Characterization of non-target-site mechanisms in imidazolinone-resistant sunflower by RNA-seq; Caracterización de mecanismos de resistencia no relacionados al sitio de acción en girasol mediante RNA-seq Gil, Mercedes; Vega Tessandori, María Fernanda; Felitti, Silvina Andrea; Picardi, Liliana Amelia; Balzergue, Sandrine; Nestares, Graciela María Los girasoles Imisun son cultivares resistentes a imidazolinonas en los cuales coexisten dos mecanismos de resistencia: (i) una mutación puntual en el sitio blanco del herbicida (resistencia relacionada al sitio de acción) y (ii) resistencia no relacionada al sitio de acción (NTSR). En la tecnología Imisun, NTSR podría estar relacionada con el metabolismo del herbicida y podría resultar de una sobreexpresión constitutiva de los genes detoxificadores, o inducida luego del tratamiento con herbicida. El objetivo de este trabajo fue caracterizar NTSR en girasoles Imisun en respuesta al tratamiento de imazetapir mediante RNA-seq, y determinar si estos mecanismos son constitutivo o inducidos por el herbicida. Las cipselas fueron germinadas en multimacetas, regadas por capilaridad y se mantuvieron en una cámara bajo condiciones controladas. Plantas de 7 días fueron tratadas con imazetapir 0 (control) y 1 μM por 12 h. Luego de la purificación del RNA de hoja, se construyeron bibliotecas de cDNA stranded y paired-end. La secuenciación se llevó a cabo en Illumina HiSeq2000. Se realizaron dos tipos de estrategias de mapeo local contra el transcriptoma de referencia HaT13l, incluyendo y filtrando multihits, respectivamente y se realizó el análisis de la expresión diferencial. Se identificaron 61 y 47 contigs (de acuerdo a la estrategia de mapeo) relacionados a metabolismo de xenobióticos: citocromos P450, transportadores ABC, glicosiltransferasas, UDPglucuronosil/glucosiltransferasas y glutatión S-transferasas. No se encontró expresión diferencial entre las plantas tratadas y sin tratar con imazetapir para ninguno de los contigs. La expresión de 17 contigs de interés fue validada mediante qRT-PCR. Estos resultados sugieren que mecanismos NTSR constitutivos estarían involucrados con la resistencia a imidazolinonas en girasol.; Imisun sunflowers (Helianthus annuus L.) are imidazolinone-resistant cultivars in which the two mechanisms of herbicide resistance coexist: (i) mutation in herbicide target-site (target-site resistance) and (ii) non-target-site resistance (NTSR). In Imisun technology, NTSR could be related to herbicide metabolism and might occur as a result of a constitutive up-regulation of resistance genes, or it can appear only after herbicide treatment. The objective of this study was to characterize NTSR in Imisun sunflower in response to imazethapyr using RNA-Seq and to determine whether these mechanisms are constitutive or herbicide-induced. Cypsels were germinated in plastic pots, watered by capillarity and growth in chamber under controlled conditions. Seven-day-old plants were treated with 0 (control) and 1 μM imazethapyr for 12 h. After leaf RNA purification, stranded, paired-end cDNA libraries were constructed. Sequencing was performed with Illumina HiSeq2000. Local mapping, with and without multihits, was carried out over the reference transcriptome HaT13l and differential expression was analysed. Sixty one and 47 contigs (according to mapping strategy) related to xenobiotic metabolism were found: cytochromes P450s, ABC transporters, glycosyltransferases, UDPglucuronosyl/glucosyltransferases and glutathione S-transferases. None of these contigs showed differential expression between control and imazethapyr-treated plants. Seventeen interesting contigs were verified by qRT-PCR. These results suggest that constitutive NTSR mechanisms may account for imidazolinone resistance in Imisun sunflower.

Trichinella spiralis in a South American sea lion (Otaria flavescens) from Patagonia, Argentina Pasqualetti, Mariana Ines; Fariña, Fernando Adrián; Krivokapich, Silvio Jesús; Gatti, G. M.; Daneri, Gustavo Adolfo; Varela, Esperanza Amalia; Lucero, Sergio; Ercole, Mariano Emmanuel; Bessi, Clara; Winter, Marina; Ribicich, Miriam Mabel Trichinella spp. from a sylvatic cycle has been found in several animal species such as pumas (Puma concolor), armadillos (Chaetophractus villosus), rats (Rattus norvegicus), and wild boars (Sus scrofa) in Argentina. Moreover, Trichinella infection has been detected in a wide range of marine mammals around the world, including polar bears (Ursus maritimus) and walruses (Odobenus rosmarus). Until the present time, Trichinella spp. infection has not been detected in marine mammals of South America. Samples from four South American sea lions (Otaria flavescens) found dead in Rio Negro, Argentina, were analyzed by artificial digestion, and in the case of one animal, Trichinella larvae were identified at the species level by nested multiplex PCR as Trichinella spiralis. This is the first report of a Trichinella species infecting marine mammals from South America.

Development and Validation of a Novel HPLC Method for the Analysis and Quantification of Dehydroleucodine in Plant Extracts Mariani, María Laura Lucía; Penissi, Alicia Beatriz Background: Dehydroleucodine is a sesquiterpene lactone isolated from Artemisia douglasiana Besser. Distinctive biological and pharmacological activities have been shown extensively for this molecule. Only one analytical method has been described for the quantification of dehydroleucodine in biological experimental systems. However, this assay involves fluorescent detection that is normally not recommended for routine analysis. Objective: The goal of this study was to develop and validate a novel methodology for rapid detection and quantitation of dehydroleucodine by HPLC with UV detection. Method: The method involved the use of a C18 separation column, an acetonitrile/water (80:20, v/v) solution as a mobile phase in an isocratic mode at a flow rate of 1 ml/min, and UV detection at 254 nm. Results: In the selected experimental conditions, dehydroleucodine exhibited a well-defined chromatographic peak with a retention time of 3.51 min. The chromatographic signal shows a linear dependence with the dehydroleucodine concentration. Correlation coefficient: 0.99. LOD: 1.5 ng/mL. LOQ: 15 ng/mL. Conclusion: The current method is simpler, faster, and cheaper than the previously reported one, and besides it could be useful to quantify this lactone and related pharmacological compounds. Furthermore, quality control of medicinal extracts of plant origin could be analyzed, and the concentration of the active constituent could be certified by this method.

Androgens downregulate anti-Müllerian hormone promoter activity in the Sertoli cell through the androgen receptor and intact steroidogenic factor 1 sites Edelsztein, Nadia Yasmín; Racine, Chrystèle; di Clemente, Nathalie; Schteingart, Helena Fedora; Rey, Rodolfo Alberto Testicular anti-Müllerian hormone (AMH) production is inhibited by androgens around pubertal onset, as observed under normal physiological conditions and in patients with precocious puberty. In agreement, AMH downregulation is absent in patients with androgen insensitivity. The molecular mechanisms underlying the negative regulation of AMH by androgens remain unknown. Our aim was to elucidate the mechanisms through which androgens downregulate AMH expression in the testis. A direct negative effect of androgens on the transcriptional activity of the AMH promoter was found using luciferase reporter assays in the mouse prepubertal Sertoli cell line SMAT1. A strong inhibition of AMH promoter activity was seen in the presence of both testosterone and DHT and of the androgen receptor. By site-directed mutagenesis and chromatin immunoprecipitation assays, we showed that androgen-mediated inhibition involved the binding sites for steroidogenic factor 1 (SF1) present in the proximal promoter of the AMH gene. In this study, we describe for the first time the mechanism behind AMH inhibition by androgens, as seen in physiological and pathological conditions in males. Inhibition of AMH promoter activity by androgens could be due to protein-protein interactions between the ligand-bound androgen receptor and SF1 or by blockage of SF1 binding to its sites on the AMH promoter.

Widespread but heterogeneous responses of Andean forests to climate change Fadrique, Belén; Báez, Selene; Duque, Álvaro; Malizia, Agustina; Blundo, Cecilia Mabel; Carilla, Julieta; Osinaga Acosta, Oriana; Malizia, Lucio Ricardo; Silman, Miles; Farfán Ríos, William; Malhi, Yadvinder; Young, Kenneth R.; Cuesta C., Francisco; Homeier, Jurgen; Peralvo, Manuel; Pinto, Esteban; Jadan, Oswaldo; Aguirre, Nikolay; Aguirre, Zhofre; Feeley, Kenneth J. Global warming is forcing many species to shift their distributions upward, causing consequent changes in the compositions of species that occur at specific locations. This prediction remains largely untested for tropical trees. Here we show, using a database of nearly 200 Andean forest plot inventories spread across more than 33.5° latitude (from 26.8° S to 7.1° N) and 3,000-m elevation (from 360 to 3,360 m above sea level), that tropical and subtropical tree communities are experiencing directional shifts in composition towards having greater relative abundances of species from lower, warmer elevations. Although this phenomenon of ‘thermophilization’ is widespread throughout the Andes, the rates of compositional change are not uniform across elevations. The observed heterogeneity in thermophilization rates is probably because of different warming rates and/or the presence of specialized tree communities at ecotones (that is, at the transitions between distinct habitats, such as at the timberline or at the base of the cloud forest). Understanding the factors that determine the directions and rates of compositional changes will enable us to better predict, and potentially mitigate, the effects of climate change on tropical forests.

La Filosofía dentro del contexto de la política científica actual en Argentina Mie, Fabian Gustavo La supervivencia académica de la filosofía está sometida actualmente en Argentina a una presión impuesta por criterios de productividad e impacto alentados a través del rediseño en curso del sistema científico. Si bien este proceso en desarrollo creciente atañe a las ciencias básicas en general, puede advertirse que aspectos específicos de la elaboración del conocimiento filosófico, incluyendo sus períodos de tiempo y criterios de validación tradicionales, son difícilmente compatibles con una idea de conocimiento socialmente dominante cada vez más orientada a la aplicación y al retorno económico de la inversión en ciencia. En este contexto, es dudoso que la filosofía pueda apelar a justificaciones como la de la ?potencial utilidad?, que tienen a su alcance otras ciencias básicas (Schwarz 2017). Hay dos cuestiones candentes y conjuntas que considerar aquí: (a) ¿qué hace de la filosofía todavía hoy una forma del saber socialmente aceptable?, y (b) ¿por qué el estado tiene que seguir manteniendo con fondos públicos esa disciplina dentro de las instituciones académicas? En este artículo me propongo esbozar una justificación posible del papel que puede caberle a la filosofía en el contexto actual (primeramente enfocado en Argentina); sugiero que esa justificación proviene de la necesidad de revisar críticamente la idea dominante del saber y apunta a reformular el proyecto del ideal humano de racionalidad.

El Jano socialista. Juan B. Justo y el lugar de los símbolos en la política moderna Reyes, Francisco Jerónimo El artículo analiza la forma en que, a lo largo de su carrera política, un dirigente clave del socialismo argentino, Juan B. Justo, concibió el lugar singular que debían ocupar distintas manifestaciones de un fenómeno significativo de la política: los símbolos. A partir de sus experiencias locales y de su conocimiento de otras realidades del mundo occidental, se argumenta que sus valoraciones y propuestas en torno a dicho problema resultaron siempre atadas a cambiantes coyunturas particulares, evidenciando un carácter oscilante y demostrando el peso de las dos fuentes de su pensamiento y acción: una cultura científica ampliamente extendida y la cultura política del socialismo de la Segunda Internacional en que abrevara. El corpus documental se compone de un amplio conjunto de intervenciones de este intelectual-militante (artículos periodísticos y conferencias a cargo del Partido Socialista, así folletos y libros que condensan sus principales aportes doctrinarios), para luego cotejarse con el aporte de otras voces provenientes del socialismo argentino que tensionan los postulados de dicha cultura política sobre el lugar de los símbolos en la modernidad, en general, y en la política argentina de inicios del siglo XX, en particular, en donde el fenómeno nacionalista ocupa un lugar ineludible.

Desfiguración y redención de la naturaleza Grossi, Bruno La ligazón entre narración y experiencia, o como la progresiva desaparición de una causa el empobrecimiento de la otra, es el diagnostico que, aun con sus matices, Lukács y Benjamin afirman a comienzos de los años 30. La crítica a la «descripción» o la «novela pura» (en suma, la autonomía del arte) en ambos autores, supone la pérdida, la separación con aquella inmediatez que ligaba la ficción con la vida. Lo que parece discutirse es siempre el lugar, la relación, el dialogo polémico que el arte establece con la naturaleza. Nuestra lectura intenta reponer el contexto de la discusión y replantear ciertos supuestos que operan en la escritura de ambos filósofos.

Corrosion protection of AZ91D magnesium alloy by a cerium-molybdenum coating. The effect of citric acid as an additive Lehr, Ivana Leticia; Saidman, Silvana Beatriz In order to improve the corrosion resistance of AZ91D magnesium alloy, a coating was formed by a potentiostatic technique from a solutions containing Ce(NO3)3, Na2MoO4 and citric acid (H3Cit). The degree of corrosion protection achieved was evaluated in simulated physiological solution by monitoring the open circuit potential, polarization techniques and electrochemical impedance spectroscopy (EIS). Surface analysis techniques (SEM, EDS, X-ray diffraction and X-ray photoelectron spectroscopy (XPS)) were used for coating characterization. The film is mainly composed by cerium and molybdenum oxides and magnesium oxides and hydroxides. The obtained results show that the corrosion resistance of the coated electrodes has been increased significantly. This improvement in the anticorrosive performance is in part due to the corrosion inhibition properties of H3Cit.

Nuevos registros para el colicorto monodelphis domestica (Wagner, 1842) (didelphimorphia, didelphidae) en Argentina; New records for the short-tailed opossum monodelphis domestica (Wagner, 1842) (didelphi-morphia, didelphidae) in Argentina Ochoa, Ana Cecilia; Paez, Ricardo Andrés; Teta, Pablo Vicente Se reportan dos nuevas localidades de registro para Monodelphis domestica en Argentina, que son a su vez las primeras para la provincia de Santiago del Estero. Los ejemplares fueron capturados en dos localidades del departamento Copo: i) cercanías de Caburé Sur (26° 07´ 37.4″ S, 62° 30´ 41.07″ O) y ii) Parque Provincial Copo (25° 55´ 2.54″ S, 61° 54´ 54.55″ O). Estos nuevos registros extienden 200 km al SSO la distribución conocida de este marsupial.; We report two new localities for Monodelphis domestica in Argentina; these are also the first records for the province of Santiago del Estero. The species was captured in two localities of Copo Department: i) vicinity of Caburé Sur. (S26° 07´ 37.4″, W62° 30´ 41.07″) and ii) Parque Provincial Copo (S5° 55´ 2.54″, W61° 54´ 54.55″). These records extend the known distribution of this marsupial 200 km SSW.

Effects of water quality on aspects of reproductive biology of Cnesterodon decemmaculatus Zambrano Schmidt Deussen, Micaela Jimena; Rautenberg, Gisela Evelín; Bonifacio, Alejo Fabian; Filippi, Iohanna; Amé, María Valeria; Bonansea, Rocio Ines; Hued, Andrea Cecilia The Suquía River basin (Córdoba, Argentina) is under a strong negative impact due to multiple sources of anthropic pollution. The main goal of our study was to evaluate if variations in the water quality of Suquía river basin affect the reproductive biology of Cnesterodon decemmaculatus and determine if the responses provided by the species can be considered as biomarkers of river quality. This assessment was performed through the measurement of morphological, histological and somatic parameters in adult males collected at four sampling sites during the beginning and the end of the breeding season. The water quality evaluation carried out through the estimation of a water quality index (WQI) and pesticides concentrations in water, revealed a pollution gradient along the studied basin. The same variation pattern was registered for the somatic index. In addition, the analysis of the morphology of the male copulatory organ (gonopodium) showed that individuals collected at Córdoba city had the lowest Gonopodium-Somatic Index (Gonop-SI) value, while those sampled at the most polluted site showed abnormalities in the small structures of the gonopodium. On the other hand, few histological alterations were found in the liver whereas no alterations were found in gonads along the river. The results obtained allowed us to characterize the environmental conditions of the studied basin and demonstrated the water quality deterioration along the Suquía River.

Natural history of the threatened coral snake Micrurus altirostris (Serpentes, Elapidae) in Argentina Rodríguez, María Eugenia; Arzamendia, Vanesa; Bellini, Gisela Paola; Giraudo, Alejandro Raul The genus Micrurus comprises nearly 80 endemic species in the American continent. Knowledge on its natural history is based on populations from Brazil and Uruguay, making it necessary to intensify ecological research in Argentina. We present data on morphology, diet, and reproduction for a threatened Argentine population of M. altirostris from the Atlantic Forest biodiversity hotspot. Ecological data were obtained from collected specimens and scientific collections. Females attained sexual maturity at a longer body size than males, but the latter reached a larger size, which is related to male-male combat, a behavior reported in this study. We report a female with 3 oviductal eggs, and 2 ovipositions of 4 and 6 eggs in the late spring-early summer period. Males seemed to have a seasonal reproductive cycle. The diet of M. altirostris was based on elongated reptilians and was mostly similar to the diet of populations from Brazil and Uruguay. We reported 4 new prey types for M. altirostris and confirm the consumption of reptile eggs for the genus Micrurus. Our results contribute to a better understanding of the natural history of M. altirostris, providing valuable information for designing strategic conservation plans.

Reviewing theoretical and numerical models for PCM-embedded cementitious composites Caggiano, Antonio; Mankel, Christoph; Koenders, Eddie Accumulating solar and/or environmental heat in walls of apartment buildings or houses is a way to level-out daily temperature differences and significantly cut back on energy demands. A possible way to achieve this goal is by developing advanced composites that consist of porous cementitious materials with embedded phase change materials (PCMs) that have the potential to accumulate or liberate heat energy during a chemical phase change from liquid to solid, or vice versa. This paper aims to report the current state of art on numerical and theoretical approaches available in the scientific literature for modelling the thermal behavior and heat accumulation/liberation of PCMs employed in cement-based composites. The work focuses on reviewing numerical tools for modelling phase change problems while emphasizing the so-called Stefan problem, or particularly, on the numerical techniques available for solving it. In this research field, it is the fixed grid method that is the most commonly and practically applied approach. After this, a discussion on the modelling procedures available for schematizing cementitious composites with embedded PCMs is reported.

Shopping mall attraction and social mixing at a city scale Beiro, Mariano Gastón; Bravo, Loreto; Caro, Diego; Cattuto, Ciro; Ferres, Leo; Graells-Garrido, Eduardo In Latin America, shopping malls seem to offer an open, safe and democratic version of the public space. However, it is often difficult to quantitatively measure whether they indeed foster, hinder, or are neutral with respect to social inclusion. In this work, we investigate if, and by how much, people from different social classes are attracted by the same malls. Using a dataset of mobile phone network records from 387,152 devices identified as customers of 16 malls in Santiago de Chile, we performed several analyses to study whether malls with higher social mixing attract more people. Our pipeline, which starts with the socio-economic characterization of mall visitors, includes the estimation of social mixing and diversity of malls, the application of the gravity model of mobility, and the definition of a co-visitation model. Results showed that people tend to choose a profile of malls more in line with their own socio-economic status and the distance from their home to the mall, and that higher mixing does positively contribute to the process of choosing a mall. We conclude that (a) there is social mixing in malls, and (b) that social mixing is a factor at the time of choosing which mall to go to. Thus, the potential for social mixing in malls could be capitalized by designing public policies regarding transportation and mobility to make some malls strong social inclusion hubs.

Analysis of the Bitcoin blockchain: socio-economic factors behind the adoption Parino, Francesco; Beiro, Mariano Gastón; Gauvin, Laetitia As the first decentralized digital currency introduced in 2009 together with the blockchain, Bitcoin offers new opportunities both for developed and developing countries. Bitcoin peer-to-peer transactions are independent of the banking system, facilitating foreign exchanges with low transaction fees, such as remittances, and offering a high degree of anonymity. These opportunities together with other key factors led the Bitcoin to become extremely popular and caused its price to skyrocket during 2017 (Henry et al. in J Digit Bank 2(4):311–337, 2018). However, while the Bitcoin blockchain attracts a lot of attention, it remains difficult to investigate where this attention comes from, due to the pseudo-anonymity of the system, and consequently to appreciate its social impact. Here we make an attempt to characterize the adoption of the Bitcoin blockchain by country. In the first part of the work we show that information about the number of Bitcoin software client downloads, the IP addresses that act as relays for the transactions, and the Internet searches about Bitcoin provide together a coherent picture of the system evolution in different countries. Using these quantities as a proxy for user adoption, we identify several socio-economic indexes such as the GDP per capita, freedom of trade and the Internet penetration as key variables correlated with the degree of user adoption. In the second part of the work, we build a network of Bitcoin transactions between countries using the IP addresses of nodes relaying transactions and we develop an augmented version of the gravity model of trade in order to identify socio-economic factors linked to the flow of Bitcoin between countries. In a nutshell our study provides a new insight on Bitcoin adoption by country and on the potential socio-economic drivers of the international Bitcoin flow.

Mujeres afroargentinas y el proyecto Certificar nuestra existencia: Una experiencia de trabajo multidisciplinar en Ciudad Evita (Gran Buenos Aires); Afro-Argentine Women and the Research Project Certifying our Existence: A multidisciplinary research experience in Ciudad Evita (Greater Buenos Geler, Lea Natalia; Egido, Alejandra; Recalt, Rosario; Yannone, Carmen Este trabajo presenta los primeros resultados de la investigación Certificar nuestra existencia, llevada a cabo por la Asociación de Mujeres Afrodescendientes en la Argentina durante el año 2016 en La Matanza. Su objetivo era conocer acerca de la vida de las mujeres afrodescendientes de la zona. El proyecto es pionero en el país porque focaliza en un grupo que se considera “desparecido”, y por su metodología. Se utilizaron métodos cualitativos –arte y antropología– y cuantitativos –toma de encuestas– para realizar un abordaje más complejo que tuviera en cuenta las necesidades de las propias mujeres afroargentinas. Se describen los desarrollos de las distintas etapas de trabajo y se exponen resultados obtenidos.; The article introduces the multidisciplinary research project titled Certifying our Existence carried out by TES, Association of Women of African Descent in Argentina, in 2016. Its main objective was to know about the life of Afro-Argentine women from the area. This is a pioneering work in Argentina because of its methodology and because it focuses on a group considered no longer existent in the country. The research made use of qualitative methodology- art and anthropology- and also of quantitative methodology- surveys and statistical data. It centers on the different stages of the research process and presents preliminary results.

Crystallization and initial X-ray diffraction analysis of the multi-domain Brucella blue light-activated histidine kinase LOV-HK in its illuminated state Rinaldi, Jimena Julieta; Fernandez, Ignacio; Poth, Lucia Milagros; Shepard, William E.; Savko, Martin; Goldbaum, Fernando Alberto; Klinke, Sebastian The pathogenic bacterium Brucella abortus codes for a multi-domain dimeric cytoplasmic histidine kinase called LOV-HK, which is a key blue light-activated virulence factor in this microorganism. The structural basis of the light activation mechanism of this protein remains unclear. In this work, full-length LOV-HK was cloned, expressed and purified. The protein was activated by light and crystallized under a controlled illumination environment. The merge of 14 individual native data sets collected on a single crystal resulted in a complete X-ray diffraction data set to a resolution of 3.70 Å with over 2 million reflections. Crystals belong to space group P212121, with unit-cell parameters a = 95.96, b = 105.30, c = 164.49 Å with a dimer in the asymmetric unit. Molecular replacement with Phaser using the individual domains as search models allowed for the reconstruction of almost the whole protein. Very recently, improved LOV-HK crystals led to a 3.25-Å resolution dataset. Refinement and model building is underway. This crystal model will represent one of the very few examples of a multi-domain histidine kinase with known structure.

Regulation and function of p53: A perspective from Drosophila studies Ingaramo, María Clara; Sánchez, Juan Andrés; Dekanty, Andres Tp53 is a central regulator of cellular responses to stress and one of the most frequently mutated genes in human cancers. P53 is activated by a myriad of stress signals and drives specific cellular responses depending on stress nature, cell type and cellular context. Additionally to its classical functions in regulating cell cycle arrest, apoptosis and senescence, newly described non-canonical functions of p53 are increasingly coming under the spotlight as important functions not only for its role as a tumour suppressor but also for its non-cancer associated activities. Drosophila melanogaster is a valuable model to study multiple aspects of normal animal physiology, stress response and disease. In this review, we discuss the contribution of Drosophila studies to the current knowledge on p53 and highlight recent evidences pointing to p53 novel roles in promoting tissue homeostasis and metabolic adaptation.

Predicting protein targets for drug-like compounds using transcriptomics Pabon, Nicolas A.; Xia, Yan; Estabrooks, Samuel K.; Ye, Zhaofeng; Herbrand, Amanda K.; Süß, Evelyn; Biondi, Ricardo Miguel; Assimon, Victoria A.; Gestwicki, Jason E.; Brodsky, Jeffrey L.; Camacho, Carlos J.; Bar-Joseph, Ziv An expanded chemical space is essential for improved identification of small molecules for emerging therapeutic targets. However, the identification of targets for novel compounds is biased towards the synthesis of known scaffolds that bind familiar protein families, limiting the exploration of chemical space. To change this paradigm, we validated a new pipeline that identifies small molecule-protein interactions and works even for compounds lacking similarity to known drugs. Based on differential mRNA profiles in multiple cell types exposed to drugs and in which gene knockdowns (KD) were conducted, we showed that drugs induce gene regulatory networks that correlate with those produced after silencing protein-coding genes. Next, we applied supervised machine learning to exploit drug-KD signature correlations and enriched our predictions using an orthogonal structure-based screen. As a proof-of-principle for this regimen, top-10/top-100 target prediction accuracies of 26% and 41%, respectively, were achieved on a validation of set 152 FDA-approved drugs and 3104 potential targets. We then predicted targets for 1680 compounds and validated chemical interactors with four targets that have proven difficult to chemically modulate, including non-covalent inhibitors of HRAS and KRAS. Importantly, drug-target interactions manifest as gene expression correlations between drug treatment and both target gene KD and KD of genes that act up- or down-stream of the target, even for relatively weak binders. These correlations provide new insights on the cellular response of disrupting protein interactions and highlight the complex genetic phenotypes of drug treatment. With further refinement, our pipeline may accelerate the identification and development of novel chemical classes by screening compound-target interactions.

Las primeras ocupaciones en el alero Potrok Aike 1 (Santa Cruz): evidencias líticas, óseas y paleoambientales; First human occupations in Potrok Aike 1 rockshelter (Santa Cruz): stone tools, bones and paleoenvironmental data Charlin, Judith Emilce; Borrero, Luis Alberto; Gomez Otero, Julieta En este trabajo se presenta información inédita sobre los materiales líticos y óseos de los niveles más tempranos (97-152 cm de profundidad) de la cuadrícula C del alero Potrok Aike 1 (sur de Santa Cruz, campo volcánico Pali Aike). La misma es puesta en relación con las evidencias paleoambientales disponibles a partir del estudio de núcleos de sedimentos de la laguna Potrok Aike. Los resultados señalan cambios y continuidades en diferentes aspectos relacionados con el uso de los recursos faunísticos y de las materias primas líticas entre las ocupaciones más tempranas (≤2300≥1300 años AP) y más tardías del alero (<1300 años AP), como así también en la intensidad de uso del sitio en concordancia con las variaciones climáticas. Finalmente, a partir de una comparación con los estudios arqueológicos previos se evalúa el significado de los hallazgos realizados en el alero en las escalas del sitio, la localidad y la región.; Unpublished information from the lower levels of Potrok Aike 1 Rockshelter, Santa Cruz, Pali Aike Volcanic Field is presented. Lithic and archaeofaunal materials were recovered between 97 and 152 cm at Square C of the rockshelter. This evidence is related with available paleoenvironmental information from deep cores obtained in the Potrok Aike lagoon. Results indicate changes and continuities in the use of faunal remains and lithic raw materials between the older (≥2300≥1300 years BP) and recent (<1300 years BP) occupations. Also changes in the intensity of use of the site concordant with climatic variation were identified. Finally, by comparison with previous archaeological results, the significance of the human occupations recovered at the Potrok Aike Rockshelter is evaluated at the scale of the site, the locality and the region.