Computational identification of natural senotherapeutic compounds that mimic dasatinib based on gene expression data.

The major risk factor for chronic disease is chronological age, and age-related chronic diseases account for the majority of deaths worldwide. Targeting senescent cells that accumulate in disease-related tissues presents a strategy to reduce disease burden and to increase healthspan. The senolytic combination of the tyrosine-kinase inhibitor dasatinib and the flavonol quercetin is frequently used in clinical trials aiming to eliminate senescent cells. Here, our goal was to computationally identify natural senotherapeutic repurposing candidates that may substitute dasatinib based on their similarity in gene expression effects. The natural senolytic piperlongumine (a compound found in long pepper), and the natural senomorphics parthenolide, phloretin and curcumin (found in various edible plants) were identified as potential substitutes of dasatinib. The gene expression changes underlying the repositioning highlight apoptosis-related genes and pathways. The four compounds, and in particular the top-runner piperlongumine, may be combined with quercetin to obtain natural formulas emulating the dasatinib + quercetin formula.

Correction: Vector mapping and bloodmeal metabarcoding demonstrate risk of urban Chagas disease transmission in Caracas, Venezuela.

[This corrects the article DOI: 10.1371/journal.pntd.0010613.].

Vector mapping and bloodmeal metabarcoding demonstrate risk of urban Chagas disease transmission in Caracas, Venezuela.

Chagas disease is a significant public health risk in rural and semi-rural areas of Venezuela. Triatomine infection by the aetiological agent Trypanosoma cruzi is also observed in the Metropolitan District of Caracas (MDC), where foodborne T. cruzi outbreaks occasionally occur but active vector-to-human transmission (infection during triatomine bloodmeal) is considered absent. Citizen science-based domiciliary triatomine collection carried out between 2007 and 2013 in the MDC has advanced understanding of urban T. cruzi prevalence patterns and represents an important public awareness-building tool. The present study reports on the extension of this triatomine collection program from 2014 to 2019 and uses mitochondrial metabarcoding to assess feeding behavior in a subset of specimens. The combined, thirteen-year dataset (n = 4872) shows a high rate of T. cruzi infection (75.2%) and a predominance of Panstrongylus geniculatus (99.01%) among triatomines collected in domiciliary areas by MDC inhabitants. Collection also involved nymphal stages of P. geniculatus in 18 of 32 MDC parishes. Other collected species included Triatoma nigromaculata, Triatoma maculata, Rhodnius prolixus, and Panstrongylus rufotuberculatus. Liquid intestinal content indicative of bloodmeal was observed in 53.4% of analyzed specimens. Dissection pools representing 108 such visually blooded P. geniculatus specimens predominantly tested positive for human cytochrome b DNA (22 of 24 pools). Additional bloodmeal sources detected via metabarcoding analysis included key sylvatic T. cruzi reservoirs (opossum and armadillo), rodents, and various other synanthropic and domesticated animals. Results suggest a porous sylvatic-domiciliary transmission interface and ongoing adaptation of P. geniculatus to the urban ecotope. Although P. geniculatus defecation traits greatly limit the possibility of active T. cruzi transmission for any individual biting event, the cumulation of this low risk across a vast metropolitan population warrants further investigation. Efforts to prevent triatomine contact with human food sources also clearly require greater attention to protect Venezuela's capital from Chagas disease.

Remarkable genetic diversity of Trypanosoma cruzi and Trypanosoma rangeli in two localities of southern Ecuador identified via deep sequencing of mini-exon gene amplicons.

BACKGROUND: Trypanosoma cruzi, the causative agent of Chagas disease, and T. rangeli are kinetoplastid parasites endemic to Latin America. Although closely related to T. cruzi and capable of infecting humans, T. rangeli is non-pathogenic. Both parasite species are transmitted by triatomine bugs, and the presence of T. rangeli constitutes a confounding factor in the study of Chagas disease prevalence and transmission dynamics. Trypanosoma cruzi possesses high molecular heterogeneity: seven discrete typing units (DTUs) are currently recognized. In Ecuador, T. cruzi TcI and T. rangeli KP1(-) predominate, while other genetic lineages are seldom reported. METHODS: Infection by T. cruzi and/or T. rangeli in different developmental stages of triatomine bugs from two communities of southern Ecuador was evaluated via polymerase chain reaction product size polymorphism of kinetoplast minicircle sequences and the non-transcribed spacer region of the mini-exon gene (n = 48). Forty-three mini-exon amplicons were also deep sequenced to analyze single-nucleotide polymorphisms within single and mixed infections. Mini-exon products from ten monoclonal reference strains were included as controls. RESULTS: Trypanosoma cruzi genetic richness and diversity was not significantly greater in adult vectors than in nymphal stages III and V. In contrast, instar V individuals showed significantly higher T. rangeli richness when compared with other developmental stages. Among infected triatomines, deep sequencing revealed one T. rangeli infection (3%), 8 T. cruzi infections (23.5%) and 25 T. cruzi + T. rangeli co-infections (73.5%), suggesting that T. rangeli prevalence has been largely underestimated in the region. Furthermore, deep sequencing detected TcIV sequences in nine samples; this DTU had not previously been reported in Loja Province. CONCLUSIONS: Our data indicate that deep sequencing allows for better parasite identification/typing than amplicon size analysis alone for mixed infections containing both T. cruzi and T. rangeli, or when multiple T. cruzi DTUs are present. Additionally, our analysis showed extensive overlap among the parasite populations present in the two studied localities (c.28 km apart), suggesting active parasite dispersal over the study area. Our results highlight the value of amplicon sequencing methodologies to clarify the population dynamics of kinetoplastid parasites in endemic regions and inform control campaigns in southern Ecuador.