Impact of rosuvastatin on pulse-wave velocity in men with HIV at moderate cardiovascular risk.

This single-centre substudy of a double-blind, randomized, placebo-controlled trial aimed to determine the effect of 96 weeks of rosuvastatin on pulse wave velocity (PWV) in men (n = 55, 54 years) with HIV at moderate cardiovascular risk (Framingham risk score 10-15%). PWV increased in both rosuvastatin [0.54 m/s standard error of difference (SED) 0.26] and placebo [0.50 m/s (SED 0.26), P = 0.896] arms, leading to no difference in PWV at week 96 [rosuvastatin 9.40 m/s (SE 0.31); placebo 9.21 m/s (SE0.31), P = 0.676].

Antagonism of propofol anesthesia by alkyl-fluorobenzene derivatives.

Despite their frequent use across many clinical settings, general anesthetics are medications with lethal side effects and no reversal agents. A fluorinated analogue of propofol has previously been shown to antagonize propofol anesthesia in tadpoles and zebrafish, but little further investigation of this class of molecules as anesthetic antagonists has been conducted. A 13-member library of alkyl-fluorobenzene derivatives was tested in an established behavioral model of anesthesia in zebrafish at 5 days post fertilization. These compounds were examined for their ability to antagonize propofol and two volatile anesthetics, as well as their interaction with the anesthetic-binding model protein apoferritin. Two compounds provided significant antagonism of propofol, and when combined, were synergistic, suggesting more than one antagonist sensitive target site. These compounds did not antagonize the volatile anesthetics, indicating some selectivity amongst general anesthetics. For the compounds with the most antagonistic potency, similarities in structure and binding to apoferritin may be suggestive of competitive antagonism; however, this was not supported by a Schild analysis. This is consistent with multiple targets contributing to general anesthesia, but whether these are physiologic antagonists or are antagonists at only some subset of the many anesthetic potential targets remains unclear, and will require additional investigation.

Community end user perceptions of hessian fabric transfluthrin vapour emanators for protecting against mosquitoes under conditions of routine use in Port-au-Prince, Haiti.

BACKGROUND: A treated fabric device for emanating the volatile pyrethroid transfluthrin was recently developed in Tanzania that protected against night-biting Anopheles and Culex mosquitoes for several months. Here perceptions of community end users provided with such transfluthrin emanators, primarily intended to protect them against day-active Aedes vectors of human arboviruses that often attack people outdoors, were assessed in Port-au-Prince, Haiti. METHODS: Following the distribution of transfluthrin emanators to participating households in poor-to-middle class urban neighbourhoods, questionnaire surveys and in-depth interviews of end-user households were supplemented with conventional and Photovoice-based focus group discussions. Observations were assessed synthetically to evaluate user perceptions of protection and acceptability, and to solicit advice for improving and promoting them in the future. RESULTS: Many participants viewed emanators positively and several outlined various advantages over current alternatives, although some expressed concerns about smell, health hazards, bulkiness, unattractiveness and future cost. Most participants expressed moderate to high satisfaction with protection against mosquitoes, especially indoors. Protection against other arthropod pests was also commonly reported, although satisfaction levels were highly variable. Diverse use practices were reported, some of which probably targeted nocturnal Culex resting indoors, rather than Aedes attacking them outdoors during daylight hours. Perceived durability of protection varied: While many participants noted some slow loss over months, others noted rapid decline within days. A few participants specifically attributed efficacy loss to outdoor use and exposure to wind or moisture. Many expressed stringent expectations of satisfactory protection levels, with even a single mosquito bite considered unsatisfactory. Some participants considered emanators superior to fans, bedsheets, sprays and coils, but it is concerning that several preferred them to bed nets and consequently stopped using the latter. CONCLUSIONS: The perspectives shared by Haitian end-users are consistent with those from similar studies in Brazil and recent epidemiological evidence from Peru that other transfluthrin emanator products can protect against arbovirus infection. While these encouraging sociological observations contrast starkly with evidence of essentially negligible effects upon Aedes landing rates from parallel entomological assessments across Haiti, Tanzania, Brazil and Peru, no other reason to doubt the generally encouraging views expressed herein by Haitian end users could be identified.

Mosquito Shield™, a transfluthrin passive emanator, protects against pyrethroid-resistant Anopheles gambiae sensu lato in central Benin.

BACKGROUND: Spatial repellents can provide personal and household protection against biting vector mosquitoes by volatizing repellents into the air within a given area. Mosquito Shield™ is a transfluthrin passive emanator undergoing evaluation for malaria control. Studies evaluating its entomological impact against different local malaria vector populations would help guide its deployment in endemic countries. METHODS: A two-arm single-blinded small-scale household randomised entomological trial was conducted to assess the impact of Mosquito Shield™ on the human landing rate of wild pyrethroid-resistant Anopheles gambiae sensu lato (s.l.) vector mosquitoes in houses in the Ganhoua village of the Zakpota District of central Benin. From a total of 30 houses, 15 were randomly allocated to receive Mosquito Shield™, while the remainder received a placebo product. The trial lasted through the life of the Mosquito Shield™ product (32 days). Mosquito sampling was performed by human landing catches at baseline and at 6 timepoints post-intervention (days 0-1, 7-8, 14-15, 21-22, 28-29 and 31-32). Collections were performed for 2 nights at each sampling time point. WHO cylinder bioassays were conducted during the trial with F1 An. gambiae s.l. mosquitoes that emerged from larvae from the study area to assess the intensity of resistance to pyrethroids in the wild vector population. RESULTS: The vector population in the study area showed a high intensity of resistance to pyrethroids. Baseline An. gambiae s.l. human landing rates were similar in houses in both study arms before product application (11.53/person/night vs 11.67/person/night, p > 0.05). A total of 5736 mosquitoes were collected in the placebo control arm and 3862 in the Mosquito Shield™ arm post-intervention. Overall An. gambiae s.l. post-intervention human landing rates were significantly lower in houses in the Mosquito Shield™ arm (18.13/person/night) compared to the houses in the placebo control arm (26.84/person/night, IRR = 0.658, p < 0.001). Over the lifespan of the product, Mosquito Shield™ provided a significant protective efficacy of 34.2% (22.1-44.4%, p < 0.001) against wild pyrethroid-resistant An. gambiae s.l. vectors compared to the placebo. Human landing rates of other nuisance vector mosquito species (Culex and Mansonia) were also reduced in houses treated with Mosquito Shield™ compared to the placebo. CONCLUSION: Mosquito Shield™, a transfluthrin passive emanator, provided significant protection against pyrethroid-resistant malaria vectors to households in Benin. The spatial repellent shows potential to reduce malaria transmission by pyrethroid-resistant An. gambiae s.l. vector mosquitoes and cover gaps in malaria control when deployed to complement existing vector control interventions.

Field evaluation of a volatile pyrethroid spatial repellent and etofenprox treated clothing for outdoor protection against forest malaria vectors in Cambodia.

Cambodia's goal to eliminate malaria by 2025 is challenged by persistent transmission in forest and forest fringe areas, where people are exposed to Anopheles mosquito bites during the day and night. Volatile pyrethroid spatial repellents (VPSRs) and insecticide-treated clothing (ITC) could address these gaps. This study evaluated the outdoor application of one passive transfluthrin-based VPSR, four etofenprox-ITCs paired with a picaridin topical repellent, and a combination of VPSR and ITC against wild Anopheles landing in Cambodia. A 7 × 7 Latin-square study was conducted over 49 collection nights in temporary open structures in Mondulkiri Province. All interventions substantially reduced Anopheles landing, with protective efficacy ranging from 61 to 95%. Mathematical modeling showed significant reductions in vectoral capacity, especially with the combined ITC and VPSR and VPSR alone, albeit with decreased effectiveness over time. These interventions have the potential to reduce outdoor and daytime Anopheles biting, offering valuable contributions to malaria elimination efforts in Cambodia and the Greater Mekong Subregion, contingent upon achieving effective coverage and adherence.

Entomological assessment of hessian fabric transfluthrin vapour emanators for protecting against outdoor-biting Aedes aegypti in coastal Tanzania.

BACKGROUND: A low technology emanator device for slowly releasing vapour of the volatile pyrethroid transfluthrin was recently developed in Tanzania that provides robust protection against night biting Anopheles and Culex vectors of malaria and filariasis for several months. Here these same emanator devices were assessed in Dar es Salaam city, as a means of protection against outdoor-biting Aedes (Stegomia) aegypti, the most important vector of human arboviruses worldwide, in parallel with similar studies in Haiti and Brazil. METHODS: A series of entomological experiments were conducted under field and semi-field conditions, to evaluate whether transfluthrin emanators protect against wild Ae. aegypti, and also compare the transfluthrin responsiveness of Ae. aegypti originating from wild-caught eggs to established pyrethroid-susceptible Ae. aegypti and Anopheles gambiae colonies. Preliminary measurements of transfluthrin vapour concentration in air samples collected near treated emanators were conducted by gas chromatography-mass spectrometry. RESULTS: Two full field experiments with four different emanator designs and three different transfluthrin formulations consistently indicated negligible reduction of human landing rates by wild Ae. aegypti. Under semi-field conditions in large cages, 50 to 60% reductions of landing rates were observed, regardless of which transfluthrin dose, capture method, emanator placement position, or source of mosquitoes (mildly pyrethroid resistant wild caught Ae. aegypti or pyrethroid-susceptible colonies of Ae. aegypti and An. gambiae) was used. Air samples collected immediately downwind from an emanator treated with the highest transfluthrin dose (15g), contained 12 to 19 µg/m3 transfluthrin vapour. CONCLUSIONS: It appears unlikely that the moderate levels of pyrethroid resistance observed in wild Ae. aegypti can explain the modest-to-undetectable levels of protection exhibited. While potential inhalation exposure could be of concern for the highest (15g) dose evaluated, 3g of transfluthrin appears sufficient to achieve the modest levels of protection that were demonstrated entomologically. While the generally low levels of protection against Aedes reported here from Tanzania, and from similar entomological studies in Haiti and Brazil, are discouraging, complementary social science studies in Haiti and Brazil suggest end-users perceive valuable levels of protection against mosquitoes. It therefore remains unclear whether transfluthrin emanators have potential for protecting against Aedes vectors of important human arboviruses.

Evaluating human landing catches as a measure of mosquito biting and the importance of considering additional modes of action.

Entomological evaluations of vector control tools often use human landing catches (HLCs) as a standard measure of a direct human-vector contact. However, some tools have additional characteristics, such as mortality, and HLCS are not sensitive for measuring other effects beyond landing inhibition. Therefore, additional measures may need to be considered when evaluating these tools for public health use. This study has two main aims (1) the evaluate the accuracy of HLCs as a proxy for feeding and (2) to compare the predicted reduction in vectorial capacity when we do and do not consider these additional characteristics. To achieve this, we analyse previously published semi-field data from an experiment which used HLCs and another where mosquitoes were allowed to feed in the presence of different dosages of the volatile pyrethroid spatial repellent, transfluthrin. We compare results for two mathematical models: one which only considers the reduction in feeding effect and one which also considers mortality before and after feeding (using data gathered by the aspiration of mosquitoes after the semi-field feeding/landing period and 24 h survival monitoring). These Bayesian hierarchical models are parameterised using Bayesian inference. We observe that, for susceptible mosquitoes, reduction in landing is underestimated by HLCs. For knockdown resistant mosquitoes the relationship is less clear; with HLCs sometimes appearing to overestimate this characteristic. We find HLCs tend to under-predict the relative reduction in vectorial capacity in susceptible mosquitoes while over-predicting this impact in knockdown-resistant mosquitoes. Models without secondary effects have lower predicted relative reductions in vectorial capacities. Overall, this study highlights the importance of considering additional characteristics to reduction in biting of volatile pyrethroid spatial repellents. We recommend that these are considered when evaluating novel vector control tools.

Entomological assessment of hessian fabric transfluthrin vapour emanators as a means to protect against outdoor-biting Aedes after providing them to households for routine use in Port-au-Prince, Haiti.

BACKGROUND: A simple treated fabric device for passively emanating the volatile pyrethroid transfluthrin was recently developed in Tanzania that protected against nocturnal Anopheles and Culex mosquitoes for several months. Here these transfluthrin emanators were assessed in Port-au-Prince, Haiti against outdoor-biting Aedes. METHODS: Transfluthrin emanators were distributed to participating households in poor-to-middle class urban neighbourhoods and evaluated once every two months in terms of their effects on human landing rates of wild Aedes populations. A series of three such entomological assessment experiments were conducted, to examine the influence of changing weather conditions, various transfluthrin formulations and emanator placement on protective efficacy measurements. Laboratory experiments assessed resistance of local Aedes aegypti to transfluthrin and deltamethrin, and the irritancy and repellency of the transfluthrin-treated fabric used in the field. RESULTS: Across all three entomological field assessments, little evidence of protection against wild Ae. aegypti was observed, regardless of weather conditions, transfluthrin formulation or emanator placement: A generalized linear mixed model fitted to the pooled data from all three assessment rounds (921 females caught over 5129 hours) estimated a relative landing rate [95% Confidence interval] of 0.87 [0.73, 1.04] for users of treated versus untreated emanators (P = 0.1241). Wild Ae. aegypti in this setting were clearly resistant to transfluthrin when compared to a fully susceptible colony. CONCLUSIONS: Transfluthrin emanators had little if any apparent effect upon Aedes landing rates by wild Ae. aegypti in urban Haiti, and similar results have been obtained by comparable studies in Tanzania, Brazil and Peru. In stark contrast, however, parallel sociological assessments of perspectives among these same end-users in urban Haitian communities indicate strong satisfaction in terms of perceived protection against mosquitoes. It remains unclear why the results obtained from these complementary entomological and sociological assessments in Haiti differ so much, as do those from a similar set of studies in Brazil. It is encouraging, however, that similar contrasts between the entomological and epidemiological results of a recent large-scale assessment of another transfluthrin emanator product in Peru, which indicate they provide useful protection against Aedes-borne arboviral infections, despite apparently providing only modest protection against Aedes mosquito bites.

A complementary method with PFBBr-derivatization based on a GC-EI-MS platform for the simultaneous quantitation of short-, medium- and long-chain fatty acids in murine plasma and feces samples.

Fatty acids (FAs) are essential molecules in all organisms and are involved in various physiological and pathophysiological processes. Pentafluorobenzyl bromide (PFBBr) is commonly used for FA derivatization for gas chromatography-mass spectrometry (GC-MS) quantification by chemical ionization (CI). While CI is the conventional ionization mode for PFBBr derivatization, the electron ionization (EI) source has also demonstrated efficacy in achieving satisfactory analytical performance for the analysis of PFB esters. In this study, we present a novel approach utilizing PFBBr-derivatization on a GC-EI-MS platform to quantitatively analyze a comprehensive range of 44 fatty acids (FAs) spanning from C2 to C24. The method's sensitivity, precision, accuracy, linearity, recovery, and matrix effect were rigorously validated against predetermined acceptance criteria. In comparison to the conventional CI ionization mode, the utilization of PFBBr-derivatization in GC-EI-MS exhibits a wider range of applications and achieves comparable sensitivity levels to the conventional CI platform. By using this method, we successfully quantified 44 FAs in plasma and feces samples from the mice with deoxynivalenol (DON)-induced kidney injury. Among these, the levels of most FA species were increased in the DON-exposure group compared with the control group. The orthogonal partial least squares discriminant analysis (OPLS-DA) of all the tested FAs showed a visual separation of the two groups, indicating DON exposure resulted in a disturbance of the FA profile in mice. These results indicate that the established method by integration of GC-MS with PFBBr derivatization is an efficient approach to quantify the comprehensive FA profile, which includes short-, medium- and long-chain FAs. In addition, our study provides new insights into the mechanism underlying DON exposure-induced kidney injury.

5-HT 2A and 5-HT 2C receptor antagonism differentially modulate reinforcement learning and cognitive flexibility: behavioural and computational evidence.

RATIONALE: Cognitive flexibility, the ability to adapt behaviour in response to a changing environment, is disrupted in several neuropsychiatric disorders, including obsessive-compulsive disorder and major depressive disorder. Evidence suggests that flexibility, which can be operationalised using reversal learning tasks, is modulated by serotonergic transmission. However, how exactly flexible behaviour and associated reinforcement learning (RL) processes are modulated by 5-HT action on specific receptors is unknown. OBJECTIVES: We investigated the effects of 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR) antagonism on flexibility and underlying RL mechanisms. METHODS: Thirty-six male Lister hooded rats were trained on a touchscreen visual discrimination and reversal task. We evaluated the effects of systemic treatments with the 5-HT2AR and 5-HT2CR antagonists M100907 and SB-242084, respectively, on reversal learning and performance on probe trials where correct and incorrect stimuli were presented with a third, probabilistically rewarded, stimulus. Computational models were fitted to task choice data to extract RL parameters, including a novel model designed specifically for this task. RESULTS: 5-HT2AR antagonism impaired reversal learning only after an initial perseverative phase, during a period of random choice and then new learning. 5-HT2CR antagonism, on the other hand, impaired learning from positive feedback. RL models further differentiated these effects. 5-HT2AR antagonism decreased punishment learning rate (i.e. negative feedback) at high and low doses. The low dose also decreased reinforcement sensitivity (beta) and increased stimulus and side stickiness (i.e., the tendency to repeat a choice regardless of outcome). 5-HT2CR antagonism also decreased beta, but reduced side stickiness. CONCLUSIONS: These data indicate that 5-HT2A and 5-HT2CRs both modulate different aspects of flexibility, with 5-HT2ARs modulating learning from negative feedback as measured using RL parameters and 5-HT2CRs for learning from positive feedback assessed through conventional measures.

Distinct effects of rosuvastatin and rosuvastatin/ezetimibe on senescence markers of CD8+ T cells in patients with type 2 diabetes mellitus: a randomized controlled trial.

Objectives: Chronic low-grade inflammation is widely recognized as a pathophysiological defect contributing to ß-cell failure in type 2 diabetes mellitus (T2DM). Statin therapy is known to ameliorate CD8+ T cell senescence, a mediator of chronic inflammation. However, the additional immunomodulatory roles of ezetimibe are not fully understood. Therefore, we investigated the effect of statin or statin/ezetimibe combination treatment on T cell senescence markers. Methods: In this two-group parallel and randomized controlled trial, we enrolled 149 patients with T2DM whose low-density lipoprotein cholesterol (LDL-C) was 100 mg/dL or higher. Patients were randomly assigned to either the rosuvastatin group (N=74) or the rosuvastatin/ezetimibe group (N=75). The immunophenotype of peripheral blood mononuclear cells and metabolic profiles were analyzed using samples from baseline and post-12 weeks of medication. Results: The fractions of CD8+CD57+ (senescent CD8+ T cells) and CD4+FoxP3+ (Treg) significantly decreased after intervention in the rosuvastatin/ezetimibe group (-4.5 ± 14.1% and -1.2 ± 2.3%, respectively), while these fractions showed minimal change in the rosuvastatin group (2.8 ± 9.4% and 1.4 ± 1.5%, respectively). The degree of LDL-C reduction was correlated with an improvement in HbA1c (R=0.193, p=0.021). Changes in the CD8+CD57+ fraction positively correlated with patient age (R=0.538, p=0.026). Notably, the fraction change in senescent CD8+ T cells showed no significant relationship with changes in either HbA1c (p=0.314) or LDL-C (p=0.592). Finally, the ratio of naïve to memory CD8+ T cells increased in the rosuvastatin/ezetimibe group (p=0.011), but not in the rosuvastatin group (p=0.339). Conclusions: We observed a reduction in senescent CD8+ T cells and an increase in the ratio of naive to memory CD8+ T cells with rosuvastatin/ezetimibe treatment. Our results demonstrate the immunomodulatory roles of ezetimibe in combination with statins, independent of improvements in lipid or HbA1c levels.

The psychomotor, reinforcing, and discriminative stimulus effects of synthetic cathinone mexedrone in male mice and rats.

The chronic use of the novel synthetic cathinone mexedrone, like other psychoactive drugs, can be considered addictive, with a high potential for abuse and the ability to cause psychological dependence in certain users. However, little is known about the neurobehavioral effects of mexedrone in association with its potential for abuse. We investigated the abuse potential for mexedrone abuse through multiple behavioral tests. In addition, serotonin transporter (SERT) levels were measured in the synaptosome of the dorsal striatum, and serotonin (5-HT) levels were measured in the dorsal striatum of acute mexedreone (50 mg/kg)-treated mice. To clarify the neuropharmacological mechanisms underlying the locomotor response of mexedrone, the 5-HT2A receptor antagonist M100907 (0.5 or 1.0 mg/kg) was administered prior to the acute injection of mexedrone in the locomotor activity experiment in mice. Mexedrone (10-50 mg/kg) produced a significant place preference in mice and mexedrone (0.1-0.5 mg/kg/infusion) maintained self-administration behavior in rats in a dose-dependent manner. In the drug discrimination experiment, mexedrone (5.6-32 mg/kg) was fully substituted for the discriminative stimulus effects of cocaine in rats. Mexedrone increased locomotor activity, and these effects were reversed by pretreatment with M100907. Acute mexedrone significantly increased c-Fos expression in the dorsal striatum and decreased SERT levels in the synaptosome of the dorsal striatum of mice, resulting in an elevation of 5-HT levels. Taken together, our results provide the possibility that mexedrone has abuse potential, which might be mediated, at least in part, by the activation of the serotonergic system in the dorsal striatum.

Green infant formula analysis: Optimizing headspace solid-phase microextraction of carbonyl compounds associated with lipid peroxidation using GC-MS and pentafluorophenylhydrazine derivatization.

The refinement and optimization of a method combining headspace solid-phase microextraction (HS-SPME) with gas chromatography-mass spectrometry (GC-MS) was successfully performed for the first time to determine seven carbonyl and dicarbonyl compounds, including glyoxal, methylglyoxal, dimethylglyoxal, and malondialdehyde in infant formulae, related to lipid peroxidation. HS-SPME was utilized for simultaneous extraction and derivatization with pentafluorophenylhydrazine (PFPH). Critical parameters such as temperature, pH, extractive phase, and salting-out were meticulously investigated and fine-tuned by an asymmetrical 2232//9 screening design to ensure the method's efficacy and reliability. Optimal conditions included a PFPH concentration of 5 g/L, pH 5.0, head-space extraction at 60 °C within 10 min, utilizing a DVB/CAR/PDMS coating, and a 20% w/w salting-out. The analytical validation of this method, compliant with FDA guidelines, demonstrated exceptional linearity, sensitivity, specificity, precision (RSD ≤13.8%), and accuracy (84.8% ≤ recovery ≤111.5%). The metric approach AGREEprep confirms its eco-friendliness, marking a significant step towards an environmentally conscious approach in infant formula analysis. An occurrence study conducted on 25 infant formula samples revealed widespread carbonyl and dicarbonyl compounds in both powdered and liquid variants. ANOVA results exhibited variations in compound concentrations among different sample groups. Clustering analyses delineated distinct groups based on carbonyl content, indicating the potential of these compounds as markers for lipid peroxidation and food quality assessment. This method serves as a valuable tool for evaluating infant formula quality, stability towards oxidation, and safety.

Fecundity decline is male derived following transfluthrin exposures in a field strain of Aedes albopictus (Diptera: Culicidae).

Volatile pyrethroids are effective in reducing mosquito populations and repelling vectors away from hosts. However, many gaps in knowledge exist for the sublethal impacts of volatile pyrethroids on mosquitoes. To that end, transfluthrin exposures were conducted on a field strain of Aedes albopictus (Skuse) held as a laboratory colony. Dose-response analysis was conducted on both sexes at either 1-4 days old or 5-10 days old. Resultant concentration data were used to evaluate the LC20 and LC50 values in various mate pairings of treatments and controls in which either the male or female was from a selectively treated group and mated with a counterpart that was treated independently. Blood feeding proportion, delayed mortality after a 24-h recovery period, egg collection totals, and F1 larval survival were determined following transfluthrin treatment in the F0, but outcomes were not significant. In contrast, sterility was predicated on male treatment, with treated females resulting in higher overall egg viability. Treated males in the mating pair resulted in significantly lower egg viability and accelerated larval hatch in the F1. Additionally, the presence of sperm in female spermathecae was significantly diminished in test groups containing treated male mosquitoes. Male sublethal effects may be a critical determinant of a mixed population's reproductive success.

The novel non-hallucinogenic compound DM506 (3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole) induces sedative- and anxiolytic-like activity in mice by a mechanism involving 5-HT2A receptor activation.

The anxiolytic and sedative-like effects of 3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (DM506), a non-hallucinogenic compound derived from ibogamine, were studied in mice. The behavioral effects were examined using Elevated O-maze and novelty suppressed feeding (NSFT) tests, open field test, and loss of righting reflex (LORR) test. The results showed that 15 mg/kg DM506 induced acute and long-lasting anxiolytic-like activity in naive and stressed/anxious mice, respectively. Repeated administration of 5 mg/kg DM506 did not cause cumulative anxiolytic activity or any side effects. Higher doses of DM506 (40 mg/kg) induced sedative-like activity, which was inhibited by a selective 5-HT2A receptor antagonist, volinanserin. Electroencephalography results showed that 15 mg/kg DM506 fumarate increased the transition from a highly alert state (fast γ wavelength) to a more synchronized deep-sleeping activity (δ wavelength), which is reflected in the sedative/anxiolytic activity in mice but without the head-twitch response observed in hallucinogens. The functional, radioligand binding, and molecular docking results showed that DM506 binds to the agonist sites of human 5-HT2A (Ki = 24 nM) and 5-HT2B (Ki = 16 nM) receptors and activates them with a potency (EC50) of 9 nM and 3 nM, respectively. DM506 was relatively less potent and behaved as a partial agonist (efficacy <80%) for both receptor subtypes compared to the full agonist DOI (2,5-dimethoxy-4-iodoamphetamine). Our study showed for the first time that the non-hallucinogenic compound DM506 induces anxiolytic- and sedative-like activities in naïve and stressed/anxious mice in a dose-, time-, and volinanserin-sensitive manner, likely through mechanisms involving 5-HT2A receptor activation.

Effects of mosquito age and batch size on knockdown and mortality of laboratory-reared Anopheles dirus, Anopheles minimus, and wild-caught Anopheles harrisoni (Diptera: Culicidae) exposed to transfluthrin using WHO tube and CDC bottle bioassays.

WHO tube and CDC bottle bioassays are currently available for insecticide resistance monitoring and malaria transmission research. Multiple parameters including mosquito density, age, and nutritional status may affect the readout in these bioassays' tests. This study aims to assess the effects of experimental factors on knockdown and mortality measurements in dominant malaria vectors in Thailand following exposure to sublethal and lethal doses of transfluthrin. The effects of (i) 3 different mosquito batch sizes (5, 10, and 20 individuals) and (ii) 2 age groups (3-5 and 20-23 days old) on outcomes measured using the WHO tube (14.7 µg/cm2) and CDC bottle bioassay discriminating concentration (0.006 µg/cm2) against 2 laboratory strains: Anopheles dirus Peyton & Harrison and Anopheles minimus Theobald (species A) and wild-caught Anopheles harrisoni Harbach & Manguin (species C). Our results showed higher knockdown at 1-h exposure using WHO tube and CDC bottle bioassays containing 20 individuals compared to batches containing 10 and 5 individuals. Older mosquitoes showed greater susceptibility than younger test population, especially for An. mininus. Our study supports WHO recommendations for using 3- to 5-day-old mosquitoes. It also validates Praulin et al. (2022) proposal to divide the cohort into smaller batches with more test replicates when it is not practicable to test 25 mosquitoes per replicate.

Impact of a spatial repellent intervention on Anopheles kdr insecticide resistance allele in Sumba, Indonesia.

BACKGROUND: The emergence of insecticide resistance and outdoor transmission in malaria-endemic areas underlines the urgent need to develop innovative tools, such as spatial repellents (SR), that may circumvent this residual transmission. With limited options for effective insecticides, regular resistance monitoring is warranted for selecting and using appropriate tools. This study evaluates the pyrethroid knockdown resistance (kdr) allele before and after implementing a transfluthrin-based spatial repellent (SR) intervention in placebo-treated clusters. METHODS: This study looks at the frequency distribution of the kdr allele in Sumba Island from June 2015 to August 2018. Insecticide susceptibility tests were carried out on female Anopheles sp. aged 3-5 days against permethrin 21.5 µg/ml, deltamethrin 12.5 µg/ml, and transfluthrin 10 µg/ml using CDC bottle assay. PCR sequencing of representative samples from adult mosquito collections and insecticide tests revealed the presence of kdr mutations (L1014F and L1014S) in the VGSC gene. RESULTS: A total of 12 Anopheles species, Anopheles tesselatus, Anopheles. aconitus, Anopheles barbirostris, Anopheles kochi, Anopheles annularis, Anopheles maculatus, Anopheles sundaicus, Anopheles flavirostris, Anopheles balabacensis, Anopheles indefinitus, Anopheles subpictus, and Anopheles vagus were analysed. Anopheles vagus and An. sundaicus predominated in the larval populations. Susceptibility assays for all insecticides identified fully susceptible phenotypes in all species examined. Anopheles increasing frequency of kdr mutant alleles during the 3 year SR deployment was observed in both SR-treated and placebo areas, a statistically significant increase occurred in each arm. However, it is unclear how significant SR is in causing the increase in mutant alleles. The L1014S, knockdown resistance east type (kdr-e) allele was detected for the first time among the mosquito samples in this study. The L1014F, knockdown resistance west type (kdr-w) allele and heteroduplex form (wild-type-mutant) were found in almost all Anopheles species examined, including An. vagus, An. aconitus, An. subpictus, An. tesselatus, An. annularis, An. flavirostris and An. sundaicus. CONCLUSION: The presence of fully susceptible phenotypes over time, along with an increase in the frequency distribution of the L1014F/S mutations post-intervention, suggest drivers of resistance external to the study, including pyrethroid use in agriculture and long-lasting insecticidal nets (LLINs). However, this does not negate possible SR impacts that support resistance. More studies that enable the comprehension of possible SR-based drivers of resistance in mosquitoes need to be conducted.

Effects of transfluthrin-treated jute and cotton clothing against resistant and susceptible Aedes aegypti (Diptera: Culicidae) in a semifield system.

Volatile pyrethroids exert a range of both lethal and behavioral effects on mosquitoes through the passive release of insecticides into the atmosphere. We investigated the protective efficacy (PE) of transfluthrin-treated jute (TI-jute) and cotton (TI-cotton) fabrics, worn at the back of a protective black vest, against laboratory-reared pyrethroid susceptible and resistant strains of Aedes aegypti (L.) in a semifield system (SFS). Each fabric (1,029 cm2) was treated with 1.79 mg/cm2 of transfluthrin as the intervention. Human landing collections were conducted by 2 collectors seated in designated treatment and control compartments of the SFS. The trials were conducted for 41 days, with 16 days partitioned into morning and evening phases. Furthermore, we examined blood feeding behavior and fecundity of the surviving mosquitoes post-exposure. Results showed that in the morning, the PE of TI-jute (49.4%) was higher than that of TI-cotton (36.8%). TI-jute demonstrated a lower PE of 9.6% against the transfluthrin-resistant strain. Remarkably, a significantly higher number of eggs were laid by the transfluthrin-resistant mosquitoes that survived the intervention (36.5 eggs/female) compared to the control group (11.8 eggs/female). These findings suggest that TI-jute can help protect against bites and alter the life traits of Ae. aegypti. The study highlights that the timing of the intervention during the day affected the efficacy of TI-jute and TI-cotton, while sublethal exposure to transfluthrin stimulated egg production in the resistant strain. These are critical challenges that warrant attention in vector control strategies. Investigating this phenomenon in mosquito reproduction necessitates future research at a molecular level.

Conversion of amino-terephthalonitriles to multi-substituted single benzene fluorophores with utility in bioimaging.

Substitution of two fluorine atoms of the tetrafluoroterephthalonitrile (TFTN) ring (ortho to each other) by amine nucleophiles through SNAr chemistry is achievable. However, tri- and tetra-substitution towards multi-substituted single benzene fluorophores (SBFs) is harder due to increased electron richness of the TFTN moiety. Tertiary amine donors promote the molecule towards such multi-substitution guided by the steric obstruction to intramolecular charge transfer to the TFTN ring. Contrarily, secondary amine substituents with better lone pair donation to the TFTN ring cannot induce the SNAr pathway and instead promote hydrolysis of the nitrile groups of the TFTN moiety. Theoretical investigations have helped unearth the reasons for this observed difference in chemical reactivities and also explain the differences in the emission spectra. Finally, the success of the synthetic method towards multi-substitution is showcased through creation of a highly lipophilic SBF bearing an octyl unit and demonstrating its utility in in vitro cellular imaging.

Effect of electronegative atoms on π - π stacking and hydrogen bonding behavior in simple aromatic molecules - An Ab initio MD study.

Ab initio molecular dynamics studies have been performed on fluorobenzene, phenol, and aniline, which have the three most electronegative atoms, fluorine, oxygen, and nitrogen, respectively. Radial distribution functions show strong hydrogen bonding in the phenolic -OH group, whereas it is less prominent in the -NH2 group of aniline. Fluorobenzene does not show strong hydrogen bonds as no solvation shell is found between the fluorine atom and different aromatic hydrogens of the molecule. Spatial distribution functions show that the nitrogen atom of aniline interacts with the aromatic plane, the oxygen atom of phenol is concentrated near the -OH group and fluorobenzene's fluorine atom interacts with the para hydrogen. Liquid phase dimer structures of these systems reveal that perpendicular orientation (Y-shaped) is preferred over parallel ones. Almost half of the total dimer population tends to prefer 90∘±30° angle. H-bond analyses show that fluorobenzene has the longest mean H-bond lifetime for the H-bond between the aromatic hydrogens and the fluorine atoms, whereas the aniline has the least. The mean lifetime between aromatic hydrogens and electronegative atoms increases steadily from aniline to fluorobenzene. Phenolic -OH and amino -NH2 groups show considerably longer mean H-bond lifetime than the aromatic hydrogens. Gas-phase binding energies obtained from quantum chemical calculations show that aniline and phenol dimers have higher binding energy values than the fluorobenzene dimer. Only the phenol dimer shows a perpendicular structure as a stable one, while aniline and fluorobenzene prefer the parallel orientation.