Toxoplasmosis, a protozoan infection caused by Toxoplasma gondii, is estimated to affect around 2.5 billion people worldwide. Nevertheless, the side effects of drugs combined with the long period of therapy usually result in discontinuation of the treatment. New therapies should be developed by exploring peculiarities of the parasite’s metabolic pathways, similarly to what has been well described in cancer cell metabolism. An example is the switch in the metabolism of cancer that blocks the conversion of pyruvate into acetyl coenzyme A in mitochondria. In this context, dichloroacetate (DCA) is an anticancer drug that reverts the tumor proliferation by inhibiting the enzymes responsible for this switch: the pyruvate dehydrogenase kinases (PDKs). DCA has also been used in the treatment of certain symptoms of malaria; however, there is no evidence of how this drug affects apicomplexan species. In this paper, we studied the metabolism of T. gondii and demonstrate that DCA also inhibits T. gondii’s in vitro infection with no toxic effects on host cells. DCA caused an increase in the activity of pyruvate dehydrogenase followed by an unbalanced mitochondrial activity. We also observed morphological alterations frequently in mitochondria and in a few apicoplasts, essential organelles for parasite survival. To date, the kinases that potentially regulate the activity of pyruvate metabolism in both organelles have never been described. Here, we confirmed the presence in the genome of two putative kinases (T. gondii PDK [TgPDK] and T. gondii branched-chain α-keto acid dehydrogenase kinase [TgBCKDK]), verified their cellular localization in the mitochondrion, and provided in silico data suggesting that they are potential targets of DCA. IMPORTANCE Currently, the drugs used for toxoplasmosis have severe toxicity to human cells, and the treatment still lacks effective and safer alternatives. The search for novel drug targets is timely. We report here that the treatment of T. gondii with an anticancer drug, dichloroacetate (DCA), was effective in decreasing in vitro infection without toxicity to human cells. It is known that PDK is the main target of DCA in mammals, and this inactivation increases the conversion of pyruvate into acetyl coenzyme A and reverts the proliferation of tumor cells. Moreover, we verified the mitochondrial localization of two kinases that possibly regulate the activity of pyruvate metabolism in T. gondii, which has never been studied. DCA increased pyruvate dehydrogenase (PDH) activity in T. gondii, followed by an unbalanced mitochondrial activity, in a manner similar to what was previously observed in cancer cells. Thus, we propose the conserved kinases as potential regulators of pyruvate metabolism and interesting targets for new therapies.

In trypanosomatids, transcription is polycistronic and all mRNAs are processed by trans-splicing, with export mediated by noncanonical mechanisms. Although mRNA export is central to gene regulation and expression, few orthologs of proteins involved in mRNA export in higher eukaryotes are detectable in trypanosome genomes, necessitating direct identification of protein components. We previously described conserved mRNA export pathway components in Trypanosoma cruzi, including orthologs of Sub2, a component of the TREX complex, and eIF4AIII (previously Hel45), a core component of the exon junction complex (EJC). Here, we searched for protein interactors of both proteins using cryomilling and mass spectrometry. Significant overlap between TcSub2 and TceIF4AIII-interacting protein cohorts suggests that both proteins associate with similar machinery. We identified several interactions with conserved core components of the EJC and multiple additional complexes, together with proteins specific to trypanosomatids. Additional immunoisolations of kinetoplastid-specific proteins both validated and extended the superinteractome, which is capable of supporting RNA processing from splicing through to nuclear export and cytoplasmic events. We also suggest that only proteomics is powerful enough to uncover the high connectivity between multiple aspects of mRNA metabolism and to uncover kinetoplastid-specific components that create a unique amalgam to support trypanosome mRNA maturation.

Background: Alterations in PI3K function are directly related to cancer, making PI3K inhibitors suitable options for anticancer therapies. Information on therapy using different types of PI3K inhibitors is available in literature, providing indications of trends in developing new therapies. Although some studies on PI3K inhibitors for cancer treatment provide clinical evidence, they do not allow a careful search for potential PI3K inhibitors conducted by development indicators. Here, we performed a foresight study of clinical trials involving PI3K inhibitors from the past 11 years using indicators of clinical evolution to identify technological trends and provide data for supporting recommendations for new study designs. Methods: A comprehensive foresight study was designed based on documents from clinical trials on PI3K inhibitors to perform a systematic and comparative analysis, in order to identify technological trends on new cancer therapies. Results: Our results demonstrate that total number of clinical trials has decreased over the years and, currently, there is a clear prevalence of studies using isoform-specific inhibitors in combined interventions. Clinical trials in Phases I and II were the most frequently found in the database, whereas Phase III trials correspond to 7% of studies. The measurement of clinical trials progression using indicators (drugs in Phase III profile, top-10 drugs, and top-10 combined drugs) demonstrated that the 3 new medicines BKM120, IBI-376, and PF-05212384 have a high potential to provide more efficient cancer treatment in combined interventions. These data also include the groups of targets for each drug, providing a useful and reliable source for design new combinations to overcome the resistance and the poor tolerability observed in some PI3K therapies. Conclusions: The establishment of development indicators based on clinical trials for cancer treatment was useful to highlight the clinical investment in 3 new PI3K drugs and the advantages of combine therapy using FDA-approved drugs.

Histone H1, or linker histone, is an important protein that binds to the nucleosome, aiding chromatin compaction. Here, we characterize for the first time a linker histone in T. gondii , named TgH1-like.

Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi. This protozoan developed several mechanisms to infect, propagate, and survive in different hosts. The specific expression of proteins is responsible for morphological and metabolic changes in different parasite stages along the parasite life cycle. The virulence strategies at the cellular and molecular levels consist of molecules responsible for mediating resistance mechanisms to oxidative damage, cellular invasion, and immune evasion, performed mainly by surface proteins. Since parasite surface coat remodeling is crucial to invasion and infectivity, surface proteins are essential virulence elements. Understanding the factors involved in these processes improves the knowledge of parasite pathogenesis. Genome sequencing has opened the door to high-throughput technologies, allowing us to obtain a deeper understanding of gene reprogramming along the parasite life cycle and identify critical molecules for survival. This review therefore focuses on proteins regulated during differentiation into infective forms considered virulence factors and addresses the current known mechanisms acting in the modulation of gene expression, emphasizing mRNA signals, regulatory factors, and protein complexes.

Purpose: This study aimed to analyze the strategies and challenges related to technology transfer (TT) in technology transfer offices (TTOs), specifically regarding actions to offer technologies in their portfolios.Design/methodology/approach: The qualitative research used a multiple case study based on interviews with TTO managers from seven Brazilian public Science and Technology Institutions (STIs): University of São Paulo (USP), State University of Campinas (UNICAMP), Paulista State University (UNESP), Federal University of Minas Gerais (UFMG), Federal University of Paraná (UFPR), Federal Technological University of Paraná (UTFPR) and Oswaldo Cruz Foundation (FIOCRUZ).Findings: STIs that invest more resources in their portfolio’s active offering and marketing are more successful in TT than STIs with a passive strategy. Although this active strategy has grown in importance, there is a disparity among Brazilian TTOs as some are still passive in commercializing their intellectual property. This research also highlights the need for clear policies to overcome obstacles related to legal uncertainty for researchers who wish to undertake projects as entrepreneurs using the intellectual property of STIs.Research limitations/implications: The results of this study cannot be generalized since its conclusions are limited to the studied institutions. However, the outcomes indicate some interesting matters for managers of STIs, public policymakers and TT researchers.Originality/value: Literature on marketing and innovation related to TT between research institutions and companies in developing countries is still limited. Thus, this research contributes to generating knowledge in the field and improving TTOs.