Antiplasmodial activity of chloroquine analogs against chloroquine-resistant parasites, docking studies and mechanisms of drug action

Submitted by Nuzia Santos ([email protected]) on 2015-03-02T17:19:49Z No. of bitstreams: 1 2014_121.pdf: 1273925 bytes, checksum: 09c618c236f85c7e45f2ad6a53efc484 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2015-03-02T17:19:57Z (GMT) No. of bitstreams: 1 2014_121.pdf: 1273925 bytes, checksum: 09c618c236f85c7e45f2ad6a53efc484 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2015-03-02T17:23:45Z (GMT) No. of bitstreams: 1 2014_121.pdf: 1273925 bytes, checksum: 09c618c236f85c7e45f2ad6a53efc484 (MD5)Made available in DSpace on 2015-03-02T17:23:45Z (GMT). No. of bitstreams: 1 2014_121.pdf: 1273925 bytes, checksum: 09c618c236f85c7e45f2ad6a53efc484 (MD5) Previous issue date: 2014Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Malária. Belo Horizonte, MG, BrazilUniversidade Federal de Juiz de Fora. Instituto de Ciências Exatas. Departamento de Química. Juiz de Fora, MG, BrazilUniversidade Federal de Juiz de Fora. Instituto de Ciências Exatas. Departamento de Química. Juiz de Fora, MG, BrazilInstituto Militar de Engenharia. Laboratório de Modelagem Molecular Aplicada à Defesa Química e Biológica. Rio de Janeiro, RJ, BrazilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Malária. Belo Horizonte, MG, BrazilBackground: Given the threat of resistance of human malaria parasites, including to artemisinin derivatives, new agents are needed. Chloroquine (CQ) has been the most widely used anti-malarial, and new analogs (CQAns) presenting alkynes and side chain variations with high antiplasmodial activity were evaluated. Methods: Six diaminealkyne and diaminedialkyne CQAns were evaluated against CQ-resistant (CQ-R) (W2) and CQ-sensitive (CQ-S) (3D7) Plasmodium falciparum parasites in culture. Drug cytotoxicity to a human hepatoma cell line (HepG2) evaluated, allowed to calculate the drug selectivity index (SI), a ratio of drug toxicity to activity in vitro. The CQAns were re-evaluated against CQ-resistant and -sensitive P. berghei parasites in mice using the suppressive test. Docking studies with the CQAns and the human (HssLDH) or plasmodial lactate dehydrogenase (PfLDH) enzymes, and, a β-haematin formation assay were performed using a lipid as a catalyst to promote crystallization in vitro. Results: All tested CQAns were highly active against CQ-R P. falciparum parasites, exhibiting half-maximal inhibitory concentration (IC50) values below 1 μΜ. CQAn33 and CQAn37 had the highest SIs. Docking studies revealed the best conformation of CQAn33 inside the binding pocket of PfLDH; specificity between the residues involved in H-bonds of the PfLDH with CQAn37. CQAn33 and CQAn37 were also shown to be weak inhibitors of PfLDH. CQAn33 and CQAn37 inhibited β-haematin formation with either a similar or a 2-fold higher IC50 value, respectively, compared with CQ. CQAn37 was active in mice with P. berghei, reducing parasitaemia by 100%. CQAn33, -39 and -45 also inhibited CQ-resistant P. berghei parasites in mice, whereas high doses of CQ were inactive. Conclusions: The presence of an alkyne group and the size of the side chain affected anti-P. falciparum activityin vitro. Docking studies suggested a mechanism of action other than PfLDH inhibition. The β-haematin assay suggested the presence of an additional mechanism of action of CQAn33 and CQAn37. Tests with CQAn34, CQAn37, CQAn39 and CQAn45 confirmed previous results against P. berghei malaria in mice, and CQAn33, 39 and 45 were active against CQ-resistant parasites, but CQAn28 and CQAn34 were not. The result likely reflects structure-activity relationships related to the resistant phenotype

Freezing and water availability structure the evolutionary diversity of trees across the Americas

The historical course of evolutionary diversification shapes the current distribution of biodiversity, but the main forces constraining diversification are still a subject of debate. We unveil the evolutionary structure of tree species assemblages across the Americas to assess whether an inability to move or an inability to evolve is the predominant constraint in plant diversification and biogeography. We find a fundamental divide in tree lineage composition between tropical and extratropical environments, defined by the absence versus presence of freezing temperatures. Within the Neotropics, we uncover a further evolutionary split between moist and dry forests. Our results demonstrate that American tree lineages tend to retain their ancestral environmental relationships and that phylogenetic niche conservatism is the primary force structuring the distribution of tree biodiversity. Our study establishes the pervasive importance of niche conservatism to community assembly even at intercontinental scales

Natural archives of long-range transported contamination at the remote lake Letšeng-la Letsie, Maloti Mountains, Lesotho

Naturally accumulating archives, such as lake sediments and wetland peats, in remote areas may be used to identify the scale and rates of atmospherically deposited pollutant inputs to natural ecosystems. Co-located lake sediment and wetland cores were collected from Letšeng-la Letsie, a remote lake in the Maloti Mountains of southern Lesotho. The cores were radiometrically dated and analysed for a suite of contaminants including trace metals and metalloids (Hg, Pb, Cu, Ni, Zn, As), fly-ash particles, stable nitrogen isotopes, polycyclic aromatic hydrocarbons (PAHs) and persistent organic pollutants such as polychlorinated biphenyls (PCBs), polybrominated flame retardants (PBDEs) and hexachlorobenzene (HCB). While most trace metals showed no recent enrichment, mercury, fly-ash particles, high molecular weight PAHs and total PCBs showed low but increasing levels of contamination since c.1970, likely the result of long-range transport from coal combustion and other industrial sources in the Highveld region of South Africa. However, back-trajectory analysis revealed that atmospheric transport from this region to southern Lesotho is infrequent and the scale of contamination is low. To our knowledge, these data represent the first palaeolimnological records and the first trace contaminant data for Lesotho, and one of the first multi-pollutant historical records for southern Africa. They therefore provide a baseline for future regional assessments in the context of continued coal combustion in South Africa through to the mid-21st century

Produção orgânica de rabanete em plantio direto sobre cobertura morta e viva.

O objetivo deste trabalho foi avaliar o uso de plantas espontâneas e cobertura viva de amendoim forrageiro(Arachis pintoi), associado à aplicação de composto orgânico na produção orgânica do rabanete em plantio direto. O experimento foi instalado na Universidade Federal do Acre, em Rio Branco-AC, de 15/06 a 14/07/2007. O delineamento experimental utilizado foi em blocos casualizados com parcelas subdivididas 4x3, em quatro repetições. As parcelas corresponderam ao sistema de plantio direto com cobertura viva de amendoim forrageiro, cobertura viva de planta espontânea, cobertura morta de planta espontânea e sistema de plantio em canteiro com solo descoberto. As subparcelas foram compostas pelas doses de composto orgânico de 5, 10 e 15 t ha-1 (base seca). O plantio direto na palha de plantas espontâneas teve desempenho semelhante ao preparo convencional do solo, ambos superiores ao plantio sobre as coberturas vivas. A produtividade do rabanete cv. Cometo, não foi afetada pelas doses crescentes de composto orgânico, podendo aplicar-se apenas 5 t ha-1, enquanto em preparo convencional do solo, o aumento da produtividade ultrapassa o plantio direto na palha apenas na dose maior de composto (15 t ha-1)

COVID-SGIS: A Smart Tool for Dynamic Monitoring and Temporal Forecasting of Covid-19

Background: The global burden of the new coronavirus SARS-CoV-2 is increasing at an unprecedented rate. The current spread of Covid-19 in Brazil is problematic causing a huge public health burden to its population and national health-care service. To evaluate strategies for alleviating such problems, it is necessary to forecast the number of cases and deaths in order to aid the stakeholders in the process of making decisions against the disease. We propose a novel system for real-time forecast of the cumulative cases of Covid-19 in Brazil. / Methods: We developed the novel COVID-SGIS application for the real-time surveillance, forecast and spatial visualization of Covid-19 for Brazil. This system captures routinely reported Covid-19 information from 27 federative units from the Brazil.io database. It utilizes all Covid-19 confirmed case data that have been notified through the National Notification System, from March to May 2020. Time series ARIMA models were integrated for the forecast of cumulative number of Covid-19 cases and deaths. These include 6-days forecasts as graphical outputs for each federative unit in Brazil, separately, with its corresponding 95% CI for statistical significance. In addition, a worst and best scenarios are presented. / Results: The following federative units (out of 27) were flagged by our ARIMA models showing statistically significant increasing temporal patterns of Covid-19 cases during the specified day-to-day period: Bahia, Maranhão, Piauí, Rio Grande do Norte, Amapá, Rondônia, where their day-to-day forecasts were within the 95% CI limits. Equally, the same findings were observed for Espírito Santo, Minas Gerais, Paraná, and Santa Catarina. The overall percentage error between the forecasted values and the actual values varied between 2.56 and 6.50%. For the days when the forecasts fell outside the forecast interval, the percentage errors in relation to the worst case scenario were below 5%. / Conclusion: The proposed method for dynamic forecasting may be used to guide social policies and plan direct interventions in a cost-effective, concise, and robust manner. This novel tools can play an important role for guiding the course of action against the Covid-19 pandemic for Brazil and country neighbors in South America

Covid-19 Dynamic Monitoring and Real-Time Spatio-Temporal Forecasting

Background: Periodically, humanity is often faced with new and emerging viruses that can be a significant global threat. It has already been over a century post—the Spanish Flu pandemic, and we are witnessing a new type of coronavirus, the SARS-CoV-2, which is responsible for Covid-19. It emerged from the city of Wuhan (China) in December 2019, and within a few months, the virus propagated itself globally now resulting more than 50 million cases with over 1 million deaths. The high infection rates coupled with dynamic population movement demands for tools, especially within a Brazilian context, that will support health managers to develop policies for controlling and combating the new virus. / Methods: In this work, we propose a tool for real-time spatio-temporal analysis using a machine learning approach. The COVID-SGIS system brings together routinely collected health data on Covid-19 distributed across public health systems in Brazil, as well as taking to under consideration the geographic and time-dependent features of Covid-19 so as to make spatio-temporal predictions. The data are sub-divided by federative unit and municipality. In our case study, we made spatio-temporal predictions of the distribution of cases and deaths in Brazil and in each federative unit. Four regression methods were investigated: linear regression, support vector machines (polynomial kernels and RBF), multilayer perceptrons, and random forests. We use the percentage RMSE and the correlation coefficient as quality metrics. / Results: For qualitative evaluation, we made spatio-temporal predictions for the period from 25 to 27 May 2020. Considering qualitatively and quantitatively the case of the State of Pernambuco and Brazil as a whole, linear regression presented the best prediction results (thematic maps with good data distribution, correlation coefficient >0.99 and RMSE (%) <4% for Pernambuco and around 5% for Brazil) with low training time: [0.00; 0.04 ms], CI 95%. / Conclusion: Spatio-temporal analysis provided a broader assessment of those in the regions where the accumulated confirmed cases of Covid-19 were concentrated. It was possible to differentiate in the thematic maps the regions with the highest concentration of cases from the regions with low concentration and regions in the transition range. This approach is fundamental to support health managers and epidemiologists to elaborate policies and plans to control the Covid-19 pandemics

Revealing the clinical phenotype of atypical neuronal ceroid lipofuscinosis type 2 disease: Insights from the largest cohort in the world

Aim: Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is an autosomal recessive inherited neurodegenerative lysosomal storage disorder caused by deficient tripeptidyl peptidase 1 (TPP1) enzyme, leading to progressive deterioration of neurological functions commonly occurring in children aged 2–4 years and culminating in early death. Atypical cases associated with earlier or later symptom onset, or even protracted course, have already been reported. Such variable manifestations may constitute an additional challenge to early diagnosis and initiation of appropriate treatment. The present work aimed to analyse clinical data from a cohort of Latin American CLN2 patients with atypical phenotypes. Methods: Experts in inborn errors of metabolism from Latin America selected patients from their centres who were deemed by the clinicians to have atypical forms of CLN2, according to the current literature on this topic and their practical experience. Clinical and genetic data from the medical records were retrospectively revised. All cases were presented and analysed by these experts at an Advisory Board Meeting in S~ao Paulo, Brazil, in October 2018. Results: Seizures, language abnormalities and behavioural disorders were found as the first manifestations, appearing at the median age of 6 years, an older age than classically described for the late infantile form. Three novel mutations were also identified. Conclusion: Our findings reinforce the inclusion of CLN2 in the differential diagnosis of children presenting with seizures, behavioural disorders and language abnormalities. Early diagnosis will allow early initiation of specific therapy