Establishment of a screening platform based on human coronavirus OC43 for the identification of microbial natural products with antiviral activity.

IMPORTANCE: The COVID-19 pandemic has revealed the lack of effective treatments against betacoronaviruses and the urgent need for new broad-spectrum antivirals. Natural products are a valuable source of bioactive compounds with pharmaceutical potential that may lead to the discovery of new antiviral agents. Specifically, compared to conventional synthetic molecules, microbial natural extracts possess a unique and vast chemical diversity and are amenable to large-scale production. The implementation of a high-throughput screening platform using the betacoronavirus OC43 in a human cell line infection model has provided proof of concept of the approach and has allowed for the rapid and efficient evaluation of 1,280 microbial extracts. The identification of several active compounds validates the potential of the platform for the search for new compounds with antiviral capacity.

Corrigendum: Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes.

[This corrects the article DOI: 10.3389/fmicb.2023.1149145.].

A nuclear orthologue of the dNTP triphosphohydrolase SAMHD1 controls dNTP homeostasis and genomic stability in Trypanosoma brucei.

Maintenance of dNTPs pools in Trypanosoma brucei is dependent on both biosynthetic and degradation pathways that together ensure correct cellular homeostasis throughout the cell cycle which is essential for the preservation of genomic stability. Both the salvage and de novo pathways participate in the provision of pyrimidine dNTPs while purine dNTPs are made available solely through salvage. In order to identify enzymes involved in degradation here we have characterized the role of a trypanosomal SAMHD1 orthologue denominated TbHD82. Our results show that TbHD82 is a nuclear enzyme in both procyclic and bloodstream forms of T. brucei. Knockout forms exhibit a hypermutator phenotype, cell cycle perturbations and an activation of the DNA repair response. Furthermore, dNTP quantification of TbHD82 null mutant cells revealed perturbations in nucleotide metabolism with a substantial accumulation of dATP, dCTP and dTTP. We propose that this HD domain-containing protein present in kinetoplastids plays an essential role acting as a sentinel of genomic fidelity by modulating the unnecessary and detrimental accumulation of dNTPs.

Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes.

Acanthamoeba species, Naegleria fowleri, and Balamuthia mandrillaris are opportunistic pathogens that cause a range of brain, skin, eye, and disseminated diseases in humans and animals. These pathogenic free-living amoebae (pFLA) are commonly misdiagnosed and have sub-optimal treatment regimens which contribute to the extremely high mortality rates (>90%) when they infect the central nervous system. To address the unmet medical need for effective therapeutics, we screened kinase inhibitor chemotypes against three pFLA using phenotypic drug assays involving CellTiter-Glo 2.0. Herein, we report the activity of the compounds against the trophozoite stage of each of the three amoebae, ranging from nanomolar to low micromolar potency. The most potent compounds that were identified from this screening effort were: 2d (A. castellanii EC50: 0.92 ± 0.3 µM; and N. fowleri EC50: 0.43 ± 0.13 µM), 1c and 2b (N. fowleri EC50s: <0.63 µM, and 0.3 ± 0.21 µM), and 4b and 7b (B. mandrillaris EC50s: 1.0 ± 0.12 µM, and 1.4 ± 0.17 µM, respectively). With several of these pharmacophores already possessing blood-brain barrier (BBB) permeability properties, or are predicted to penetrate the BBB, these hits present novel starting points for optimization as future treatments for pFLA-caused diseases.

Achievement Goals across Persistence-Validation of the Spanish Version of the Motivational Persistence Scale.

BACKGROUND: An important aspect of achievement goals is the persistence and determination that the person possesses in order to achieve it. Spain does not have an adequate instrument for its measurement. First, this article had the aim of adapt and validate the Motivational Persistence Scale of Constantin et al. in a Spanish population and athletes. Second, it had the aim of prove the relationship with deliberate practice and performance. METHODS: In this study, 384 university students participated, where the factor structure was analyzed by means of a Confirmatory Factor Analysis (CFA). In study 2 of 169 athletes was used to confirm its validity in a homogeneous population and its predictive capacity on the hours of deliberate practice (DP) and performance. RESULTS: The AFC showed a two-factor structure, reducing the original three-factor structure, presenting a good fit in both Spanish and homogeneous population of athletes and achieving a significant predictive capacity on deliberate practice. The new dimensions were Purpose Pursuing (PP) and Recurrence of Unattained Purposes (RUP). CONCLUSIONS: Overall, our results provide evidence that this scale could be a useful tool for the assessment of Persistence in the Spanish adult and athlete population.

Lead Optimization of 3,5-Disubstituted-7-Azaindoles for the Treatment of Human African Trypanosomiasis.

Neglected tropical diseases such as human African trypanosomiasis (HAT) are prevalent primarily in tropical climates and among populations living in poverty. Historically, the lack of economic incentive to develop new treatments for these diseases has meant that existing therapeutics have serious shortcomings in terms of safety, efficacy, and administration, and better therapeutics are needed. We now report a series of 3,5-disubstituted-7-azaindoles identified as growth inhibitors of Trypanosoma brucei, the parasite that causes HAT, through a high-throughput screen. We describe the hit-to-lead optimization of this series and the development and preclinical investigation of 29d, a potent antitrypanosomal compound with promising pharmacokinetic (PK) parameters. This compound was ultimately not progressed beyond in vivo PK studies due to its inability to penetrate the blood-brain barrier (BBB), critical for stage 2 HAT treatments.

A Mitochondrial Orthologue of the dNTP Triphosphohydrolase SAMHD1 Is Essential and Controls Pyrimidine Homeostasis in Trypanosoma brucei.

The maintenance of deoxyribonucleotide triphosphate (dNTP) homeostasis through synthesis and degradation is critical for accurate genomic and mitochondrial DNA replication fidelity. Trypanosoma brucei makes use of both the salvage and de novo pathways for the provision of pyrimidine dNTPs. In this respect, the sterile α motif and histidine-aspartate domain-containing protein 1 (SAMHD1) appears to be the most relevant dNTPase controlling dNTP/deoxynucleoside homeostasis in mammalian cells. Here, we have characterized the role of a unique trypanosomal SAMHD1 orthologue denominated TbHD52. Our results show that TbHD52 is a mitochondrial enzyme essential in bloodstream forms of T. brucei. Knockout cells are pyrimidine auxotrophs that exhibit strong defects in genomic integrity, cell cycle progression, and nuclear DNA and kinetoplast segregation in the absence of extracellular thymidine. The lack of TbHD52 can be counteracted by the overexpression of human dCMP deaminase, an enzyme that is directly involved in dUMP formation yet absent in trypanosomes. Furthermore, the cellular dNTP quantification and metabolomic analysis of TbHD52 null mutants revealed perturbations in the nucleotide metabolism with a substantial accumulation of dCTP and cytosine-derived metabolites while dTTP formation was significantly reduced. We propose that this HD-domain-containing protein unique to kinetoplastids plays an essential role in pyrimidine dNTP homeostasis and contributes to the provision of deoxycytidine required for cellular dTTP biosynthesis.

How Enaction and Ecological Approaches Can Contribute to Sports and Skill Learning.

The purpose of this paper is to explain learning in sports and physical education (PE) from the perspective of enactive and ecological psychology. The learning process is first presented from the enactive perspective, and some relevant notions such as sense-making and sensorimotor schemes are developed. Then, natural learning environments are described, and their importance in the human development process is explained. This is followed by a section devoted to the learner's experience in which some research methods are explained, such as neurophenomenology, in addition to self-confrontation, interviews aimed at bringing out the meaning, sensations, and emotions that performers experience when they are immersed in their sport or a PE class. The sections on the ecological approach deal with the attunement, calibration, the education of intention, and the importance of representative experimental designs. The last section addresses the main similarities and differences between the two approaches. Finally, we state our theoretical position in favor of a common project that brings together the main elements of both post-cognitive approaches.

Motor competence difficulties and attention deficit and hyperactivity disorder (ADHD) among secondary students / Problemas de competencia motriz y el trastorno por déficit de atención e hiperactividad (TDAH) entre los estudiantes de Secundaria / Problemas de competência motora e transtorno do déficit de atenção e hiperatividade (TDAH) em estudantes do ensino médio

A high proportion of children with Attention problems (ADHD) experience motor competence problems. The present study sought to compare the motor competence between a group of ADHD students and a normative sample before and after controlling for motor coordination problems, and check if there are differences between the group with ADHD and the group with DT, depending on the presence or not of the DCD concurrent with the ADHD. A total of 22 children with ADHD combined type (ADHD-CT; 12-13 years, SD 0.7, 16 males, 6 females) and 23 age-matched typically developing children with no movement difficulties (12-13 years, SD 0.7 16 males, 7 females) participated in this study. Motor coordination was measured using the Movement Assessment Battery for Children-2nd Edition (MABC-2). ADHD symptoms were assessed by the school's Department of Psychology.The ADHD diagnosis is based on diagnostic criteria established by the Diagnostic and statistical manual of mental disorders, fifth edition (DSM-5), and the application of the following behavioral scales and evaluation of executive functions have been followed: Child Behavior Checklist for ages; Behavior Ratting Inventory of Executive Functions (BRIEF); Scales for the Evaluation of ADHD (EDAH). Based on the MABC-2 score (percentile score ≤ 5th), ADHD children were classified into two groups: co-occurring DCD/ADHD and ADHD group. Results showed that children with ADHD and typically developing (TD) children showed big individual differences on all motor skill areas and on overall percentile scores. Thirteen children with ADHD were delayed, and three were at risk for motor delays. Only four TD children were at risk for motor delays. DCD/ADHD group scored significantly lower than the TD group across all motor skill areas, while ADHD group scored lower than the TD group only on manual dexterity

Existe una alta proporción de niños en los que coexisten los problemas de atención e hiperactividad, con bajos niveles de competencia motriz. El presente estudio, busca comparar los niveles de competencia motriz entre un grupo de niños con diagnóstico por Trastorno por Déficit de Atención e Hiperactividad (TDAH) y un grupo con desarrollo típico (DT), y comprobar si hay diferencias entre el grupo con TDAH y el grupo con DT, en función de la presencia o no del TDC concurrente con el TDAH. Un total de 22 niños con TDAH, subtipo combinado (TDAH-TC; 12 a 13 años,DT0.7 16 varones, 6 mujeres) y 23 niños con desarrollo típico, sin dificultades de movimiento (12 a 13 años, DT0.7,16 hombres y 7 mujeres), participaron en este estudio. La coordinación motora o competencia motriz, fue evaluada a través de la Batería de Evaluación del Movimiento para niños ABC-Movement, en su 2ª edición (MABC-2). El diagnóstico de TDAH, procede del Departamento de Orientación y Psicología del Centro Educativo del que proceden los niños evaluados. Para ello, se han seguido los criterios de diagnóstico que establece el Manual diagnóstico y estadístico de los trastornos mentales, quinta edición (DSM-5),y la aplicación de las siguientes escalas de comportamiento, y de evaluación de las funciones ejecutivas: Child Behavior Checklist for ages; Behavior Ratting Inventory of Executive Functions (BRIEF); Escalas para la Evaluación del TDAH (EDAH). Los resultados mostraron que, aquellos niños con TDAH, obtuvieron valores más bajos en el test de evaluación, que aquellos que mostraban un desarrollo típico. Además, en el grupo de niños con TDAH, se determinó que 13 de ellos, presentaban problemas en el desarrollo de la coordinación

Uma alta proporção de crianças com problemas de atenção (TDAH) tem problemas de competênciamotora. O presente estudo buscou comparar a competência motora entre um grupo de alunos com TDAH e uma amostra normativa antes e após o controle de problemas de coordenação motora, e verifique se há diferenças entre o grupo com TDAH e o grupo com DT, dependendo da presença ou não do TDC concomitante ao TDAH.Um total de 22 crianças com TDAH do tipo combinado (ADHD-CT; 12-13 anos,DT0.7, 16 homens, 6 mulheres) e 23 crianças com idade de desenvolvimento típico sem dificuldades de movimento (12-13 anos, DT0.7, 16 homens, 7 mulheres) participaram deste estudo. A coordenação motora foi medida usando a Bateria de Avaliação de Movimento para Crianças -2ª Edição (MABC-2). Sintomas de TDAH foram avaliados pelo Departamento de Psicologia da escola. Para tanto, foram seguidos os critérios diagnósticos estabelecidos no Manual Diagnóstico e Estatístico de Transtornos Mentais, quinta edição (DSM-5), e a aplicação das seguintes escalas comportamentais e avaliação das funções executivas: Comportamento Infantil Lista de verificação para idades; Comportamento Ratting Inventory of Executive Functions (BRIEF); Escalas para a avaliação do TDAH (EDAH). Com base no escore MABC-2 (escore percentual ≤ 5), as crianças com TDAH foram classificadas em dois grupos: grupo com DCD / TDAH e TDAH. Os resultados mostraram que crianças com TDAH e crianças com desenvolvimento típico (DT) apresentaram grandes diferenças individuais em todas as áreas de habilidades motoras e nos escores percentuais gerais. Treze crianças com TDAH foram atrasadas e três correram risco de atrasos motores. Apenas quatro crianças com DT estavam em risco de atrasos motores. DCD / ADHD grupo marcou significativamente menor do que o grupo TD em todas as áreas de habilidades motoras, enquanto o grupo TDAH marcou menos do que o grupo TD apenas na destreza manual

Structure-property studies of an imidazoquinoline chemotype with antitrypanosomal activity.

Human African trypanosomiasis is a neglected tropical disease (NTD) that is fatal if left untreated. Although approximately 13 million people live in moderate- to high-risk areas for infection, current treatments are plagued by problems with safety, efficacy, and emerging resistance. In an effort to fill the drug development pipeline for HAT, we have expanded previous work exploring the chemotype represented by the compound NEU-1090, with a particular focus on improvement of absorption, distribution, metabolism and elimination (ADME) properties. These efforts resulted in several compounds with substantially improved aqueous solubility, although these modifications typically resulted in a loss of trypanosomal activity. We herein report the results of our investigation into the antiparasitic activity, toxicity, and ADME properties of this class of compounds in the interest of informing the NTD drug discovery community and avoiding duplication of effort.

Selectivity and Physicochemical Optimization of Repurposed Pyrazolo[1,5-b]pyridazines for the Treatment of Human African Trypanosomiasis.

From a high-throughput screen of 42 444 known human kinases inhibitors, a pyrazolo[1,5-b]pyridazine scaffold was identified to begin optimization for the treatment of human African trypanosomiasis. Previously reported data for analogous compounds against human kinases GSK-3ß, CDK-2, and CDK-4 were leveraged to try to improve the selectivity of the series, resulting in 23a which showed selectivity for T. b. brucei over these three human enzymes. In parallel, properties known to influence the absorption, distribution, metabolism, and excretion (ADME) profile of the series were optimized resulting in 20g being progressed into an efficacy study in mice. Though 20g showed toxicity in mice, it also demonstrated CNS penetration in a PK study and significant reduction of parasitemia in four out of the six mice.

Deliberate practice in training differentiates the best Kenyan and Spanish long-distance runners.

The aim of this novel research was to compare the amount of systematic training and the different training activities undertaken by elite-standard long-distance runners during their first seven years of systematic training. Participants were divided into three performance groups: world-class Kenyans (N = 19), European-standard Spanish athletes (N = 18), and Spanish national-standard athletes (N = 18). Performance and training data were obtained for two-year periods using retrospective recall (including training diaries) from the time the athletes began systematic training, until the seventh year after. These activities included high-intensity training sessions considered deliberate practice (DP) and easy runs. There was no evidence that starting systematic training at a younger age was advantageous, and easy runs (a non-DP activity) were the most used by participants as a proportion of overall running distance. As part of an overall higher accumulation of distance run (P < 0.001, d ≥ 1.35), the Kenyans completed more tempo runs and short-interval training than the other groups (P < 0.001, d ≥ 1.38), but did not complete more long intervals or races. There were few differences between the European- and national-standard athletes except for easy runs, which highlights the value of these easy runs but also the need for higher-intensity training to compete with world-class performers. When planning for training overload and progression, long-distance running coaches should consider increasing the volume of tempo runs and short intervals, in addition to easier runs that develop cardiovascular conditioning.

Validation of Plasmodium falciparum dUTPase as the target of 5'-tritylated deoxyuridine analogues with anti-malarial activity.

BACKGROUND: Malaria remains as a major global problem, being one of the infectious diseases that engender highest mortality across the world. Due to the appearance of resistance and the lack of an effective vaccine, the search of novel anti-malarials is required. Deoxyuridine 5'-triphosphate nucleotido-hydrolase (dUTPase) is responsible for the hydrolysis of dUTP to dUMP within the parasite and has been proposed as an essential step in pyrimidine metabolism by providing dUMP for thymidylate biosynthesis. In this work, efforts to validate dUTPase as a drug target in Plasmodium falciparum are reported. METHODS: To investigate the role of PfdUTPase in cell survival different strategies to generate knockout mutants were used. For validation of PfdUTPase as the intracellular target of four inhibitors of the enzyme, mutants overexpressing PfdUTPase and HsdUTPase were created and the IC50 for each cell line with each compound was determined. The effect of these compounds on dUTP and dTTP levels from P. falciparum was measured using a DNA polymerase assay. Detailed localization studies by indirect immunofluorescence microscopy and live cell imaging were also performed using a cell line overexpressing a Pfdut-GFP fusion protein. RESULTS: Different attempts of disruption of the dut gene of P. falciparum were unsuccessful while a 3' replacement construct could recombine correctly in the locus suggesting that the enzyme is essential. The four 5'-tritylated deoxyuridine analogues described are potent inhibitors of the P. falciparum dUTPase and exhibit antiplasmodial activity. Overexpression of the Plasmodium and human enzymes conferred resistance against selective compounds, providing chemical validation of the target and confirming that indeed dUTPase inhibition is involved in anti-malarial activity. In addition, incubation with these inhibitors was associated with a depletion of the dTTP pool corroborating the central role of dUTPase in dTTP synthesis. PfdUTPase is mainly localized in the cytosol. CONCLUSION: These results strongly confirm the pivotal and essential role of dUTPase in pyrimidine biosynthesis of P. falciparum intraerythrocytic stages.

Contribution of Cytidine Deaminase to Thymidylate Biosynthesis in Trypanosoma brucei: Intracellular Localization and Properties of the Enzyme.

Cytidine deaminase (CDA) is a pyrimidine salvage enzyme that catalyzes cytidine and deoxycytidine hydrolytic deamination to yield uridine and deoxyuridine. Here we report the biochemical characterization of Trypanosoma brucei CDA as an enzyme within the tetrameric class of the CDA family that efficiently deaminates cytidine, deoxycytidine, and the nucleoside analogue 5-methyl-2'-deoxycytidine. In line with previous studies, we show that RNA interference (RNAi)-mediated CDA depletion impairs T. brucei proliferation when grown in pyrimidine-deficient medium, while supplementation with thymidine or deoxyuridine restores growth, further underscoring the role of this enzyme in providing deoxyuridine for dUMP formation via thymidine kinase, the substrate required for de novo thymidylate biosynthesis. This observation contrasts with the existence in T. brucei of a dimeric deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), an essential enzyme that can produce dUMP via the hydrolysis of dUTP/dUDP. Thus, T. brucei dUTPase-null mutants are thymidine auxotrophs, suggesting that dUTPase might have a role in providing dUMP for thymidylate biosynthesis. We show that overexpression of human dCMP deaminase (DCTD), an enzyme that provides directly dUMP through dCMP deamination, does not reverse the lethal phenotype of dUTPase knockout cells, which further supports the notion that in T. brucei, CDA is uniquely involved in providing dUMP, while the main role of dUTPase would be the withdrawal of the excess of dUTP to avoid its incorporation into DNA. Furthermore, we report the mitochondrial localization of CDA, highlighting the importance of this organelle in pyrimidine metabolism.IMPORTANCE Cytidine deaminases (CDAs) catalyze the hydrolytic deamination of cytidine and deoxycytidine in the pyrimidine salvage pathway. In kinetoplastids, pyrimidine metabolism has been extensively studied as a source of potential drug targets, given the fact that many of the enzymes of the pathway are essential. Thymidylate (dTMP) synthesis in Trypanosoma brucei exhibits unique characteristics. Thus, it has been suggested that the production of dUMP, the substrate for dTMP formation, is solely dependent on cytidine deaminase and thymidine kinase. Here we characterize recombinant T. brucei CDA (TbCDA) and present evidence that indeed the alternative route for dUMP formation via deoxyuridine 5'-triphosphate nucleotidohydrolase does not have a prominent role in de novo dTMP formation. Furthermore, we provide a scheme for the compartmentalization of dTMP biosynthesis, taking into account the observation that CDA is located in the mitochondrion, together with available information on the intracellular localization of other enzymes involved in the dTTP biosynthetic pathway.

Evaluation of a class of isatinoids identified from a high-throughput screen of human kinase inhibitors as anti-Sleeping Sickness agents.

New treatments are needed for neglected tropical diseases (NTDs) such as Human African trypanosomiasis (HAT), Chagas disease, and schistosomiasis. Through a whole organism high-throughput screening campaign, we previously identified 797 human kinase inhibitors that grouped into 59 structural clusters and showed activity against T. brucei, the causative agent of HAT. We herein report the results of further investigation of one of these clusters consisting of substituted isatin derivatives, focusing on establishing structure-activity and -property relationship scope. We also describe their in vitro absorption, distribution, metabolism, and excretion (ADME) properties. For one isatin, NEU-4391, which offered the best activity-property profile, pharmacokinetic parameters were measured in mice.

1,2-Diphenoxiethane salts as potent antiplasmodial agents.

In this article we present a series of non-cytotoxic potent human choline kinase (CK) inhibitors that exhibit nanomolar antiplasmodial activity in vitro. The most active antiplasmodial compounds, 10a-b, bearing a pyridinium cationic head were inactive against CK, while compounds 10g and 10j with a quinolinium moiety exhibit moderate inhibition of both the parasite and the enzyme. The results point towards an additional mechanism of action unrelated to CK inhibition that remains to be established.

Insights into the role of endonuclease V in RNA metabolism in Trypanosoma brucei.

Inosine may arise in DNA as a result of oxidative deamination of adenine or misincorporation of deoxyinosine triphosphate during replication. On the other hand, the occurrence of inosine in RNA is considered a normal and essential modification induced by specific adenosine deaminases acting on mRNA and tRNA. In prokaryotes, endonuclease V (EndoV) can recognize and cleave inosine-containing DNA. In contrast, mammalian EndoVs preferentially cleave inosine-containing RNA, suggesting a role in RNA metabolism for the eukaryotic members of this protein family. We have performed a biochemical characterization of EndoV from the protozoan parasite Trypanosoma brucei. In vitro, TbEndoV efficiently processes single-stranded RNA oligonucleotides with inosine, including A to I-edited tRNA-like substrates but exhibits weak activity over DNA, except when a ribonucleotide is placed 3' to the inosine. Immunolocalization studies performed in procyclic forms indicate that TbEndoV is mainly cytosolic yet upon nutritional stress it redistributes and accumulates in stress granules colocalizing with the DEAD-box helicase TbDhh1. RNAi-mediated depletion of TbEndoV results in moderate growth defects in procyclic cells while the two EndoV alleles could be readily knocked out in bloodstream forms. Taken together, these observations suggest an important role of TbEndoV in RNA metabolism in procyclic forms of the parasite.

Los corredores kenianos y españoles de larga distancia y su práctica deliberada / Corredores de longa distância quenianos e espanhóis e sua prática deliberada / Kenyan and Spanish long distance runners and their deliberate practice

El presente estudio analizó las percepciones subjetivas de un grupo de corredores kenianos y españoles de larga distancia de nivel internacional sobre sus tareas de entrenamiento. Para alcanzar este objetivo cumplimentaron un cuestionario basado en una taxonomía de actividades de entrenamiento valoradas en cuatro dimensiones: Relevancia, Esfuerzo, Concentración y Diversión. En este estudio participaron 38 corredores divididos en dos grupos por su nacionalidad. Todos estos atletas eran varones y especialistas de pruebas de larga distancia (10000 metros, Media Maratón y Maratón). Los dos grupos de nacionalidad fueron: Kenianos (n= 20) y Españoles (n= 18). Los resultados mostraron que actividades de entrenamiento como la competición o los tests, el interval training largo y corto y las carreras largas a ritmo elevado fueron consideradas como las tareas que mejor caracterizaban la práctica deliberada. Además de ser las que mayor concentración y esfuerzo les reclamaban también fueron las más divertidas. Como diferencias entre grupos más destacadas, los corredores kenianos no practicaban algunas actividades de entrenamiento como el trabajo de pesas y condición física, la técnica de carrera o el entrenamiento alternativo, a diferencia de los españoles. Otro hallazgo ha sido comprobar como los corredores kenianos, en comparación con los corredores españoles, otorgaron una mayor importancia a las carreras largas a ritmo elevado, valorando en ellas de forma clara la concentración (AU)

Within the context of expert performance and the deliberate practice approach, the present study analysed the subjective perceptions about the training tasks of a group of international long distance runners from Spain and Kenya. To do so the athletes fulfilled a questionnaire based on taxonomy of training activities that assessed four dimensions: Relevance, Effort, Concentration, and Enjoyment. Thirty eight male runners participated in this study split into two groups according to their nationality as Kenyan (n= 20) or Spanish (n= 18). All the athletes were long distance runners (10,000 meters, Half Marathon and Marathon). The results showed that training activities such as Competition or tests, Long and short interval training and Tempo runs, were considered the tasks that best characterized their deliberate practice. In addition, these tasks produced more enjoyment and demanded more concentration and effort. The most important differences between groups were that Kenyan runners did not practice some training activities that Spanish runners did such as weights and physical fitness training, running technique or alternative trainings. Also, the Kenyan runners gave more importance to Tempo runs, activity which involved them more concentration than to the Spanish runners (AU)

No contexto do desempenho de peritos e da abordagem da prática deliberada, o presente estudo analisou as percepções subjetivas sobre as tarefas de treinamento de um grupo de corredores internacionais de longa distância de Espanha e Quênia. Para isso, os atletas preencheram um questionário baseado em uma taxonomia de atividades de treinamento que avaliaram quatro dimensões: Relevância, Esforço, Concentração e Prazer. Trinta e oito corredores masculinos participaram deste estudo dividido em dois grupos de acordo com sua nacionalidade como queniano (n = 20) ou espanhol (n = 18). Todos os atletas foram corredores de longa distância (10.000 metros, Meia Maratona e Maratona). Os resultados mostraram que as atividades de treinamento como competição ou testes, treinamento de intervalo longo e curto e corridas Tempo foram consideradas as tarefas que melhor caracterizaram sua prática deliberada. Além disso, essas tarefas produziam mais prazer e exigiam mais concentração e esforço. As diferenças mais importantes entre os grupos foram que os corredores quenianos não praticaram algumas atividades de treinamento que os corredores espanhóis fizeram, como pesos e treinamento físico, técnicas de corrida ou treinamentos alternativos. Além disso, os corredores quenianos deram mais importância às corridas Tempo, atividade que envolveu mais concentração do que para os corredores espanhóis (AU)

Discovery of New Compounds Active against Plasmodium falciparum by High Throughput Screening of Microbial Natural Products.

Due to the low structural diversity within the set of antimalarial drugs currently available in the clinic and the increasing number of cases of resistance, there is an urgent need to find new compounds with novel modes of action to treat the disease. Microbial natural products are characterized by their large diversity provided in terms of the chemical complexity of the compounds and the novelty of structures. Microbial natural products extracts have been underexplored in the search for new antiparasitic drugs and even more so in the discovery of new antimalarials. Our objective was to find new druggable natural products with antimalarial properties from the MEDINA natural products collection, one of the largest natural product libraries harboring more than 130,000 microbial extracts. In this work, we describe the optimization process and the results of a phenotypic high throughput screen (HTS) based on measurements of Plasmodium lactate dehydrogenase. A subset of more than 20,000 extracts from the MEDINA microbial products collection has been explored, leading to the discovery of 3 new compounds with antimalarial activity. In addition, we report on the novel antiplasmodial activity of 4 previously described natural products.

Microwave-assisted synthesis of C-8 aryl and heteroaryl inosines and determination of their inhibitory activities against Plasmodium falciparum purine nucleoside phosphorylase.

8-Arylinosines have been scarcely studied for therapeutic purposes, probably due to difficulties in their synthesis. The recently described direct arylation reaction at position 8 of purine nucleosides has been employed to synthesize a series of 8-aryl and 8-pyridylinosines. These compounds have been studied for hydrolytic stability and subjected to biological evaluation. Three compounds have shown a pronounced specific inhibition of Plasmodium falciparum-encoded purine nucleoside phosphorylase, an important target for antimalarial chemotherapy.