Experimental Chemotherapy for Chagas Disease: A Morphological, Biochemical, and Proteomic Overview of Potential Trypanosoma cruzi Targets of Amidines Derivatives and Naphthoquinones

Chagas disease (CD), caused by Trypanosoma cruzi, affects approximately eight million individuals in Latin America and is emerging in nonendemic areas due to the globalisation of immigration and nonvectorial transmission routes. Although CD represents an important public health problem, resulting in high morbidity and considerable mortality rates, few investments have been allocated towards developing novel anti-T. cruzi agents. The available therapy for CD is based on two nitro derivatives (benznidazole (Bz) and nifurtimox (Nf)) developed more than four decades ago. Both are far from ideal due to substantial secondary side effects, limited efficacy against different parasite isolates, long-term therapy, and their well-known poor activity in the late chronic phase. These drawbacks justify the urgent need to identify better drugs to treat chagasic patients. Although several classes of natural and synthetic compounds have been reported to act in vitro and in vivo on T. cruzi, since the introduction of Bz and Nf, only a few drugs, such as allopurinol and a few sterol inhibitors, have moved to clinical trials. This reflects, at least in part, the absence of well-established universal protocols to screen and compare drug activity. In addition, a large number of in vitro studies have been conducted using only epimastigotes and trypomastigotes instead of evaluating compounds' activities against intracellular amastigotes, which are the reproductive forms in the vertebrate host and are thus an important determinant in the selection and identification of effective compounds for further in vivo analysis. In addition, due to pharmacokinetics and absorption, distribution, metabolism, and excretion characteristics, several compounds that were promising in vitro have not been as effective as Nf or Bz in animal models of T. cruzi infection. In the last two decades, our team has collaborated with different medicinal chemistry groups to develop preclinical studies for CD and investigate the in vitro and in vivo efficacy, toxicity, selectivity, and parasite targets of different classes of natural and synthetic compounds. Some of these results will be briefly presented, focusing primarily on diamidines and related compounds and naphthoquinone derivatives that showed the most promising efficacy against T. cruzi

Old drawback on azlactone formation revealed by a combination of theoretical and experimental studies

New insights into the formation of azlactone heterocycles bearing different substituents are hereby presented. The sum of both kinetic and thermodynamic factors contributes for the formation of 2-alkyl or 2-aryl substituted azlactones, while the cyclization of 2-alcoxy azlactones is less favored. These results are in perfect accordance with experimental observations obtained by infrared (IR) and electrospray ionization mass spectrometry (ESI(+)-MS) of the crude reaction mixture.

Lignocellulose Conversion via Catalytic Transformations Yields Methoxyterephthalic Acid Directly from Sawdust

Poly(ethylene terephthalate) polyester represents the most common class of thermoplastic polymers widely used in the textile, bottling, and packaging industries. Terephthalic acid and ethylene glycol, both of petrochemical origin, are polymerized to yield the polyester. However, an earlier report suggests that polymerization of methoxyterephthalic acid with ethylene glycol provides a methoxy-polyester with similar properties. Currently, there are no established biobased synthetic routes toward the methoxyterephthalic acid monomer. Here, we show a viable route to the dicarboxylic acid from various tree species involving three catalytic steps. We demonstrate that sawdust can be converted to valuable aryl nitrile intermediates through hydrogenolysis, followed by an efficient fluorosulfation–catalytic cyanation sequence (>90%) and then converted to methoxyterephthalic acid by hydrolysis and oxidation. A preliminary polymerization result indicates a methoxy-polyester with acceptable thermal properties

Caloric Restriction Is More Efficient than Physical Exercise to Protect from Cisplatin Nephrotoxicity via PPAR-Alpha Activation

The antineoplastic drug cisplatin promotes renal injury, which limits its use. Protocols that reduce renal cisplatin toxicity will allow higher doses to be used in cisplatin treatment. Here, we compare physical exercise and caloric restriction (CR) as protocols to reduce cisplatin renal injury in mice. Male C57BL/6 were divided into four groups: Control, cisplatin, exercise + cisplatin, and 30% CR + cisplatin. Animals were injected with a single dose of cisplatin (20 mg/kg i.p.) and sacrificed 96 h after injection. Quantitative real time PCR, histological analyses, immunohistochemistry, and biochemical measurements were performed to investigate renal injury, necrosis, apoptosis, and inflammatory mechanisms. Both protocols protected against cisplatin renal injury, but CR was more effective in reducing uraemia and renal necrosis. The CR + Cisplatin group exhibited reduced serum IL-1 beta and INF-alpha levels. No differences were noted in the renal mRNA expression of cytokines. Both interventions reduced apoptosis, but only the CR + Cisplatin group decreased TNFR2 protein expression. PPAR-ci was activated in mice after CR. An antagonist of PPAR-alpha blocked the protective effect of CR. Both interventions attenuated the nephrotoxicity caused by cisplatin injection, but CR + Cisplatin showed a better response by modulating TNFR2. Moreover, part of the CR benefit depends on PPAR-alpha activation.FAPESP (Fundacao de Apoio a Pesquisa do Estado de Sao Paulo)CAPES/DAADUniv Fed Sao Paulo, Dept Biofis, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Med, Disciplina Nefrol, Sao Paulo, BrazilUniv Sao Paulo, Inst Ciencias Biomed, Dept Immunol, Sao Paulo, BrazilUniv Sao Paulo, Dept Clin Med, Sao Paulo, BrazilUniv Fed Pelotas, Escola Nutr, Dept Nutr, Pelotas, BrazilMax Delbruck Ctr Mol Med, Berlin, GermanyUniv Fed Sao Paulo, Dept Biofis, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Med, Disciplina Nefrol, Sao Paulo, BrazilFAPESP: 2013/06207-6FAPESP: 2015/20082-7CAPES/DAAD: 427/15Web of Scienc

Depth of maximum of air-shower profiles at the Pierre Auger Observatory. II. Composition implications

Using the data taken at the Pierre Auger Observatory between December 2004 and December 2012, we have examined the implications of the distributions of depths of atmospheric shower maximum (Xmax), using a hybrid technique, for composition and hadronic interaction models. We do this by fitting the distributions with predictions from a variety of hadronic interaction models for variations in the composition of the primary cosmic rays and examining the quality of the fit. Regardless of what interaction model is assumed, we find that our data are not well described by a mix of protons and iron nuclei over most of the energy range. Acceptable fits can be obtained when intermediate masses are included, and when this is done consistent results for the proton and iron-nuclei contributions can be found using the available models. We observe a strong energy dependence of the resulting proton fractions, and find no support from any of the models for a significant contribution from iron nuclei. However, we also observe a significant disagreement between the models with respect to the relative contributions of the intermediate components.Fil: Aab, A.. Universitat Siegen; AlemaniaFil: Abreu, P.. Universidade de Lisboa; PortugalFil: Aglietta, M.. Università di Torino; Italia. Istituto Nazionale di Fisica Nucleare; ItaliaFil: Ahn, E. J.. Fermilab; Estados UnidosFil: Al Samarai, I.. Université Paris 11; Francia. Centre National de la Recherche Scientifique; FranciaFil: Albuquerque, I. F. M.. Universidade de Sao Paulo; BrasilFil: Allekotte, Ingomar. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; ArgentinaFil: Allen, J.. New York University; Estados UnidosFil: Allison, P.. Ohio State University; Estados UnidosFil: Almela, A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; Argentina. Universidad Tecnológica Nacional. Facultad Regional Buenos Aires; ArgentinaFil: Alvarez Castillo, J.. Universidad Nacional Autónoma de México; MéxicoFil: Alvarez Muñiz, J.. Universidad de Santiago de Compostela; EspañaFil: Alves Batista, R.. Universitat Hamburg; AlemaniaFil: Dova, Maria Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Taborda Pulgarin, Oscar Alejandro. Comisión Nacional de Energía Atómica. Gerencia del Área Investigaciones y Aplicaciones no Nucleares; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Purrello, Víctor Hugo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Físicas de Mar del Plata. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Físicas de Mar del Plata; ArgentinaFil: Martins Dos Santos, Eva Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Ravignani Guerrero, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Almela, Daniel Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Josebachuili Ogando, Mariela Gisele. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Gomez Berisso, Mariano. Comisión Nacional de Energía Atómica. Gerencia del Área Investigaciones y Aplicaciones no Nucleares; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bertou, Xavier Pierre Louis. Comisión Nacional de Energía Atómica. Gerencia del Area Investigación y Aplicaciones No Nucleares. Gerencia de Física (Centro Atómico Bariloche). Grupo de Partículas y Campos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Wahlberg, Hernan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Wundheiler, Brian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Tapia Casanova, Alex Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Asorey, Hernán Gonzalo. Comisión Nacional de Energía Atómica. Gerencia del Área Investigaciones y Aplicaciones no Nucleares; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sciutto, Sergio Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Quel, Eduardo Jaime. Consejo Nacional de Investigaciones Científicas y Técnicas. Unidad de Investigación y Desarrollo Estratégico para la Defensa. Ministerio de Defensa. Unidad de Investigación y Desarrollo Estratégico para la Defensa; ArgentinaFil: Melo, Diego Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Sanchez, Federico Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; Argentin

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory

The Auger Engineering Radio Array (AERA) is part of the Pierre Auger Observatory and is used to detect the radio emission of cosmic-ray air showers. These observations are compared to the data of the surface detector stations of the Observatory, which provide well-calibrated information on the cosmic-ray energies and arrival directions. The response of the radio stations in the 30 to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of the incoming electric field. For the latter, the energy deposit per area is determined from the radio pulses at each observer position and is interpolated using a two-dimensional function that takes into account signal asymmetries due to interference between the geomagnetic and charge-excess emission components. The spatial integral over the signal distribution gives a direct measurement of the energy transferred from the primary cosmic ray into radio emission in the AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air shower arriving perpendicularly to the geomagnetic field. This radiation energy -- corrected for geometrical effects -- is used as a cosmic-ray energy estimator. Performing an absolute energy calibration against the surface-detector information, we observe that this radio-energy estimator scales quadratically with the cosmic-ray energy as expected for coherent emission. We find an energy resolution of the radio reconstruction of 22% for the data set and 17% for a high-quality subset containing only events with at least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO

Measurement of the Radiation Energy in the Radio Signal of Extensive Air Showers as a Universal Estimator of Cosmic-Ray Energy

We measure the energy emitted by extensive air showers in the form of radio emission in the frequency range from 30 to 80 MHz. Exploiting the accurate energy scale of the Pierre Auger Observatory, we obtain a radiation energy of 15.8 \pm 0.7 (stat) \pm 6.7 (sys) MeV for cosmic rays with an energy of 1 EeV arriving perpendicularly to a geomagnetic field of 0.24 G, scaling quadratically with the cosmic-ray energy. A comparison with predictions from state-of-the-art first-principle calculations shows agreement with our measurement. The radiation energy provides direct access to the calorimetric energy in the electromagnetic cascade of extensive air showers. Comparison with our result thus allows the direct calibration of any cosmic-ray radio detector against the well-established energy scale of the Pierre Auger Observatory.Comment: Replaced with published version. Added journal reference and DOI. Supplemental material in the ancillary file