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Ex vivo phenotypic screening of two small repurposing drug collections identifies nifuratel as a potential new treatment against visceral and cutaneous leishmaniasis
No full text[EN] Leishmaniases are vector-borne neglected diseases caused by single-celled parasites. The search for new antileishmanial drugs has experienced a strong boost thanks to the application of bioimaging to phenotypic screenings based on intracellular amastigotes. Mouse splenic explants infected with fluorescent strains of Leishmania are proven tools of drug discovery, where hits can be easily transferred to preclinical in vivo models. We have developed a two-staged platform for antileishmanial drugs. First, we screened two commercial collections of repurposing drugs with a total of 1769 compounds in ex vivo mouse splenocytes infected with an infrared emitting Leishmania infantum strain. The most active and safest compounds were scaled-up to in vivo models of chronic Leishmania donovani visceral leishmaniasis and Leishmania major cutaneous leishmaniasis. From the total of 1769 compounds, 12 hits with selective indices >35 were identified, and 4 of them were tested in vivo in a model of L. donovani visceral leishmaniasis. Nifuratel, a repurposed synthetic nitrofuran, when administered orally at 50 mg/kg bw once or twice a day for 10 days, caused >80% reduction in the parasitic load. Furthermore, the intralesional administration of nifuratel in a model of cutaneous leishmaniasis by L. major produced the parasitological cure. From the previous results we have deduced the great capacity of mouse splenic explants to identify new hits, a model which could be easily transferred to in vivo models, as well as the potential use of nifuratel as an alternative to the current treatment of cutaneous leishmaniasis.SIThe authors would like to thank Miguel Fernández Fernández and other members of the Animal House of University of León for their impeccable care of the animals. We would also like to thank Carlos García Estrada for his support in editing the manuscript. The first author B.D.A. (LE208−17), C.G.C. (LE255−16), and M.A.B. (LE051−18) are recipients of Junta de Castilla y Leon (JCyL) and European Social Found (ESF)’s Fellowships Scheme for Doctoral Training Programs. The IVIS Spectrum Imaging System was purchased as part of INFRARED program (2018-ULE1) of Junta de Castilla y Leon (JCyL) funded by European Regional Development Fund (ERDF). This collaborative research was funded by MINECO; SAF2017−83575-R to R.M.R
Velázquez as the rebel artist in Pasolinis’s "Calderón" and Buero Vallejo’s "Las Meninas"
Get PDF[ES] En el presente artículo se aborda el análisis de la figura de Velázquez en las obras
teatrales Calderón de Pier Paolo Pasolini y Las Meninas de Antonio Buero Vallejo por su
similitud de planteamientos a la hora de proyectar sus ideas del autor como liberador a
través de su arte en el contexto político de la segunda mitad del siglo XX, tanto en Italia
como en España. En ambos textos la obra pictórica de Las Meninas cobrará una importancia
capital a la hora de resaltar los planteamientos liberadores y sociales que cada uno de los
autores proyecta en sus obras.[EN] This paper addresses the analysis of the use of the figure of Velázquez in the plays of Calderón
by Pier Paolo Pasolini and Las Meninas by Antonio Buero Vallejo in their similarity of approaches
when projecting their ideas of the author as a liberator to through his art in the political context of
the second half of the 20th century in both Italy and Spain. In both texts, the pictorial work of Las
Meninas will take on capital importance when it comes to highlighting the liberating and social
approaches that each of the authors project in their works
Combined Metabarcoding and Co-occurrence Network Analysis to Profile the Bacterial, Fungal and Fusarium Communities and Their Interactions in Maize Stalks
Get PDF[EN] Fusarium Head Blight (FHB) is one of the most devastating diseases of cereals worldwide, threatening both crop production by affecting cereal grain development, and human and animal health by contaminating grains with mycotoxins. Despite that maize residues constitute the primary source of inoculum for Fusarium pathogenic species, the structure and diversity of Fusarium spp. and microbial communities in maize residues have received much less attention than in grains. In this study, a metabarcoding approach was used to study the bacterial, fungal and Fusarium communities encountered in maize stalks collected from 8 fields in Brittany, France, after maize harvest during fall 2015. Some predominant genera found in maize residues were cereal or maize pathogens, such as the fungal Fusarium, Acremonium, and Phoma genera, and the bacterial Pseudomonas and Erwinia genera. Furthermore, a high predominance of genera with previously reported biocontrol activity was found, including the bacterial Sphingomonas, Pedobacter, Flavobacterium, Pseudomonas, and Janthinobacterium genera; and the fungal Epicoccum, Articulospora, Exophiala, and Sarocladium genera. Among Fusarium spp., F. graminearum and F. avenaceum were dominant. We also found that the maize cultivar and previous crop could influence the structure of microbial communities. Using SparCC co-occurrence network analysis, significant negative correlations were obtained between Fusarium spp. responsible for FHB (including F. graminearum and F. avenaceum) and bacterial OTUs classified as Sphingomonas and fungal OTUs classified as Sarocladium and Epicoccum. Considering that isolates belonging to these taxa have already been associated with antagonist effect against different Fusarium spp. and/or other pathogenic microorganisms and due to their predominance and negative associations with Fusarium spp., they may be good candidates as biocontrol agents. Combining the use of Fusarium-specific primers with universal primers for bacteria and fungi allowed us to study the microbial communities, but also to track correlations between Fusarium spp. and other bacterial and fungal genera, using co-occurrence network analysis. Such approach could be a useful tool as part of a screening strategy for novel antagonist candidates against toxigenic Fusarium spp., allowing the selection of taxa of interestSIThis work was supported by the Brittany Region (Grant#9097MycoRes)andtheInstitutBrestoisSanté-Agro-Matière (IBSAM)
Challenges facing the biological control strategies for the management of Fusarium Head Blight of cereals caused by F. graminearum
Get PDF[EN] Fusarium Head Blight (FHB) is one of the most devastating diseases in the world, threatening both crop productions by affecting kernel development, and human and animal health by contaminating heads and seeds with mycotoxins. FHB is caused mainly by a Fusarium graminearum species complex, with F. graminearum sensu stricto (lineage 7) being the most prevalently isolated species from disease kernels. Recently it has been designated as the fourth fungal plant pathogen based on its economic impacts. To face the lack of effective strategies for management of FHB and the rising concerns of mycotoxin contamination, new control strategies must be developed, evaluated and applied. The use of biocontrol agents to mitigate or control plant diseases, such as FHB, has received an increase in interest. Even with a proven efficacy of many biocontrol agents, however, few are available on the market as developed products. Regulatory complexity further compounds the improvement of biocontrol strategies. This review offers an insight of the current biocontrol strategies against F. graminearum, from selection to field-testing. The steps needed to ensure the effectiveness of the candidates, as well as the assessing and monitoring of their efficacy and environmental innocuousness are also discussed.SIThis review was written as part of the Rhisotox project, which is supported by the Brittany Region [Grant #13008022 Rhisotox] and the French Association for Research and Technology ANRT [Grant #2014/108]. It is certified by the Foodstuff cluster of the future (Valorial)
Proposal of 100% renewable energy production for the City of Cuenca- Ecuador by 2050
Get PDF[EN] This research presents a scenario for a 100% renewable energy system for the City of Cuenca, Ecuador, with a projection to the year 2050. The transition process starts with Ecuador's change in the productive matrix with reforms from the legal and business strategies point of view to the year 2050. Advances in energy material are dependent on political uncertainty both at the country (Ecuador) and local (Cuenca) levels. It is possible to stop using fossil fuels due to the implementation of new renewable energy sources, potentially rich in the Ecuadorian Southwest and evidenced in the National Plan for a Lifetime. Currently, there is evidence of accelerated changes concerning legal regulations, including the construction of several electric power generation plants. This change in the national productive matrix implies, among others, the implementation of electric vehicles and the change of natural gas stoves for electric ones, and the implementation of the “4 Rios” tram that crosses the city from North-South and South-North, incorporating 100% renewable energy generation, which would provide heat in urban and marginal urban areas. All the systems created in Ecuador, such as heating, cooling, transportation, security etc., will allow an increasing penetration of renewable energy until it reaches 100%.S
Technical challenges for the optimum penetration of grid-connected photovoltaic systems: Spain as a case study
Get PDF[EN] This research reviews the technical requirements of grid-connected photovoltaic power plants to increase their competitiveness and efficiently integrate into the grid to satisfy future demand requirements and grid management challenges, focusing on Spain as a case study. The integration of distributed resources into the electric network, in particular photovoltaic energy, requires an accurate control of the system. The integration of photovoltaic energy has resulted in significant changes to the regulatory framework to ensure proper integration of distributed generation units in the grid. In this study, the requirements of the system operator for the management and smart control are first analysed and then the technical specifications established by the network operator in reference to the components of the facility are evaluated. This analysis identifies the shortcomings of the current legislation and concludes with a summary of the main technical recommendations and future regulatory challenges that need to be undertaken in the future. It is presented as a reference case that can be adapted worldwide. © 2019S
The intervention of the Supreme Court of Justice in the Kingdom of León’s social conflicts (XV-XVI centuries). The case of Barcial de la Loma
Get PDF[ES] Los conflictos jurisdiccionales que tienen lugar en la villa de Barcial de la Loma a lo
largo de las últimas décadas del siglo XV son un ejemplo paradigmático de la violencia
entre señores jurisdiccionales experimentada en el Reino de León entre la Baja Edad
Media y los inicios de la Edad Moderna. Este trabajo, enmarcado dentro de un proyecto de
mayor envergadura, toma como punto de partida la situación de esta villa para analizar la
naturaleza jurídica y los agentes implicados en los pleitos remitidos en grado de apelación
a los más altos tribunales judiciales. A través de las cartas ejecutorias expedidas tras los
sucesivos litigios sobre la villa, se recompone el proceso judicial bajomedieval, marcado
por las reformas administrativas y jurídicas llevadas a cabo por los Reyes Católicos. Gracias
a ello, se comprueba que el recurso de la justicia era uno de los mecanismos principales
para resolver este tipo de desavenencias.[EN] The jurisdictional conflicts held in the village of Barcial de la Loma over the last decades of the
XV century are a representative example of the violence between jurisdictional lords in the Kingdom
of León during the late Middle Ages and the beginning of the Modern Age. This research, which
is part of a larger project, takes the situation in this village as the starting point for the analysis of
the legal status and the agents involved in the lawsuits which are appealed to the highest courts.
Through the examination of the enforceable documents issued after the subsequent trials about the village’s jurisdiction, the medieval judicial process —in the context of the Catholic Monarchs’
administrative and judicial reforms— is reset. As a result, it is verified that applying to the courts
was one of the main mechanisms to solve this kind of conflicts
Spain in the 20th century, the music of forgotten
Get PDF[ES] Durante gran parte del siglo XX, se produce en el ámbito historiográfico nacional
español e internacional un vacío musical, que obvia a toda una serie de autores, entre los
que cabría citar la figura de Joaquín Rodrigo (junto con otros nombres, como Salvador
Bacarisse, Antonio José Martínez, Evaristo Fernández Blanco, Rosa María Ascot…), que
realizaron notorias aportaciones tanto como ejemplo de su contexto artístico particular
como con su marcado estilo artístico personal. Sin embargo, han sido vinculados, sin base
académica sólida, con la ideología del régimen nacional o reprimidos por ella, desacreditados
bajo la etiqueta de compositores retrógrados, provocando esto el olvido de sus
aportaciones, además de suponer una paradoja respecto a su devenir biográfico real y las
innovaciones profundas de su planteamiento musical. Por ello, resulta necesario no solo
recuperar su obra, sino mostrar la naturaleza de un profundo legado que marcó la música
española y mundial.[EN] During a large part of the 20th century, a musical vacuum was produced in the Spanish
national and international historiographical sphere, which ignored a whole series of authors, like
Joaquín Rodrigo (along with other names, such as Salvador Bacarisse, Antonio Jose, Evaristo Fernandez
Blanco, Rosa María Ascot...), who made notable contributions both as an example of their
particular artistic context, and with their marked personal artistic style. However, they have been
linked without a solid academic basis, with the ideology of the national regime or repressed by this,
discredited under the label of retrograde composers, causing their contributions to be forgotten, as
well as posing a paradox regarding their real biographical evolution and profound innovations. of
his musical approach. For this reason, it is necessary not only to recover his work, but also to show
the nature of a deep legacy that marked Spanish and world music
Algunas reflexiones sobre la «tímida» y «controvertida» socialización del proceso civil durante la fase de proposición de la prueba
Get PDF[ES] El proceso civil al que nuestra LEC da vida con el conjunto de disposiciones que en ella se contienen, salvo excepciones relacionadas con aquellos procesos donde no rige el principio dispositivo, se encuentra informado por el principio de aportación de parte. En este sentido, es imprescindible referirnos a los dos preceptos legales estrella donde de modo claramente incontrovertido queda reflejado el mentado principio: los arts. 216 y 282 LEC
Biofilm formation in Streptococcus suis: in vitro impact of serovars and assessment of coinfections with other porcine respiratory disease complex bacterial pathogens
Get PDF[EN] Streptococcus suis is a worldwide pathogen that impacts the swine industry, causing severe clinical signs, including meningitis and arthritis, in postweaning piglets. A key virulence mechanism of S. suis is biofilm formation, which improves its persistence and resistance to external factors. Here, we assessed the in vitro biofilm formation of 240 S. suis isolates from Spanish swine farms and evaluated the effects of serovars (SVs) and coinfections with other porcine respiratory disease complex (PRDC) pathogens. Our study revealed significant heterogeneity in biofilm formation among S. suis SVs. Notably, SV2 resulted in the lowest degree of biofilm formation, in contrast with the high biofilm-forming capacities of SV1, SV7, and SV9. Other PRDC pathogens, including Actinobacillus pleuropneumoniae, Glaesserella parasuis, and Pasteurella multocida, formed biofilms, although they were generally less robust than those of S. suis (except for SV2), which contrasts with the high biofilm formation of Staphylococcus hyicus. Coinfections enhanced biofilm formation in mixed cultures of S. suis, particularly with P. multocida. Other coinfections revealed variable results in pathogen interactions, suggesting the potential of biofilms for increased persistence and pathogenicity in coinfections. In conclusion, this study underscores the importance of serovar-specific differences in biofilm formation among S. suis isolates, with significant implications for pathogenicity and persistence. The heterogeneous biofilm formation observed in coinfections with other PRDC pathogens reveals a complex interplay that could exacerbate disease severity. These findings provide a foundation for further research on biofilm mechanisms to mitigate the impact of PRDC in the swine industrySIRubén Miguélez‑Pérez holds a grant from Junta de Castilla y León co‑financed by the European Social Fund. Alba González‑Fernández holds a grant from the University of LeónWe acknowledge the excellent technical assistance provided by María Medi‑ avilla and Vanessa Acebes. We would also like to thank the University of Leóns microscopy services and personnel for their predisposition and assistanc