Nuclear basket proteins regulate the distribution and mobility of nuclear pore complexes in budding yeast.

Nuclear pore complexes (NPCs) mediate all traffic between the nucleus and the cytoplasm and are among the most stable protein assemblies in cells. Budding yeast cells carry two variants of NPCs which differ in the presence or absence of the nuclear basket proteins Mlp1, Mlp2, and Pml39. The binding of these basket proteins occurs very late in NPC assembly and Mlp-positive NPCs are excluded from the region of the nuclear envelope that borders the nucleolus.

Getting around the roundworms: Identifying knowledge gaps and research priorities for the ascarids.

The ascarids are a large group of parasitic nematodes that infect a wide range of animal species. In humans, they cause neglected diseases of poverty; many animal parasites also cause zoonotic infections in people. Control measures include hygiene and anthelmintic treatments, but they are not always appropriate or effective and this creates a continuing need to search for better ways to reduce the human, welfare and economic costs of these infections.

Genome structure and population genomics of the canine heartworm Dirofilaria immitis.

The heartworm, Dirofilaria immitis, is a filarial parasitic nematode responsible for significant morbidity and mortality in wild and domesticated canids. Resistance to macrocyclic lactone drug prevention represents a significant threat to parasite control and has prompted investigations to understand the genetic determinants of resistance. This study aimed to improve the genomic resources of D.

C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption.

While the toxicity of PARP inhibitors to cells with defects in homologous recombination (HR) is well established, other synthetic lethal interactions with PARP1/PARP2 disruption are poorly defined. To inform on these mechanisms we conducted a genome-wide screen for genes that are synthetic lethal with PARP1/2 gene disruption and identified C16orf72/HAPSTR1/TAPR1 as a novel modulator of replication-associated R-loops. C16orf72 is critical to facilitate replication fork restart, suppress DNA damage and maintain genome stability in response to replication stress.

Effect of Food on the Pediatric Dispersible Tablet Formulations of TRIUMEQ and DOVATO in Healthy Adult Participants.

This randomized food effect study in healthy adult participants examined dispersible tablet formulations of fixed-dose combinations of dolutegravir/abacavir/lamivudine (TRIUMEQ) and dolutegravir/lamivudine (DOVATO). While adult tablet formulations of these combinations are currently approved for the treatment of human immunodeficiency virus, alternate formulations for children are urgently needed to facilitate appropriate pediatric dosing for patients who may have difficulty swallowing a conventional tablet. This study compared the effect of a high-fat, high-calorie meal on the pharmacokinetics, safety, and tolerability of dispersible tablet (DT) formulations of the two-drug and three-drug regimens, with administration under fasting conditions.

Functional validation of the truncated UNC-63 acetylcholine receptor subunit in levamisole resistance.

Levamisole is a broad-spectrum anthelmintic which permanently activates cholinergic receptors from nematodes, inducing a spastic paralysis of the worms. Whereas this molecule is widely used to control parasitic nematodes impacting livestock, its efficacy is compromised by the emergence of drug-resistant parasites. In that respect, there is an urgent need to identify and validate molecular markers associated with resistance.

A Phase 1 randomized study of GSK3732394, an investigational long-acting biologic treatment regimen for HIV-1 infection.

Background: The GSK3732394 multivalent protein was developed as a novel, long-acting, antiretroviral biologic treatment regimen with three independent, non-cross-resistant mechanisms for inhibiting HIV-1 entry.

Methods: A single-centre, Phase 1, double-blind, randomized, placebo-controlled study was conducted in healthy volunteers, using a 2-part adaptive study design: in Part 1, participants were randomized to receive subcutaneous injection of GSK3732394 or placebo (3:1) as single ascending doses (10-mg starting dose); in Part 2, participants were intended to receive multiple ascending doses. Primary and secondary objectives included safety, pharmacokinetics (PK) and pharmacodynamics (PD; cluster of differentiation four receptor occupancy [CD4 RO]) of GSK3732394 in healthy adults; PK/PD results in healthy volunteers were used to project HIV-1 treatment success.

The avermectin/milbemycin receptors of parasitic nematodes.

Glutamate-gated chloride channels are the most important target of ivermectin and related compounds in parasitic nematodes. A small family of genes encode subunits of these channels, allowing the assembly of multiple channel subtypes; the subunit composition of most of the native receptors is unknown. The members of the gene family vary between species, making extrapolation from C.

Development of Dolutegravir Single-entity and Fixed-dose Combination Formulations for Children.

Background: The World Health Organization (WHO) 2019 antiretroviral treatment guidelines recommend use of optimal treatment regimens in all populations. Dolutegravir-based regimens are the preferred first-line and second-line treatment in infants and children with HIV 4 weeks of age and above. There is an urgent need for optimal pediatric formulations of dolutegravir as single-entity (SE) and fixed-dose combination (FDC) to ensure correct dosing and adherence for swallowing and palatability.

Evaluation of the in vitro susceptibility of various filarial nematodes to emodepside.

Filariae are vector-borne nematodes responsible for an enormous burden of disease. Human lymphatic filariasis, caused by Wuchereria bancrofti, Brugia malayi, and Brugia timori, and onchocerciasis (caused by Onchocerca volvulus) are neglected parasitic diseases of major public health significance in tropical regions. To date, therapeutic efforts to eliminate human filariasis have been hampered by the lack of a drug with sufficient macrofilaricidal and/or long-term sterilizing effects that is suitable for use in mass drug administration (MDA) programs, particularly in areas co-endemic with Loa loa, the causative agent of loiasis.

Pharmacokinetics, Safety, and Tolerability of a Single Oral Dose of Abacavir/Dolutegravir/Lamivudine Combination Tablets in Healthy Japanese Study Participants.

Pharmacokinetics, safety, and tolerability of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg were assessed in this phase 1, single-arm, open-label, single-dose study in fasted healthy male (n = 4) and female (n = 8) participants of Japanese heritage. Participants received a single dose of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg after an 8-hour fast, with safety assessments and blood samples for pharmacokinetic parameters collected through 72 hours after dosing. Geometric mean maximum plasma concentrations were 5.

Lack of detectable short-term effects of a single dose of ivermectin on the human immune system.

Background: Ivermectin is widely used in human and animal medicine to treat and prevent parasite nematode infections. It has been suggested that its mode of action requires the host immune system, as it is difficult to reproduce its clinical efficacy in vitro. We therefore studied the effects of a single dose of ivermectin (Stromectol-0.

Evaluation of changes in drug susceptibility and population genetic structure in Haemonchus contortus following worm replacement as a means to reverse the impact of multiple-anthelmintic resistance on a sheep farm.

A population of Haemonchus contortus that was highly resistant to benzimidazoles and avermectin/milbemycins with a subpopulation that was resistant to levamisole, was replaced with a susceptible laboratory isolate of H. contortus in a flock of sheep. The anthelmintic susceptibility and population genetics of the newly established population were evaluated for 3.

Comparative sequences of the Wolbachia genomes of drug-sensitive and resistant isolates of Dirofilaria immitis.

The recent identification of isolates of D. immitis with confirmed resistance to the macrocyclic lactone preventatives presents an opportunity for comparative genomic studies using these isolates, and examining the genetic diversity within and between them. We studied the genomes of Wolbachia endosymbionts of five isolates of D.

The Effect of Moderate- and High-Fat Meals on the Bioavailability of Dolutegravir/Rilpivirine Fixed-Dose Combination Tablet.

Dolutegravir 50 mg (DTG) and rilpivirine 25 mg (RPV) are a newly approved 2-drug regimen for the treatment of HIV in virally suppressed patients. A 2-part study evaluated the relative bioavailability and food effect of five experimental fixed-dose combination (FDC) tablet formulations of DTG/RPV. When given with a moderate- or high-fat meal, the absorption of both DTG and RPV was increased, resulting in higher exposures.

Using population genetics to examine relationships of Dirofilaria immitis based on both macrocyclic lactone-resistance status and geography.

Prevention of infection with canine heartworm (Dirofilaria immitis) is based on the compliant administration of macrocyclic lactone (ML) drugs. Resistance to ML drugs is well documented in D. immitis; however, there remains a paucity of information on the spatial distribution and prevalence of resistant isolates.

EAT-18 is an essential auxiliary protein interacting with the non-alpha nAChR subunit EAT-2 to form a functional receptor.

Nematode parasites infect approximately 1.5 billion people globally and are a significant public health concern. There is an accepted need for new, more effective anthelmintic drugs.

Assertive outreach treatment versus care as usual for the treatment of high-need, high-cost alcohol related frequent attenders: study protocol for a randomised controlled trial.

Background: Alcohol-related hospital admissions have doubled in the last ten years to > 1.2 m per year in England. High-need, high-cost (HNHC) alcohol-related frequent attenders (ARFA) are a relatively small subgroup of patients, having multiple admissions or attendances from alcohol during a short time period.

Bioequivalence and Food Effect Assessment of 2 Fixed-Dose Combination Formulations of Dolutegravir and Lamivudine.

This single-dose study evaluated the bioequivalence, food effect, and safety of 2 experimental, 2-drug, fixed-dose formulations of 50 mg dolutegravir and 300 mg lamivudine (formulation AH and formulation AK) as compared with coadministration of single-entity tablets of 50 mg dolutegravir and 300 mg lamivudine (reference). In fasted subjects, formulation AH lamivudine exposure was similar to the reference; however, dolutegravir exposure was consistently higher in formulation AH, with area under the concentration-time curve (AUC) and maximum concentration (C ) approximately 27% to 28% greater than reference. Formulation AK met bioequivalence standards to the reference for dolutegravir (AUC and C ) and lamivudine (AUC and AUC ) exposure; however, dolutegravir AUC and lamivudine C were approximately 16% and 32% higher than the reference, respectively.

Randomized Placebo-Controlled Trial Evaluating the Ophthalmic Safety of Single-Dose Tafenoquine in Healthy Volunteers.

Introduction: Tafenoquine has been recently registered for the prevention of relapse in Plasmodium vivax malaria.

Objective: This study assessed the pharmacodynamic effects of 300-mg single-dose tafenoquine on the retina.

Methods: This phase I, prospective, multicenter, randomized, single-masked, placebo-controlled, parallel-group study was conducted between 2 February 2016 and 14 September 2017 at three US study centers.

Refugia and anthelmintic resistance: Concepts and challenges.

Anthelmintic resistance is a threat to global food security. In order to alleviate the selection pressure for resistance and maintain drug efficacy, management strategies increasingly aim to preserve a proportion of the parasite population in 'refugia', unexposed to treatment. While persuasive in its logic, and widely advocated as best practice, evidence for the ability of refugia-based approaches to slow the development of drug resistance in parasitic helminths is currently limited.

Macrocyclic lactone anthelmintic-induced leukocyte binding to Dirofilaria immitis microfilariae: Influence of the drug resistance status of the parasite.

The macrocyclic lactone anthelmintics are the only class of drug currently used to prevent heartworm disease. Their extremely high potency in vivo is not mirrored by their activity against Dirofilaria immitis larvae in vitro, leading to suggestions that they may require host immune functions to kill the parasites. We have previously shown that ivermectin stimulates the binding of canine peripheral blood mononuclear cells (PBMCs) and polymorphonuclear leukocytes (PMNs) to D.

Effects of diethylcarbamazine and ivermectin treatment on gene expression in infected gerbils ().

Lymphatic filariasis (LF) threatens nearly 20% of the world's population and has handicapped one-third of the 120 million people currently infected. Current control and elimination programs for LF rely on mass drug administration of albendazole plus diethylcarbamazine (DEC) or ivermectin. Only the mechanism of action of albendazole is well understood.

Efficacy and side effects of doxycycline versus minocycline in the three-dose melarsomine canine adulticidal heartworm treatment protocol.

Background: The American Heartworm Society currently recommends the use of a monthly macrocyclic lactone, a 28-day course of 10 mg/kg doxycycline BID, and the 3-dose protocol of melarsomine dihydrochloride for the treatment of canine heartworm disease. Doxycycline is necessary for the reduction of the bacterium Wolbachia, found in all heartworm life-stages. Previous price increases and decreasing availability prompted us to evaluate alternative tetracycline antibiotics, i.