mosquito survival and pharmacokinetic modeling show the mosquitocidal activity of nitisinone.

One approach to interrupting the transmission of insect-borne diseases that is successfully used in veterinary medicine is exploiting the ability of antiparasitic drugs to make vertebrate blood toxic for blood-feeding insects. Recent studies have identified 4-hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme of the tyrosine detoxification pathway, as essential for hematophagous arthropods to digest their blood meals. Such blood-feeding insects include anopheline mosquitoes, which transmit malaria-causing parasites.

Investigation of the threonine metabolism of Echinococcus multilocularis: The threonine dehydrogenase as a potential drug target in alveolar echinococcosis.

Alveolar echinococcosis (AE) is a severe zoonotic disease caused by the metacestode stage of the fox tapeworm Echinococcus multilocularis. We recently showed that E. multilocularis metacestode vesicles scavenge large amounts of L-threonine from the culture medium.

Discovery and Development of an Advanced Lead for the Treatment of African Trypanosomiasis.

African trypanosomiasis is a widespread disease of human and veterinary importance caused by various with a globally devastating impact and a need for novel treatment options. We here provide a comprehensive preclinical evaluation of nucleoside analogues, 6-thioether-modified tubercidins, with curative activity against African trypanosomiasis. Promising hits were identified following screening against the most relevant trypanosome species.

CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence.

Abnormal increases in cell size are associated with senescence and cell cycle exit. The mechanisms by which overgrowth primes cells to withdraw from the cell cycle remain unknown. We address this question using CDK4/6 inhibitors, which arrest cells in G0/G1 and are licensed to treat advanced HR+/HER2- breast cancer.

A conserved metabolic signature associated with response to fast-acting anti-malarial agents.

In malaria drug discovery, understanding the mode of action of lead compounds is important as it helps in predicting the potential emergence of drug resistance in the field when these drugs are eventually deployed. In this study, we have employed metabolomics technologies to characterize the potential targets of anti-malarial drug candidates in the developmental pipeline at NITD. We show that NITD fast-acting leads belonging to spiroindolone and imidazothiadiazole class induce a common biochemical theme in drug-exposed malaria parasites which is similar to another fast-acting, clinically available drug, DHA.

Alignment of multiple metabolomics LC-MS datasets from disparate diseases to reveal fever-associated metabolites.

Acute febrile illnesses are still a major cause of mortality and morbidity globally, particularly in low to middle income countries. The aim of this study was to determine any possible metabolic commonalities of patients infected with disparate pathogens that cause fever. Three liquid chromatography-mass spectrometry (LC-MS) datasets investigating the metabolic effects of malaria, leishmaniasis and Zika virus infection were used.

Microalgae show a range of responses to exometabolites of foreign species.

Studies on microalgae interspecific interactions have so far focused either on nutrient competition or allelopathic effects due to excreted substances from Harmful Algal Bloom (HAB) species. Evidence from plants, bacteria and specific microalgae groups, point to a range of responses mediated by sensing or direct chemical impact of exometabolites from foreign species. Such processes remain under-investigated, especially in non-HAB microalgae, despite the importance of such knowledge in ecology and industrial applications.

Transcriptional Shift and Metabolic Adaptations during Quiescence Using Stationary Phase and Drug Pressure as Models.

Microorganisms can adopt a quiescent physiological condition which acts as a survival strategy under unfavorable conditions. Quiescent cells are characterized by slow or non-proliferation and a deep downregulation of processes related to biosynthesis. Although quiescence has been described mostly in bacteria, this survival skill is widespread, including in eukaryotic microorganisms.

Mapping immune variation and gene switching in naive hosts infected with .

Falciparum malaria is clinically heterogeneous and the relative contribution of parasite and host in shaping disease severity remains unclear. We explored the interaction between inflammation and parasite variant surface antigen (VSA) expression, asking whether this relationship underpins the variation observed in controlled human malaria infection (CHMI). We uncovered marked heterogeneity in the host response to blood challenge; some volunteers remained quiescent, others triggered interferon-stimulated inflammation and some showed transcriptional evidence of myeloid cell suppression.

Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs.

Livestock diseases caused by Trypanosoma congolense, T. vivax and T. brucei, collectively known as nagana, are responsible for billions of dollars in lost food production annually.

Genomic instability at the locus of sterol C24-methyltransferase promotes amphotericin B resistance in Leishmania parasites.

Amphotericin B is an increasingly important tool in efforts to reduce the global disease burden posed by Leishmania parasites. With few other chemotherapeutic options available for the treatment of leishmaniasis, the potential for emergent resistance to this drug is a considerable threat. Here we characterised four novel amphotericin B-resistant Leishmania mexicana lines.

Microfluidic Devices for Drug Assays.

In this review, we give an overview of the current state of microfluidic-based high-throughput drug assays. In this highly interdisciplinary research field, various approaches have been applied to high-throughput drug screening, including microtiter plate, droplets microfluidics as well as continuous flow, diffusion and concentration gradients-based microfluidic drug assays. Therefore, we reviewed over 100 recent publications in the field and sorted them according to their approach.

Metabolomic profiling of macrophages determines the discrete metabolomic signature and metabolomic interactome triggered by polarising immune stimuli.

Priming and activating immune stimuli have profound effects on macrophages, however, studies generally evaluate stimuli in isolation rather than in combination. In this study we have investigated the effects of pro-inflammatory and anti-inflammatory stimuli either alone or in combination on macrophage metabolism. These stimuli include host factors such as IFNγ and ovalbumin-immunoglobulin immune complexes, or pathogen factors such as LPS.

Microfluidics-Based Approaches to the Isolation of African Trypanosomes.

African trypanosomes are responsible for significant levels of disease in both humans and animals. The protozoan parasites are free-living flagellates, usually transmitted by arthropod vectors, including the tsetse fly. In the mammalian host they live in the bloodstream and, in the case of human-infectious species, later invade the central nervous system.

CRISPR/Cas9 Genome Editing Reveals That the Intron Is Not Essential for Gene Activation or Silencing in .

relies on monoallelic expression of 1 of 60 virulence genes for antigenic variation and host immune evasion. Each gene contains a conserved intron which has been implicated in previous studies in both activation and repression of transcription via several epigenetic mechanisms, including interaction with the promoter, production of long noncoding RNAs (lncRNAs), and localization to repressive perinuclear sites. However, functional studies have relied primarily on artificial expression constructs.