES: To identify the prevalence of PTSD symptoms among HCWs in the Chinese mainland during the surge period of the COVID-19 pandemic; to explore their psycho-social factors of PTSD symptoms. METHODS: A multicenter cross-sectional study was conducted among HCWs in Chinese mainland from January 5 to February 9, 2023, covering seven geographical regions. 6552 participants were recruited by convenience sampling. Data were collected on demographic characteristics, work-related factors, and psychological factors by online questionnaires. Univariate analysis and binary logistic regression were used to determine the influencing factors of PTSD symptoms. RESULTS: The prevalence of PTSD symptoms among HCWs was 37.49 %. A higher level of mindfulness, resilience, and perceived social support were protective factors. Female gender, nurses, higher educational attainment, married status, more working years, higher perceived risk of contracting COVID-19 due to work, and higher perceived work intensity were risk factors. CONCLUSION: High prevalence of PTSD symptoms among HCWs necessitates psychological interventions. Tailored interventions, designed by professional psychiatrists, should be tailored to address the stressors. A comprehensive approach, incorporating mindfulness, resilience-building, and perceived social support enhancement, is vital to bolster the mental well-being of HCWs exposed to traumatic events, thus mitigating the impact of PTSD effectively. Additionally, it is essential to provide support to HCWs with other potential risk factors.

Long-term physical and psychiatric morbidities and mortality of untreated, deferred, and immediately treated epilepsy.

OBJECTIVE: In Australia, 30% of newly diagnosed epilepsy patients were not immediately treated at diagnosis. We explored health outcomes between patients receiving immediate, deferred, or no treatment, and compared them to the general population. METHODS: Adults with newly diagnosed epilepsy in Western Australia between 1999 and 2016 were linked with statewide health care data collections. Health care utilization, comorbidity, and mortality at up to 10 years postdiagnosis were compared between patients receiving immediate, deferred, and no treatment, as well as with age- and sex-matched population controls. RESULTS: Of 603 epilepsy patients (61% male, median age = 40 years) were included, 422 (70%) were treated immediately at diagnosis, 110 (18%) received deferred treatment, and 71 (12%) were untreated at the end of follow-up (median = 6.8 years). Immediately treated patients had a higher 10-year rate of all-cause admissions or emergency department presentations than the untreated (incidence rate ratio [IRR] = 2.0, 95% confidence interval [CI] = 1.4-2.9) and deferred treatment groups (IRR = 1.7, 95% CI = 1.0-2.8). They had similar 10-year risks of mortality and developing new physical and psychiatric comorbidities compared with the deferred and untreated groups. Compared to population controls, epilepsy patients had higher 10-year mortality (hazard ratio = 2.6, 95% CI = 2.1-3.3), hospital admissions (IRR = 2.3, 95% CI = 1.6-3.3), and psychiatric outpatient visits (IRR = 3.2, 95% CI = 1.6-6.3). Patients with epilepsy were also 2.5 (95% CI = 2.1-3.1) and 3.9 (95% CI = 2.6-5.8) times more likely to develop a new physical and psychiatric comorbidity, respectively. SIGNIFICANCE: Newly diagnosed epilepsy patients with deferred or no treatment did not have worse outcomes than those immediately treated. Instead, immediately treated patients had greater health care utilization, likely reflecting more severe underlying epilepsy etiology. Our findings emphasize the importance of individualizing epilepsy treatment and recognition and management of the significant comorbidities, particularly psychiatric, that ensue following a diagnosis of epilepsy.

The second dose of COVID-19 vaccine booster hesitancy among health care workers in China: A multicenter cross-sectional study.

BACKGROUND: The COVID-19 outbreak in China exposed health care workers (HCWs) to an increased risk of infection. The acquired immunity rapidly diminishes after the previous COVID-19 vaccination and the second booster vaccination has been recommended in several countries. HCWs are a priority group for vaccination because they are at increased risk of being infected, however, a certain amount of HCWs were hesitant. METHODS: The survey was conducted among 5805 HCWs in China from January 5 to February 9, 2023. Questionnaire included sociodemographic information, COVID-19-related variables, psychological factors, and the COVID-19 vaccine hesitancy scale. Multiple logistic regression analysis was used to assess the influencing factors of the second dose of COVID-19 vaccine booster hesitancy. RESULTS: 42.2% of HCWs self-reported having the second dose of COVID-19 vaccine booster hesitancy. Occupations, years of working, COVID-19 infection status were associated with less vaccine hesitancy. HCWs who had received 3 doses of COVID-19 vaccine were less likely to be hesitant compared to those had not received. HCWs with PTSD symptoms and anxiety symptoms were more likely to be hesitant. No relation was observed between COVID-19 vaccine booster hesitancy and age, marriage, salary, and perceived an increased risk of COVID-19 infection due to work (all P > 0.05). CONCLUSIONS: A considerable proportion of HCWs were hesitant to accept the second dose of the COVID-19 booster vaccine. Incorporating vaccine knowledge and new evidence into routine health educations and procedures to raise confidence and reduce complacency may be effective and feasible in promoting the vaccination and implementing future vaccination programs.

Glutathione-Responsive Pyraclostrobin-Loaded Polyurea Microcapsules for Their Intelligent Controlled Release.

The utilization of intelligent controlled release technology to create stimuli-responsive pesticide formulations has been shown to effectively improve pesticide efficacy and reduce environmental pollution. Herein, a glutathione-responsive release polyurea (PU) microcapsules (MCs) loaded with pyraclostrobin were developed via the interface polymerization method. The pyraclostrobin-loaded PU-MCs showed a regular spherical shape with an average diameter of 480 nm. It also showed good thermal stability and rheological properties. Furthermore, the pyraclostrobin-loaded PU-MCs exhibited favorable wettability on wheat leaves, which was beneficial for enhancing the retention capacity of pesticide droplets and improving pesticide utilization. The pyraclostrobin can be released from MCs and directly proportional to glutathione (GSH) concentrations with Fickian diffusion. Importantly, the control efficacy of pyraclostrobin-loaded PU-MCs against Fusarium graminearum was positively correlated with GSH, indicating a promising candidate for a controlled release of pesticides in agriculture and laying the foundation for further field experiments.

NIR Fluorescent Probe for In Situ Bioimaging of Endogenous H2S in Rice Roots under Al3+ and Flooding Stresses.

Hydrogen sulfide (H2S) is one of the typical reactive sulfur species, which exhibits an important role in regulating both physiological and pathological processes. Recent studies indicate that H2S also serves as a key signaling molecule in a broad range of regulatory processes in plants. However, in situ imaging and detection of the levels of H2S in plant tissues remains a challenge. In this work, a NIR fluorescent probe (HBTP-H2S) was synthesized to achieve H2S imaging in living plant tissues. HBTP-H2S exhibited high sensitivity toward H2S with a large Stokes shift (250 nm). HBTP-H2S could be applied to HeLa cells to detect the fluctuation of endogenous H2S levels in response to physiological stimulations. Importantly, HBTP-H2S was utilized for direct H2S imaging of rice roots and revealed the upregulation of H2S signaling in response to aluminum ions and flooding stresses. Our work thus provides a new tool to investigate H2S-involved signal interaction and protective resistance of crops under environmental stresses.

Hydroxyl ions: flexible tailoring of Cu2O crystal morphology.

The precise control architectures of Cu2O crystals are very crucial, which have a significant influence on their various performances. Herein, Cu2O crystals with diverse architectures were achieved via finely adjusting the concentration of NaOH. The intriguing results showed that the addition of specific amounts of OH- to the solution was crucial to tailor the morphology and size of the resulting microcrystals. We observed the evolution of the shapes of the Cu2O microcrystals, which change from a rhombic dodecahedron to spherical, octahedral-like and then to hexapod upon the increase in the NaOH concentration. Adjusting the volume of NaOH added provides a means to vary the particle size. Furthermore, density functional theory (DFT) may reveal that OH- ions serve as an efficient coordination agent selectively adsorbing onto different crystal faces of Cu2O crystals modifying the crystal energies, inducing the structure anisotropy on crystal growth. This work reveals that an effective and facile strategy has been developed for morphology-control of Cu2O crystals.

Synthesis of nonylphenol polyoxyethylene oligomer and application as an effective dispersant in pyraclostrobin suspension concentrate.

A versatile dispersant plays a critical role in suspension stability of pesticide aqueous suspension concentrate (SC), thus it is extremely important to design and synthesize an effective dispersant for SC. Herein, nonionic trimeric nonylphenol polyoxyethylene (10) (TNP10) was successfully synthesized using nonylphenol polyoxyethylene(10) ethers (NP10) as raw materials. The surface activities of TNP10 were evaluated according to critical micelle concentration (CMC), and the surface tension at CMC (γCMC). TNP10 showed higher surface activity due to its lower CMC value compared with that of NP10. In addition, the dispersing and stabilizing properties of TNP10 in 25 wt.% pyraclostrobin SC system were investigated. The results showed that TNP10 as a dispersant exhibited more excellent dispersion performance than NP10. Meanwhile, the obtained SC system exhibits shear thinning behavior under high-speed shearing showing typical features of pseudo-plastic non-Newtonian fluids, which conforms to the Herschel-Buckley model. The nonionic trimeric nonylphenol polyoxyethylene (10 can effectively improve the surface activities and the suspension rate and stability of SC compared with its monomer NP10.

Dynamic growth of rhombic dodecahedral Cu2O crystals controlled by reaction temperature and their size-dependent photocatalytic performance.

Compared with low-index {100} or {111} planes of Cu2O crystals, rhombic dodecahedra (RD) Cu2O crystals exposing 12 {110} facets exhibit the most superior photodegradation of organic pollutants. Herein, a series of RD Cu2O crystals with different sizes were successfully synthesized by precisely adjusting the reaction temperature ranging from 40 °C to 100 °C. The results revealed that truncated rhombic dodecahedra (TRD) Cu2O crystals were fabricated when the temperatures was 40 °C. More importantly, on raising the temperature to above 40 °C, Cu2O architectures dynamically evolved from TRD to RD. Meanwhile, the sizes gradually decreased with elevation of the temperature, while the RD morphology of Cu2O crystals remained, demonstrating the importance of temperature for determining the morphology and size of Cu2O crystals. In addition, we also carefully investigated the visible-light photodegradation performance of Cu2O crystals for methyl orange (MO). RD Cu2O crystals exhibited superior photocatalytic activity compared with TRD, and showed size-dependent photocatalytic activity for MO. The photocatalytic activity of RD Cu2O crystals can be greatly improved by decreasing the size. In particular, RD-60 with the minimum size achieved the best photocatalytic properties compared to the other RD and TRD Cu2O crystals, and still displayed high photocatalytic efficiency even after three cycles. Such results advance the understanding that temperature modulation serves as an effective means to fabricate RD Cu2O crystals.

Work function: a determining factor of the photodegradation rate of methyl orange via hollow octadecahedron Cu2O crystals.

Currently, photocatalytic degradation of methyl orange by Cu2O nanocrystals with different morphologies is mainly attributed to their narrow bandgap (Eg) and highly active lattice facets. Herein, three different sizes of hollow octadecahedron Cu2O crystals, with different degrees of exposed {110} facets, were developed and exhibited excellent, stable photocatalytic degradation performances. This study has shown that the intermediates in the photocatalytic degradation process are mainly peroxy radicals from the reaction of excited electrons in the Cu2O conduction band with oxygen molecules adsorbed on the surface. In the photodegradation process of the hollow octadecahedron (HO) Cu2O crystals, the excited-state electrons must break away from the work function restriction before participating in the reaction. HO-2 has achieved the best photocatalytic properties due to its smallest work function as a determining factor affecting the photocatalytic activity.

Interactions of Fipronil within Fish and Insects: Experimental and Molecular Modeling Studies.

Fipronil is an efficient phenylpyrazole insecticide that acts on insect γ-aminobutyric acid (GABA) receptors (GABARs) and has low toxicity to mammals but high toxicity to nontarget organisms such as fish. To develop novel efficient low-toxicity insecticides, it is necessary to determine the detailed toxic mechanism at the molecular target level. In this work, methods including affinity chromatography, fluorescent-labeled binding assays, and molecular modeling were integrated to explore the binding of fipronil to GABARs in fish ( Aristichthys nobilis) and insects ( Musca domestica). Affinity chromatography revealed that fipronil acts on two different subunits of GABARs in fish and M. domestica. Moreover, fluorescence assays revealed that fipronil exhibits similar affinity to the two GABARs. The Kd and Bmax of fipronil binding to the A. nobilis GABAR were 346 ± 6 nmol/L and 40.6 ± 3.5 pmol/mg of protein, respectively. And the Kd and Bmax of fipronil binding to the GABAR in M. domestica brain were 109 ± 9 nM and 21.3 ± 2.5 pmol/mg of protein, respectively. In addition, similar fipronil binding positions but different binding modes were observed in docking studies with Brachydanio rerio var. and M. domestica GABARs. These findings indicated similar interactions of fipronil with fish and insects, leading to high toxicity. The different binding features of fipronil between the two species might be helpful for the design and development of highly selective insecticides with low toxicity to fish.

Utilization of the fermentation residues of validamycin as a potential platform for seed treatment.

Seed coating is a versatile means to control crop pests and diseases, which can effectively reduce pesticide quantity and improve pesticide efficacy. Herein, 6% tebuconazole flowable concentrate for seed treatment (FS) was prepared by using the validamycin fermentation residue (VFR) as a pesticide carrier. Then, the effects of the VFR and dispersants on the physicochemical properties of the FS were systematically evaluated. Moreover, the germination rate and antibacterial performance of wheat seeds coated with FS were investigated through a bioactivity experiment. The experimental results show that the FS prepared by VFR, dispersant SD-816 and NNO exhibits superior suspension stability. The suspension rates at 1 h and 24 h are 99.78% and 95.11% respectively. Furthermore, the viscosity of the system only slightly changes after 30 days. In addition, the obtained FS system exhibits shear thinning behavior under high speed shearing showing typical features of pseudo-plastic non-Newtonian fluids, which conforms to the Herschel-Buckley model. A bioactivity experiment showed the germination rate of coated wheat seeds reached 90%, and increased by 7.0% and 3.0% compared to the control group and positive control Raxil respectively. Futhermore, the antibacterial rate reached 80.5%, and was higher than the control group and Raxil. In addition, the obtained FS was very efficacious in controlling wheat powdery mildew compared to the commercial formulation Raxil.

Biotemplate-directed fabrication of size-controlled monodisperse magnetic silica microspheres.

Biotemplating is an effective strategy to obtain morphology-controllable materials with structural specificity, complexity, and corresponding unique functions. Herein we take advantage of the unique heavy-metal-ion biosorption behavior of cyanobacteria cells to fabricate Fe3O4/cell composites. Meanwhile, cyanobacteria cells served as a biotemplate for fabricating solid and hollow magnetic silica microspheres (MSMs). The obtained MSMs retained the original morphology of the cells, and exhibited excellent monodispersity and uniform spherical shape with narrow size distribution. Furthermore, they demonstrated ferromagnetic behavior at room temperature when measured using a vibrating sample magnetometer.

Enhanced delivery of artemisinin and its analogues to cancer cells by their adducts with human serum transferrin.

Artemisinin (ART) and its analogues, such as dihydroartesunate (DHA) and artesunate (ATS), are sesquiterpene lactones with anticancer activities. Transferrin (Tf) receptor is frequently overexpressed in cancer cells. In order to improve the delivery and the anticancer activity of ART and its analogues, adducts of Tf with ART, DHA or ATS were fabricated by simply combining ART, DHA or ATS with Tf. Increased antitumor effects of these adducts were observed on human liver hepatocellular carcinoma (HepG2) and lung adenocarcinoma (A549) cells. Meanwhile, only a low level of toxic effect was observed on normal human liver cells (HL-7702). Improved cellular uptake of ATS-Tf adduct compared to ATS alone was confirmed by HPLC analysis. UV-vis, fluorescence spectroscopy and docking study further confirmed the formation of the adducts with relatively high binding constants at neutral pH (7.4×10(4), 4.2×10(5) and 3.4×10(5)M(-1), for ART-Tf, DHA-Tf and ATS-Tf, respectively, at pH 7.4). However, the adducts became less stable with reduced binding constants under an acidic condition (2.6×10(4), 1.9×10(4) and 1.7×10(4)M(-1), for ART-Tf, DHA-Tf and ATS-Tf, respectively, at pH 5.5). A possible mechanism of the anticancer effect by these adducts was proposed. The short term and long term stability of ART-Tf in the presence of human serum albumin (HSA) was also studied. Our results showed that adducts of ART and its analogues with Tf, especially ATS-Tf and DHA-Tf, have significant anticancer effects to cancer cells, with minimal side effects on normal cells, therefore, are promising as potential novel anticancer agents.

Utilization of environmental waste cyanobacteria as a pesticide carrier: studies on controlled release and photostability of avermectin.

Cyanobacteria (Cyb), an environment waste, was first utilized as a carrier for controlled release of avermectin (Av) and improvement of pesticide photostability. Microalgae powder prepared from Cyb blooms was characterized by elemental analysis (EA), X-ray photoelectron spectroscopy (XPS), infrared spectroscopy (IR), optical microscopy, and scanning electron microscopy (SEM). The globular morphology and the size (~3.5µm) of Cyb do not change significantly, with increase of roughness, after Av adsorption and Carbopol coating. Av manifests considerable binding affinity to Cyb in isopropanol and adsorption decreases in more polar solvents at 25°C. An extended release of Av from Cyb-Av in ethanol/water (v/v, 4:1) mixture was obtained and the release was further controlled by the Carbopol resin coated on Cyb-Av. Thicker Carbopol coating results in larger lag time (t(0)), slower release rate, and less total release amount. The release process was found to be controlled by a diffusion mechanism, but was strongly affected by polymer matrix-Av interaction and polymer relaxation. Finally, adsorbed Av on Cyb exhibits much greater UV-stability than free Av.

Investigating the putative binding-mode of GABA and diazepam within GABA A receptor using molecular modeling.

The three-dimensional structure of the GABA A receptor that included the ligand/agonist binding site was constructed and validated by using molecular modeling technology. Moreover, the putative binding-mode of GABA and diazepam with GABAA receptor were investigated by means of docking studies. Based on an rmsd-tolerance of 1.0 angstroms, the docking of GABA to alpha1/beta2 interface resulted in three multi-member conformational clusters and model 2 was supported by homologous sequence alignment data and experimental evidence. On the other hand, the docking of diazepam to alpha1/gamma2 interface revealed five multi-member conformational clusters in the binding site and model 1 seemed to represent the correct orientation of diazepam in the binding site.

Modeling of alphak/gamma2 (k=1, 2, 3 and 5) interface of GABA A receptor and docking studies with zolpidem: implications for selectivity.

The three-dimensional models of the alphak/gamma2 (k=1, 2, 3 and 5) interface of GABA(A) receptors, which included the agonist-binding site, were constructed and validated by molecular modeling technology. To investigate the mechanism of alpha subunit selectivity of zolpidem, docking calculations were used to illustrate the potential binding modes of zolpidem with different alpha subtypes. The results revealed that there were three reasons resulting in the distinct binding affinity of zolpidem to different alpha subtype. Firstly, the number of hydrogen bonds of agonist-receptor complex would determine the magnitude of binding affinity. Secondly, the His residue in loop A of alpha subunit was indicated as a key role of benzodiazepine binding. Thirdly, the side chain of Glu in loop C reduced the affinity of zolpidem to those receptors containing alpha2, alpha3 or alpha5 subunits.

Modeling the interaction of fipronil-related non-competitive antagonists with the GABA beta3-receptor.

A three-dimensional model of the beta3-homopentamer of the gamma-aminobutyric acid (GABA) receptor/chloride ionophore complex was developed by homology modeling using the cyro-electron microscopy structure of nicotinic acetylcholine as a template. Interactions between the beta3-homopentamer and two classes of fipronil-related non-competitive antagonists were investigated using docking studies. The phenyl groups of these compounds were stabilized by strong hydrophobic and hydrophilic interactions with the rings formed by Thr256 and Ala252. Leu253 and Ile255 were involved mainly in hydrophobic contact with the pyrazole moiety. Different substitution at positions 15, 16 and 17 of the pyrazole ring of fipronil resulted in weakening of the hydrogen bonds and hydrophobic interactions between the beta3-receptor and fipronil-related heterocyclic compounds, which maybe the principal cause of the decreased affinities reported in vitro. Moreover, a good correlation between total binding energies calculated by AutoDock and experimentally determined IC(50) values proved our models to be reasonable in predicting the interaction mode of the antagonist with the GABA beta3-receptor.