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Etravirine (formerly TMC125) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant strains of HIV-1. Etra virine has been approved in several countries for use as part of highly active antiretroviral therapy in treatment-experienced patients. In vivo , etravirine is a substrate for, and weak inducer of, the hepatic cytochrome P450 (CYP) isoenzyme 3A4 and a substrate and weak inhibitor of CYP2C9 and CYP2C19. Etravirine is also a weak inhibitor of P-glycoprotein. An extensive drug-drug interaction programme in HIV-negative subjects has been carried out to assess the potential for pharmacokinetic interactions between etravirine and a variety of non-antiretroviral drugs. Effects of atorvastatin, clarithromycin, methadone, omeprazole, oral contraceptives, paroxetine, ranitidine and sildenafil on the pharmacokinetic disposition of etravirine were of no clinical relevance. Likewise, etravirine had no clinically significant effect on the pharmacokinetics of fluconazole, methadone, oral contraceptives, paroxetine or voriconazole. No clinically relevant interactions are expected between etravirine and azithromycin or ribavirin, therefore, etravirine can be combined with these agents without dose adjustment. Fluconazole and voriconazole increased etravirine exposure 1.9- and 1.4-fold, respectively, in healthy subjects, however, no increase in the incidence of adverse effects was observed in patients receiving etravirine and fluconazole during clinical trials, therefore, etravirine can be combined with these antifungals although caution is advised. Digoxin plasma exposure was slightly increased when co-administered with etravirine. No dose adjustments of digoxin are needed when used in combination with etravirine, however, it is recommended that digoxin levels should be monitored. Caution should be exercised in combining rifabutin with etravirine in the presence of certain boosted HIV protease inhibitors due to the risk of decreased exposure to etravirine. Although adjustments to the dose of clarithromycin are unnecessary for the treatment of most infections, the use of an alternative macrolide (e.g. azithromycin) is recommended for the treatment of Mycobacterium avium complex infection since the overall activity of clarithromycin against this pathogen may be altered when co-administered with etravirine. Dosage adjustments based on clinical response are recommended for clopidogrel, HMG-CoA reductase inhibitors (e.g. atorvastatin) and for phosphodiesterase type-5 inhibitors (e.g. sildenafil) because changes in the exposure of these medications in the presence of co-administered etravirine may occur. When co-administered with etravirine, a dose reduction or alternative to diazepam is recommended. When combining etravirine with warfarin, the international normalized ratio (INR) should be monitored. Systemic dexamethasone should be co-administered with caution, or an alternative to dexamethasone be found as dexamethasone induces CYP3A4. Caution is also warranted when co-administering etravirine with some antiarrhythmics, calcineurin inhibitors (e.g. ciclosporin) and antidepressants (e.g. citalopram). Coadministration of etravirine with some antiepileptics (e.g. carbamazepine and phenytoin), rifampicin (rifampin), rifapentine or preparations containing St John’s wort ( Hypericum perforatum ) is currently not recommended as these are potent inducers of CYP3A and/or CYP2C and may potentially decrease etravirine exposure. Antiepileptics that are less likely to interact based on their known pharmacological properties include gabapentin, lamotrigine, levetiracetam and pregabalin. Overall, pharmacokinetic and clinical data show etravirine to be well tolerated and generally safe when given in combination with non-antiretroviral agents, with minimal clinically significant drug interactions and no need for dosage adjustments of etravirine in any of the cases, or of the non-antiretroviral agent in the majority of cases studied.

Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone which is essential in eukaryotes. It is required for the activation and stabilization of a wide variety of client proteins and many of them are involved in important cellular pathways. Since Hsp90 affects numerous physiological processes such as signal transduction, intracellular transport, and protein degradation, it became an interesting target for cancer therapy. Structurally, Hsp90 is a flexible dimeric protein composed of three different domains which adopt structurally distinct conformations. ATP binding triggers directionality in these conformational changes and leads to a more compact state. To achieve its function, Hsp90 works together with a large group of cofactors, termed co-chaperones. Co-chaperones form defined binary or ternary complexes with Hsp90, which facilitate the maturation of client proteins. In addition, posttranslational modifications of Hsp90, such as phosphorylation and acetylation, provide another level of regulation. They influence the conformational cycle, co-chaperone interaction, and inter-domain communications. In this review, we discuss the recent progress made in understanding the Hsp90 machinery.

1. Evolutionary adaptations in interactions between plants, microbes and arthropods are generally studied in interactions that involve only two of these groups, that is, plants and microbes, plants and arthropods or arthropods and microbes. 2. We review the accumulating evidence from a wide variety of systems, including plant- and arthropod-associated microbes, and symbionts as well as antagonists, that selection and adaptation in seemingly two-way interactions between plants and microbes, plants and arthropods and arthropods and microbes are often driven by the biotic context of a third partner. 3. We extend the concept of local adaptation from two-way interactions to scenarios for three-way interactions. We show that consumers can locally adapt to specific host phenotypes that are induced by a third species with which they do not directly interact. This emphasizes that indirect interactions have not only ecological but also important evolutionary consequences, and stresses the need to conduct studies of local adaptation in the proper ecological context of the species involved. 4. Overall, our review underlines the importance of three-way interactions in the evolution of plant—microbe, plant—arthropod and arthropod—microbe interactions, and we outline some promising directions for future research.

As viruses continue to pose risks to global health, having a better understanding of virus–host protein–protein interactions aids in the development of treatments and vaccines. Here, we introduce Viruses.STRING, a protein–protein interaction database specifically catering to virus–virus and virus–host interactions. This database combines evidence from experimental and text-mining channels to provide combined probabilities for interactions between viral and host proteins. The database contains 177,425 interactions between 239 viruses and 319 hosts. The database is publicly available at viruses.string-db.org, and the interaction data can also be accessed through the latest version of the Cytoscape STRING app.

1. Domesticated plants can differ from their wild counterparts in the strength and outcome of species interactions, both above- and belowground. Plant-soil feedbacks influence plant success, and plant-associated soil microbial communities can influence plant interactions with herbivores and their natural enemies, yet, it remains unclear if domestication has changed these relationships. 2. To determine the effects of domestication on plant-soil interactions, we characterized soil microbial communities associated with various cultivars of domesticated tomato and some of its wild relatives. We measured the strength and direction of plant-soil feedbacks for domesticated and wild tomatoes, and the effects of soil on plant resistance to specialist herbivory by Manduca sexta, and the attraction of a parasitoid wasp, Cotesia congregata. 3. Domesticated tomatoes and their wild relatives had negative plant-soil feedbacks, as conspecifics cultivated soil that negatively impacted performance of subsequent plants (longer germination time, lower biomass) than if they grew in non-tomato soils. Significant variation existed among domesticated and wild tomato varieties in the strength of these feedbacks, ranging from neutral to strongly negative. For above-ground plant biomass, tomato wild relatives were unaffected by growing in tomato-conditioned soil, whereas domesticated tomatoes grew smaller in tomato soil, indicating effects of plant domestication. Overall, increased microbial biomass within the rhizosphere resulted in progressively less-negative plantsoil feedbacks. 4. Plant cultivars had different levels of resistance to herbivory by M. sexta, but this did not depend on plant domestication or soil type. The parasitoid C. congregata was primarily attracted to herbivore damaged plants, independent of plant domestication status, and for these damaged plants, wasps preferred some cultivars over others, and wild plants grown in tomato soil over wild plants grown in non-tomato soil. 5. Synthesis. These results indicate that crop tomatoes are more likely to show negative plant-soil feedbacks than wild progenitors, which could partially explain their sensitivity to monocultures in agricultural soils. Furthermore, cultivar-specific variation in the ability to generate soil microbial biomass, independent of domestication status, appears to buffer the negative consequences of sharing the same soil. Last, soil legacies were relatively absent for herbivores, but not for parasitoid wasps, suggesting trophic level specificity in soil feedbacks on plant-insect interactions.