Repurposing the trypanosomatidic gsk kinetobox for the inhibition of parasitic pteridine and dihydrofolate reductases

Three open-source anti-kinetoplastid chemical boxes derived from a whole-cell phenotypic screening by GlaxoSmithKline (Tres Cantos Anti-Kinetoplastid Screening, TCAKS) were exploited for the discovery of a novel core structure inspiring new treatments of parasitic diseases targeting the trypansosmatidic pteridine reductase 1 (PTR1) and dihydrofolate reductase (DHFR) enzymes. In total, 592 compounds were tested through medium-throughput screening assays. A subset of 14 compounds successfully inhibited the enzyme activity in the low micromolar range of at least one of the enzymes from both Trypanosoma brucei and Lesihmania major parasites (pan-inhibitors), or from both PTR1 and DHFR-TS of the same parasite (dual inhibitors). Molecular docking studies of the protein–ligand interaction focused on new scaffolds not reproducing the well-known antifolate core clearly explaining the experimental data. TCMDC-143249, classified as a benzenesulfonamide derivative by the QikProp descriptor tool, showed selective inhibition of PTR1 and growth inhibition of the kinetoplastid parasites in the 5 µM range. In our work, we enlarged the biological profile of the GSK Kinetobox and identified new core structures inhibiting selectively PTR1, effective against the kinetoplastid infectious protozoans. In perspective, we foresee the development of selective PTR1 and DHFR inhibitors for studies of drug combinations

Megazol and its bioisostere 4H-1,2,4-triazole: comparing the trypanocidal, cytotoxic and genotoxic activities and their in vitro and in silico interactions with the Trypanosoma brucei nitroreductase enzyme

Megazol (7) is a 5-nitroimidazole that is highly active against Trypanosoma cruzi and Trypanosoma brucei, as well as drug-resistant forms of trypanosomiasis. Compound 7 is not used clinically due to its mutagenic and genotoxic properties, but has been largely used as a lead compound. Here, we compared the activity of 7 with its 4H-1,2,4-triazole bioisostere (8) in bloodstream forms of T. brucei and T. cruzi and evaluated their activation by T. brucei type I nitroreductase (TbNTR) enzyme. We also analysed the cytotoxic and genotoxic effects of these compounds in whole human blood using Comet and fluorescein diacetate/ethidium bromide assays. Although the only difference between 7 and 8 is the substitution of sulphur (in the thiadiazole in 7) for nitrogen (in the triazole in 8), the results indicated that 8 had poorer antiparasitic activity than 7 and was not genotoxic, whereas 7 presented this effect. The determination of Vmax indicated that although 8 was metabolised more rapidly than 7, it bounds to the TbNTR with better affinity, resulting in equivalent kcat/KM values. Docking assays of 7 and 8 performed within the active site of a homology model of the TbNTR indicating that 8 had greater affinity than 7

Co-Design of Do-It-Yourself Face Shield in Japan Under COVID-19 Pandemic

  Along with the spread of open design environments and various types of digital fabrication tools (e.g., computer numerical control machines, laser cutting devices, and 3D printers), the "maker movement" or "personal fabrication" has been spreading worldwide over the past decade. This case study introduces grassroots activities in Japan that are employing personal fabrication tools to manage the COVID-19 crisis, focusing on the co-design of do-it-yourself face shields for healthcare workers. We address various issues emerging from the activities of face shield production: (1) development of face shield designs and materials, (2) examination and information sharing regarding the practicality and safety of open-source designs, and (3) collaboration with local factories. Thus, we demonstrate the significance of maker contributions to COVID-19, and provide suggestions for challenges in the future

Avaliação da sequência mDixon Quant na medição da gordura no fígado

Mestrado em Radiações Aplicadas às Tecnologias da Saúde. - Área de especialização: Ressonância MagnéticaA esteatose hepática (EH), apesar de silenciosa, é uma patologia frequente dos dias atuais. Estudos indicam que a sua prevalência pode atingir 24% da população em geral. A presença de gordura no fígado é considerada normal, todavia quando a sua percentagem atinge ou ultrapassa 5%, deve ser tratada o mais rapidamente possível. Dentre os diferentes métodos de diagnóstico, a biópsia tem sido padrão de referência não só para a sua deteção, como também para a caracterização da sua evolução. Todavia, por se tratar de um método invasivo, nem sempre é viável. Por outro lado, dentre os diversos métodos de diagnóstico por imagem, a ultrassonografia é um método amplamente disponível e sem contraindicações, no entanto por basear-se em critérios subjetivos, não permite uma quantificação fiável da gordura. Por sua vez, a tomografia computadorizada, mais frequentemente utilizada, tem como desvantagem os efeitos nocivos da radiação ionizante. A ressonância magnética (RM) é o método não invasivo mais eficaz, tendo ainda como vantagem a não utilização de radiação ionizante. Dentro das diversas possibilidades que a RM oferece para o diagnóstico e caracterização da EH, a técnica de Dixon vem tomando grande espaço no que diz respeito à sua deteção precoce. A sequência mDixon Quant possibilita através do recurso à ROI´s ou por medição volumétrica a quantificação da fração de gordura (FG) existente no fígado. Dois softwares distintos desenvolvidos neste campo serão analisados neste estudo. Este estudo incluiu 57 voluntários (saudáveis) com idades compreendidas entre 23 e 68 anos e 11 utentes, com idades compreendidas entre 22 e 77 anos. Segundo os valores obtidos através do Software Extended MR WorkSpace Philips (ROI´s), dentre os 57 voluntários, 19,3% foram diagnosticados com EH e dentre os 11 utentes, este valor atingiu 45,5%. Por outro lado, ao considerar o valor da FG obtido através do software “Demo” (medição volumétrica) a percentagem de voluntários diagnosticados com EH subiu para 35,1% e dos utentes para 72,7%. Verificou-se que a análise obtida através do Software Extended MR WorkSpace Philips encontra-se em maior concordância com valores obtidos através da biópsia, assim como descrito na literatura, facto corroborado neste estudo. Assim sendo, segundo os valores obtidos, sugere-se a utilização da técnica que recorre aos ROI´s devido ao fato do software “Demo” apresentar na maioria dos casos superestimação dos valores de FG obtidos.ABSTRACT - Hepatic steatosis (HS), although silent, is a frequent pathology of the present day. Studies indicate that its prevalence can reach 24% of the general population. The presence of fat in the liver is considered normal, however, when the percentage of fat reaches or exceeds 5%, it should be treated as soon as possible. Among the different diagnostic methods, biopsy has been a reference standard not only for its diagnosis but also for the characterization of its evolution. However, because it is an invasive method, it is not always feasible. On the other hand, among the various diagnostic imaging methods, ultrasonography is a widely available method without contraindications, however, because it is based on subjective criteria, it does not allow reliable quantification of fat. In turn, computed tomography, more frequently used, has as a disadvantage the harmful effects of ionizing radiation. Magnetic resonance imaging (MRI) is the most effective non-invasive method, with the advantage of not using ionizing radiation. Within the various possibilities that MRI offers for the diagnosis and characterization of HS, Dixon's technique has been taking up great space with regard to the early detection of HS. The mDixon Quant sequence makes it possible through the use of ROIs or by volumetric measurement the quantification of the fat fraction in the liver. Two different software developed in this field will be analyzed in this study. This study included 57 volunteers considered healthy aged between 23 and 68 years and 11 users, aged between 22 and 77 years. According to the values obtained through the Philips Extended MR WorkSpace Software (ROI), among the 57 volunteers, 19.3% were diagnosed with HS and among the 11 users, this figure reached 45.5%. On the other hand, when considering the value of fat fraction obtained through the software "Demo" (volumetric measurement) the value of volunteers diagnosed with HS rose to 35.1% and users to 72.7%. It was verified that the analysis obtained through the Philips Extended MR WorkSpace Software is in greater agreement with values obtained through biopsy, as described in the literature, a fact corroborated by the values obtained with this study. Thus, according to this study, it is suggested the use of the technique that uses ROIs due to the fact that the software "Demo" presents in most cases overestimation of the fat fraction values obtained.N/

Synthesis of Bioactive Heterocycles

The Discovery of a variety of heterocyclic drugs for the treatment of cancer and other diseases (e.g, neglected tropical diseases) is a medical breakthrough and inspiring for the research community as a whole. A wide range of natural, semi-synthetic, and synthetic anticancer drugs are synthesized using various methods. Among them, β -lactams stand out as a novel class of antibiotics that has different types of biological as well as anti-cancer properties. β -lactam has become a premier and active research subject towards the development of revolutionary anti-cancer drugs. In recent years, a large amount of investigations have been done to find the anticancer effect of β -lactams. There exist clinically established synthetic methods to synthesize the beta-lactam ring. To find the better anticancer effect, many bicyclic, polycyclic starting materials have been selectively chosen to be used with the beta-lactam ring. Many endeavors conducted comprehensive biological studies to determine the anticancer activity of such synthetic β -lactams. Also, to investigate the binding effect of β -lactam, molecular docking studies have been performed. This review discusses several prominent synthetic methods of synthesis and anticancer activity of β -lactams

TriTrypDB: An integrated functional genomics resource for kinetoplastida.

Parasitic diseases caused by kinetoplastid parasites are a burden to public health throughout tropical and subtropical regions of the world. TriTrypDB (https://tritrypdb.org) is a free online resource for data mining of genomic and functional data from these kinetoplastid parasites and is part of the VEuPathDB Bioinformatics Resource Center (https://veupathdb.org). As of release 59, TriTrypDB hosts 83 kinetoplastid genomes, nine of which, including Trypanosoma brucei brucei TREU927, Trypanosoma cruzi CL Brener and Leishmania major Friedlin, undergo manual curation by integrating information from scientific publications, high-throughput assays and user submitted comments. TriTrypDB also integrates transcriptomic, proteomic, epigenomic, population-level and isolate data, functional information from genome-wide RNAi knock-down and fluorescent tagging, and results from automated bioinformatics analysis pipelines. TriTrypDB offers a user-friendly web interface embedded with a genome browser, search strategy system and bioinformatics tools to support custom in silico experiments that leverage integrated data. A Galaxy workspace enables users to analyze their private data (e.g., RNA-sequencing, variant calling, etc.) and explore their results privately in the context of publicly available information in the database. The recent addition of an annotation platform based on Apollo enables users to provide both functional and structural changes that will appear as 'community annotations' immediately and, pending curatorial review, will be integrated into the official genome annotation

Malaria in the prehistoric Caribbean : the hunt for hemozoin.

With the increase in resistance to anti-malarials and global warming trends expanding the habitation range of the mosquito vector, research highlighting the biogeographical contexts of infected populations is critical to understanding epidemiological patterns. A bioarchaeological approach to epidemiology can shed light on previous disease patterns and aid in the prediction of future outbreaks of diseases like malaria. Currently, there is no direct evidence of malaria in the Americas prior to European contact; however, skeletal, archaeological, paleoenvironmental, historic, and ethnohistorical evidence strongly suggest the presence of Plasmodium spp. malaria in indigenous Caribbean skeletal remains held in the Yale Peabody Museum of Natural History’s (YPMNH) Caribbean Collection. Yale’s collection is well preserved and represents indigenous populations inhabiting the Greater and Lesser Antilles from 300 BC-AD 600 and AD 1200-1500. Moreover, some individuals in this collection demonstrate healed or healing cribra orbitalia and porotic hyperostosis lesions on the cranium. One explanation for these anemia-related skeletal markers could be that they are the result of chronic hemolytic anemia, an adaptive response to malaria. Hemozoin, an insoluble biomarker produced by all species of Plasmodium, shows promise in identifying malaria infections in ancient skeletal remains. I utilized Matrix Assisted Laser Desorption Ionization Time of flight Mass Spectrometry (MALDI tof MS), Attenuated Total Reflectance- Fourier Transform Infrared Spectroscopy (ATR-FTIR), and Scanning Electron Microscopy (SEM) to identify hemozoin in indigenous Caribbean skeletal remains. The identification of Plasmodium spp. hemozoin crystals in this skeletal collection points to the presence of malaria in the Americas as early as AD 1000. These data will aid in the generation of a more complete epidemiological curve for Plasmodium spp., enhance our understanding of the early spread of malaria, and contribute to biogeographical studies on European contact with indigenous populations

BenchMarks 2008, May 9

BenchMarks. Friday, May 9, 2008 The community newsletter of The Rockefeller University BenchMarks is published monthly and is distributed on the campus of The Rockefeller University. It produced by the Office of Communications and Public Affairshttps://digitalcommons.rockefeller.edu/benchmarks_2008/1002/thumbnail.jp