Use of the synergist piperonyl butoxide can slow the development of alpha‐cypermethrin resistance in the whitefly Bemisia tabaci

The development of insecticide resistance in insect pests of crops is a growing threat to sustainable food production, and strategies that slow the development of resistance are therefore urgently required. The insecticide synergist piperonyl butoxide (PBO) inhibits certain insect detoxification systems and so may delay the evolution of metabolic resistance. In the current study we characterized resistance development in the silverleaf whitefly, Bemisia tabaci, after selection with either a neonicotinoid (thiacloprid) or pyrethroid (alpha‐cypermethrin) insecticide alone or in combination with PBO. Resistance development was significantly suppressed (> 60%) in the line selected with alpha‐cypermethrin + PBO compared to the line selected with alpha‐cypermethrin alone. RNA sequencing (RNAseq) analyses revealed an increase in frequency of a knock‐down resistance mutation but no differentially expressed genes were identified that could explain the sensitivity shift. No significant difference was observed in the level of resistance between the thiacloprid and thiacloprid + PBO selected lines, and RNA sequencing (RNAseq) analyses revealed that the cytochrome P450 monooxygenase CYP6CM1, known to metabolize neonicotinoids, was significantly upregulated (>10‐fold) in both lines. The findings of this study demonstrate that PBO used in combination with certain insecticides can suppress the development of resistance in a laboratory setting; however, the mechanism by which PBO supresses resistance development remains unclear.     

Evolution of the neural sex‐determination system in insects: does fruitless homologue regulate neural sexual dimorphism in basal insects?

In the brain of holometabolous insects such as the fruit fly Drosophila melanogaster, the fruitless gene produces sex‐specific gene products under the control of the sex‐specific splicing cascade and contributes to the formation of the sexually dimorphic circuits. Similar sex‐specific gene products of fruitless homologues have been identified in other holometabolous insects such as mosquitoes and a parasitic wasp, suggesting the fruitless‐dependent neural sex‐determination system is widely conserved amongst holometabolous insects. However, it remains obscure whether the fruitless‐dependent neural sex‐determination system is present in basal hemimetabolous insects. To address this issue, identification, characterization, and expression analyses of the fruitless homologue were conducted in the two‐spotted cricket, Gryllus bimaculatus, as a model hemimetabolous insect. The Gryllus fruitless gene encodes multiple isoforms with a unique zinc finger domain, and does not encode a sex‐specific gene product. The Gryllus Fruitless protein is broadly expressed in the neurones and glial cells in the brain, and there was no prominent sex‐related difference in the expression levels of Gryllus fruitless isoforms. The results suggest that the Gryllus fruitless gene is not involved in the neural sex‐determination in the cricket brain.     

Exome‐wide association of deltamethrin resistance in Aedes aegypti from Mexico

Aedes aegypti is the major vector of a number of arboviruses that cause disease in humans. Without vaccines or pharmaceuticals, pyrethroid insecticides remain the major tool for public health protection. Pyrethroid resistance is now widespread. Replacement substitutions in the voltage‐gated sodium channel (vgsc) that reduce the stability of pyrethroid binding account for most of the resistance, but metabolic mechanisms also inactivate pyrethroids. High‐throughput sequencing and the A. aegypti L5 annotated physical map has allowed interrogation of the exome for genes and single‐nucleotide polymorphisms associated with pyrethroid resistance. We exposed females of A. aegypti from Mexico to a deltamethrin discriminating dose to designate them as resistant (active after 1 h) or susceptible (knocked down with no recovery after 4 h). The vgsc on chromosome 3 had the highest association, followed by genes proximal to vgsc. We identified potential detoxification genes located singly (eg HPX8C) or within clusters in chromosome 2 [three esterase clusters, two of cytochrome P450 monooxygenases (CYP)] and chromosome 3 (one cluster of 16 CYP325 and seven CYP9 genes). Deltamethrin resistance in A. aegypti is associated with mutations in the vgsc gene and a large assortment of genes.     

Maternal provision of non‐sex‐specific transformer messenger RNA in sex determination of the wasp Asobara tabida

In many insect species maternal provision of sex‐specifically spliced messenger RNA (mRNA) of sex determination genes is an essential component of the sex determination mechanism. In haplodiploid Hymenoptera, maternal provision in combination with genomic imprinting has been shown for the parasitoid Nasonia vitripennis, known as maternal effect genomic imprinting sex determination (MEGISD). Here, we characterize the sex determination cascade of Asobara tabida, another hymenopteran parasitoid. We show the presence of the conserved sex determination genes doublesex (dsx), transformer (tra) and transformer‐2 (tra2) orthologues in As. tabida. Of these, At‐dsx and At‐tra are sex‐specifically spliced, indicating a conserved function in sex determination. At‐tra and At‐tra2 mRNA is maternally provided to embryos but, in contrast to most studied insects, As. tabida females transmit a non‐sex‐specific splice form of At‐tra mRNA to the eggs. In this respect, As. tabida sex determination differs from the MEGISD mechanism. How the paternal genome can induce female development in the absence of maternal provision of sex‐specifically spliced mRNA remains an open question. Our study reports a hitherto unknown variant of maternal effect sex determination and accentuates the diversity of insect sex determination mechanisms.     

Overviewing a Nurse‐Led,Community‐Based HIV PEP Program: Applying the Extant Literature in Frontline Practice

This clinical concept paper overviews a program to facilitate access to postexposure prophylaxis (PEP) for gay, bisexual, and other men who have sex with men. The project, which was a collaborative initiative involving the local School of Nursing, public health unit, AIDS service organization, hospital‐based HIV clinic, and an outpatient pharmacy, was implemented to circumvent common barriers to care identified in the literature. In this project, persons who present to one of the two participating clinics after having come, or likely having come, into contact with HIV within the previous 72 hr, are offered rapid HIV testing, also known as point‐of‐care (POC) testing, to rule out existing HIV infection, and provided with a follow‐up appointment booked at the HIV clinic. Clients are also offered comprehensive STI testing, and HIV prevention counseling. The implementation of this collaborative community‐based access‐to‐PEP project demonstrates the application of research to a real‐world health care setting, and it is hoped that others will adapt this model to their local setting, enabling ease of access to PEP for members of groups that are disproportionately affected by HIV.     

The transformer genes in the fig wasp Ceratosolen solmsi provide new evidence for duplications independent of complementary sex determination

Transformer (tra) is the key gene that turns on the sex‐determination cascade in Drosophila melanogaster and in some other insects. The honeybee Apis mellifera has two duplicates of tra, one of which (complementary sex determiner, csd) is the primary signal for complementary sex‐determination (CSD), regulating the other duplicate (feminizer). Two tra duplicates have been found in some other hymenopteran species, resulting in the assumption that a single ancestral duplication of tra took place in the Hymenoptera. Here, we searched for tra homologues and pseudogenes in the Hymenoptera, focusing on five newly published hymenopteran genomes. We found three tra copies in the fig wasp Ceratosolen solmsi. Further evolutionary and expression analyses also showed that the two duplicates (Csoltra‐B and Csoltra‐C) are under positive selection, and have female‐specific expression, suggesting possible sex‐related functions. Moreover, Aculeata species exhibit many pseudogenes generated by lineage‐specific duplications. We conclude that phylogenetic reconstruction and pseudogene screening provide novel evidence supporting the hypothesis of independent duplications rather an ancestral origin of multiple tra paralogues in the Hymenoptera. The case of C. solmsi is the first example of a non‐CSD species with duplicated tra, contrary to the previous assumption that derived tra paralogues function as the CSD locus.     

A population analysis of the DGAT1 inhibitor GSK3008356 and its effect on endogenous and meal‐induced triglyceride turnover in healthy subjects

Non‐alcoholic steatohepatitis (NASH) is a liver disease in which fatty infiltration is accompanied by liver inflammation. GSK3008356 is under development as a selective inhibitor of diacylglycerol acyltransferase 1 (DGAT1), a key enzyme involved in the formation of triglyceride (TG). Decreased DGAT1 activity can reduce circulating TG and liver TG, and therefore could potentially prevent or treat NASH. The aim of the current study was to develop a population pharmacokinetic–pharmacodynamic (PKPD) model that characterizes the PK disposition of GSK3008356 and its relation to the changes in blood TG. Drug concentrations were measured in 104 healthy adults receiving various single (SD) and repeat doses (RD) in a first time in human (FiH) study. A 30% fat meal was given at hour 2 postdose, and blood postprandial TG concentrations were measured at various time points. The population PKPD model consists of several parts including a PK model, drug effect model, meal effect model, and a turnover model. The pharmacokinetic data were described using a 3‐compartment model. Drug effect was described by an inhibitory sigmoidal Emax model. Since TG levels change with the introduction of a meal, a bi‐exponential meal effect model was utilized. The total change in TG was fitted using a turnover model with drug and meal effects on the TG production rate. The current analysis presents a PKPD modeling strategy of time‐varying TG data coming from both endogenous and exogenous sources. In general, the presented model could be utilized in the model‐based drug development of drugs that influence TG levels in blood.