The Moderate Alcohol and Cardiovascular Health Trial (MACH15): Design and methods for a randomized trial of moderate alcohol consumption and cardiometabolic risk Spiegelman, Donna; Lovato, Laura C.; Khudyakov, Polyna; Wilkens, Trine L.; Adebamowo, Clement A.; Adebamowo, Sally N.; Appel, Lawrence J.; Beulens, Joline W.J.; Coughlin, Janelle W.; Dragsted, Lars Ove; Edenberg, Howard J; Eriksen, Jane N.; Estruch, Ramon; Grobbee, Diederick E.; Gulayin, Pablo Elías; Irazola, Vilma; Krystal, John H.; Lazo, Mariana; Murray, Margaret M.; Rimm, Eric B.; Schrieks, Ilse C.; Williamson, Jeff D.; Mukamal, Kenneth J. Background: Observational studies have documented lower risks of coronary heart disease and diabetes among moderate alcohol consumers relative to abstainers, but only a randomized clinical trial can provide conclusive evidence for or against these associations. Aim: The purpose of this study was to describe the rationale and design of the Moderate Alcohol and Cardiovascular Health Trial, aimed to assess the cardiometabolic effects of one alcoholic drink daily over an average of six years among adults 50 years or older. Methods: This multicenter, parallel-arm randomized trial was designed to compare the effects of one standard serving (∼11–15 g) daily of a preferred alcoholic beverage to abstention. The trial aimed to enroll 7800 people at high risk of cardiovascular disease. The primary composite endpoint comprised time to the first occurrence of non-fatal myocardial infarction, non-fatal ischemic stroke, hospitalized angina, coronary/carotid revascularization, or total mortality. The trial was designed to provide >80% power to detect a 15% reduction in the risk of the primary outcome. Secondary outcomes included diabetes. Adverse effects of special interest included injuries, congestive heart failure, alcohol use disorders, and cancer. Results: We describe the design, governance, masking issues, and data handling. In three months of field center activity until termination by the funder, the trial randomized 32 participants, successfully screened another 70, and identified ∼400 additional interested individuals. Conclusions: We describe a feasible design for a long-term randomized trial of moderate alcohol consumption. Such a study will provide the highest level of evidence for the effects of moderate alcohol consumption on cardiovascular disease and diabetes, and will directly inform clinical and public health guidelines.

El significado de las últimas palabras: las notas suicidas como acciones comunicativas: Buenos Aires, 1859-1888; The meaning of the last words: suicide notes as a communicative actions: Buenos Aires, 1859-1888 Arroyo, Julián En el presente artículo abordamos, desde una perspectiva histórica y sociocultural, un conjunto de casos de suicidio ocurridos en la ciudad de Buenos Aires entre 1859 y 1888, con el fin de estudiar las cartas de los que se quitaban la vida. Entendemos estos escritos como acciones comunicativas que tenían diferentes significados, y transmitían mensajes a los integrantes de la red vincular del suicida. En relación con este propósito general, uno de nuestros objetivos específicos es explorar las circunstancias, preocupaciones y conflictos que formaban parte del contexto en el que estos textos fueron elaborados. Es decir, nos proponemos dar pasos orientados a responder la siguiente pregunta: ¿en qué situaciones era más frecuente que los suicidas dejaran registradas sus últimas palabras? Tomando como punto de partida los indicios extraídos de los sumarios judiciales, en este trabajo mostramos que las cartas aparecían de forma más frecuente en expedientes que narraban una serie de hechos particulares. Asimismo, sostenemos que estas explicaciones verosímiles de los actos suicidas, y las notas asociadas a estos, eran enunciadas a partir de los horizontes de expectativas que tenían los hombres y mujeres de la ciudad de Buenos Aires durante el último tercio del siglo XIX.; In this article we study, from a historical and sociocultural perspective, a set of suicide cases that occurred in the city of Buenos Aires between 1859 and 1888 to analyze the letters left by those who committed suicide. We understand these writings as communicative actions that had different meanings, and transmitted messages to the members of the deceased's social network. Also, one of our specific objectives is to explore the circumstances, concerns and conflicts that were part of the context in which these texts were produced. In other words, we seek to answer the following question: in which situations did suicide notes appear more frequently? Based on the evidence from the the judicial summaries, in this paper we show that letters appeared more frequently in files that narrated a series of particular events. Likewise, we argue that these plausible explanations of suicidal acts, and the notes associated with them, were stated based on the expectations of men and women from Buenos Aires during the last third of the 19th century.

El Archivo Histórico del Agua del Departamento General de Irrigación de la Provincia de Mendoza, Argentina; The Historical Archive of Water of the General Department of Irrigation of the Province of Mendoza, Argentina Martin, Facundo Damian; Healey, Mark; Fili, Juan Pablo; Parise Schneider, Nicolás; Engelman, Anabella Ayelén En este artículo presentamos el Archivo Histórico del Agua (AHA) del Departamento General de Irrigación perteneciente a la Provincia de Mendoza. Para esto realizamos un recorrido por la historia de las instituciones productoras de los archivos, caracterizamos los principales fondos hallados y delineamos los desafíos y oportunidades que implica el des-cubrimiento de fuentes históricas poco visibles o no analizadas hasta el momento.; This article presents the Historical Water Archive of the General Irrigation Department of the provincial government of Mendoza, Argentina. The article begins with the historical development of the institutions producing the archive, then surveys the main collections it contains, and sketches the challenges and opportunities of un-covering historical sources barely visible or analyzed until the present.

La expansión agrícola en el cinturón verde de la Ciudad de Mendoza: Aportes sobre la trayectoria de las explotaciones agropecuarias en el caso de Fray Luis Beltrán; Agricultural expansion in Mendoza's city green belt: Contributions on the trajectory of farms in the case of Fray Luis Beltrán Dalmasso, Caterina; Mussetta, Paula Cecilia Las transformaciones territoriales del Área Metropolitana de Mendoza han impactado en su cinturón verde. Sin embargo, estudios recientes indican que, pese a la expansión urbana, la superficie cultivada se ha mantenido relativamente estable e identifican que los productores que salen de un sitio, se relocalizan en otras zonas menos competitivas. Bajo una metodología cuanti-cualitativa, este trabajo profundiza en las particularidades de la dinámica territorial en Fray Luis Beltrán (Maipú), distrito que en los últimos años ha registrado un importante crecimiento de superficie cultivada. Desde un enfoque territorial, el artículo da cuenta del proceso de expansión agrícola en este distrito e identifica las condiciones territoriales que lo habilitan. Encuentra, además, que dicho proceso es protagonizado por actores locales que cuentan con larga trayectoria en el cinturón verde de Mendoza. Como resultado, el estudio destaca que el avance de la horticultura en Fray Luis Beltrán no es un fenómeno directa o linealmente impulsado por la relocalización de las fincas urbanizadas. Asimismo, resalta la conformación de un modelo de horticultura que se distingue de la existente en otras áreas del cinturón verde, así como de procesos expansivos generados en otras áreas productivas.; Transformations of Mendoza Metropolitan Area have impacted the green belt. Recent studies indicate that despite urban expansion, the cultivated area has remained relatively stable. Additionally, they identify a trend that would indicate that producers who leave one site are relocating to other less competitive areas. Applying a quantitative-qualitative methodology, this work examines the particularities of the territorial dynamics in Fray Luis Beltrán (Maipú), a district that in recent years has registered a significant growth in cultivated area. Taking a territorial approach, this article reports the process of agricultural expansion in this district and identifies the conditions that enable it. It also finds that this process is led by local actors with a long trajectory in Mendoza's green belt. The study highlights that the advance of horticulture in Fray Luis Beltrán is not a direct or linear phenomenon driven by the relocation of urbanized farms. Furthermore, it points out the conformation of a horticulture model that differs from the existing one in other areas of the green belt, as well as from expansive processes generated in other productive areas.

Tratamiento quirúrgico en acromegalia: experiencia en Córdoba; Surgical treatment in acromegaly: Experience in Córdoba Rendón, Matilde Inés; Cecenarro, Laura Anahi; Andrada, Marta Cecilia; Barovero, Mariela Susana; Bertolino, María Lorena; Cagliolo, Mariela; Carpentieri, Agata Rita; Damilano, Roxana Analía; De Battista, Juan Carlos; Estario, Paula; Fernández, Silvia; Marquez, Maria Eugenia; Monteserin, Natalia; Quintero, María Lorena; Sala, Claudia Susana; Sosa, Gabriela Alejandra; Surraco, María Elena; de Paul, Ana Lucia; Szafryk de Mereshian, Paula Maria; Fux Otta, Carolina La acromegalia tiene una prevalencia de 35-70/millón. La cirugía transesfenoidales el tratamiento de elección, siendo la tasa de remisión del 80% en microadenomas y 50% en macroadenomas. Debido a la falta de registros, nos propusimos evaluar los resultados quirúrgicos en Córdoba y determinar factores predictivos de remisión.Métodos: Estudio retrospectivo-descriptivo de pacientes con cirugía como primera línea terapéutica. Criterios de remisión: normalización de IGF1 para edad/sexo, con GH ≤1,0 g/L.TestX2 y test exacto de Fisher y p<0,05.Resultados:Se incluyeron 38 pacientes: 61% mujeres y 39% hombres; edad promedio 45 años. Motivos de consulta más frecuentes: cefalea y crecimiento acral (26%), alteraciones visuales (20%). El 84% de los tumores fueron macroadenomas. De 37 pacientes, 54% se sometierona cirugía microscópica, 38% endoscópica y 8% transcraneal. El 29% evidenció complicaciones postquirúrgicas, siendo la diabetes insípida la más frecuente (10%). El porcentaje de las mismas fue: cirugía transcraneal el 33%, endoscópica 29% y microscópica 25% (p= 0,557). La remisión bioquímica a los 6 meses fue de 34% y a los 12 meses 55% (p=0,0001). Sin diferencias significativas entre la vía endoscópica y microscópica (p=0,071). De 36 pacientes el 31% evidenció resección tumoral completa. La mejoría clínicasubjetiva fue del 88%. No hubo factores predictivos de remisión bioquímica estadísticamente significativos. La remisión bioquímica con la cirugía fue similar a la bibliografía. No encontramos factores predictivos deremisión pero un número mayor de casos podría modificar estos resultados; Acromegaly prevalence is 35-70 / million. Transsphenoidal surgery is the first-line treatment, with a remission rate of 80% for microadenomas and 50% for macroadenomas. Our aim was to evaluate the surgical results in Córdoba and determine predictive remission factors due to the lack of records. Methods: Retrospective-descriptive study of patients with surgery as the first therapeutic line. Remission criteria: IGF1 normalization for age/sex, with GH ≤1.0 g/L. Test X2 and Fisher´s exact test with p<0.05. Results: 38 patients were included: 61% women and 39% men; Average age 45 years. Most frequent chief complaint: headache and acral growth (26%), visual disturbances (20%). Macroadenomas were the 84% of the tumors. Of 37 patients, 54% underwent microscopic surgery, 38% endoscopic and 8% transcranial. The 29% of patients showed post-operative complications and diabetes insipidus was the most frequent (10%). The percentage of them was: 33% transcranial surgery, 29% endoscopic and 25% microscopic (p = 0.557). The biochemical remission at 6 months was 34% and at 12 months 55% (p= 0.0001). No significant differences between the endoscopic and microscopic approach (p = 0.071). Of 36 patients, 31% showed complete tumor resection. The subjective clinical improvement was 88%. There weren´t predictive remission factors with significant differences. Conclusion: The surgical biochemical remission was similar to the bibliography. We didn´t find predictive remission factors but a larger number of patients could modify these results.Key words: acromegaly; neurosurgery; postoperative complications; remission induction

Role of VAMP7-Dependent Secretion of Reticulon 3 in Neurite Growth Wojnacki, José; Nola, Sébastien; Bun, Philippe; Cholley, Béatrice; Filippini, Francesca; Pressé, Mary T.; Lipecka, Joanna; Man Lam, Sin; N'guyen, Julie; Simon, Axelle; Ouslimani, Amine; Shui, Guanghou; Fader Kaiser, Claudio Marcelo; Colombo, Maria Isabel; Guerrera, Ida Chiara; Galli, Thierry VAMP7 is involved in autophagy and in exocytosis-mediated neurite growth, two yet unconnected cellular pathways. Here, we find that nutrient restriction and activation of autophagy stimulate axonal growth, while autophagy inhibition leads to loss of neuronal polarity. VAMP7 knockout (KO) neuronal cells show impaired neurite growth, whereas this process is increased in autophagy-null ATG5 KO cells. We find that endoplasmic reticulum (ER)-phagy-related LC3-interacting-region-containing proteins Atlastin 3 and Reticulon 3 (RTN3) are more abundant in autophagy-related protein ATG5 KO and less abundant in VAMP7 KO secretomes. Treatment of neuronal cells with ATG5 or VAMP7 KO conditioned medium does not recapitulate the effect of these KOs on neurite growth. A nanobody directed against VAMP7 inhibits axonal overgrowth induced by nutrient restriction. Furthermore, expression of the inhibitory Longin domain of VAMP7 impairs the subcellular localization of RTN3 in neurons. We propose that VAMP7-dependent secretion of RTN3 regulates neurite growth.

Patagones en el mapa del Amazonas de Samuel Fritz (1707); Patagones no mapa do Amazonas de Samuel Fritz (1707); Patagonians on Samuel Fritz's map of the Amazon (1707); Patagons dans la carte de l’Amazone de Samuel Fritz (1707) Martinez, Carolina Desde las perspectivas abiertas por la historia cultural y la historia de la cartografía, este trabajo examina la iconografía presente en el mapa de El Gran Rio Marañón o Amazonas, realizado por el padre jesuita Samuel Fritz e impreso en el Colegio Máximo de la ciudad de Quito en 1707. A diferencia de los enfoques historiográficos que han visto en las imágenes que ilustran la cartela del mapa un reflejo del trabajo misional de la Compañía de Jesús en la cuenca del Amazonas, el análisis de las figuras centrales del mapa revela que sus orígenes se encuentran en la experiencia de los holandeses que navegaron el área magallánico-fueguina hacia fines del siglo XVI. El trabajo se centra, entonces, en los procesos de producción y circulación de aquellas imágenes cartográficas que, desplazadas de sus contextos originales de producción, devinieron representativas de América meridional en su totalidad cuando no de la región amazónica en particular.

Las familias toman la calle en el barrio: Acción colectiva, participación política y disputas simbólicas en torno a lo escolar; Families take up the streets in the neighborhood: Collective action, political participation and symbolic disputes over what counts as “schooling” Meo, Analía Inés; Heras Monner Sans, Ana Ines En este ensayo argumentamos que la toma de la calle, literal y simbólica, llevada adelante por familias de una escuela primaria, es una acción política auto-organizada. Para ello, hemos mapeado el campo local de posicionamientos conceptuales y examinamos una acción de las familias, llamada LaMesita por sus creadorxs, con el propósito de analizar las particularidades que este accionar colectivo asume, así como evidenciar de qué modo su estudio enriquece al emergente -aunque aún marginal- corpus de investigaciones sobre las formas de auto-organización de familias en el ámbito escolar. El análisis de este caso nos servirá para reflexionar críticamente sobre los estudios de la acción política en el campo escolar y apuntar a la necesidad de prestar más atención a las intervenciones locales,; This essay argues that a group of families of a primary school takes the street and this material and symbolic intervention is a self-organised political action. On the one hand, we map out conceptual positions in Argentina around collective action in the field of schooling. On the other, we examine the features, scope, and effects of one collective action called by its creators LaMesita. This piece evidences how the study of the latter enriches the emergent (although still marginal) body of research on self-organised political action of families in primary schooling. This case will help us to critically reflect on the studies on political action around compulsory schooling. Furthermore, it allows us to argue for the need to pay more attention to local, every day and face to face interactions in order to recognise the variety of forms that struggles over the legitimate participation in schooling take place.

Amphiphilic ionic liquids as sustainable components to formulate promising vesicles to be used in nanomedicine Falcone, Ruben Dario; Correa, Nestor Mariano; Silber, Juana J. Ionic Liquids (ILs) are an interesting category of compounds particularly because of the possibility to easily synthesize them with different attractive properties, in the lab. The interest for ILs with amphiphilic character (IL-like surfactants) has been growing up because of versatility in creating useful supramolecular assemblies. In this short review, the current state of IL-like surfactants to prepare vesicles in water is described. Particularly, the focus has been put on the experiments performed by South American researchers using protic and aprotic surfactants. Finally, it summarizes some preliminary results obtained in our lab about the application in nanomedicine that these novel vesicles can offer.

Testosterone-loaded GM1 micelles targeted to the intracellular androgen receptor for the specific induction of genomic androgen signaling Peinetti, Nahuel; Cuello Rubio, Mariana Micaela; Sosa, Liliana del Valle; Scalerandi, María Victoria; Alasino, Roxana Valeria; Peyret, Victoria; de Nicola, Juan Pablo; Beltramo, Dante Miguel; Quintar, Amado Alfredo; Maldonado, Cristina Alicia Androgens play a central role in homeostatic and pathological processes of the prostate gland. At the cellular level, testosterone activates both the genomic signaling pathway, through the intracellular androgen receptor (AR), and membrane-initiated androgen signaling (MIAS), by plasma membrane receptors. We have previously shown that the activation of MIAS induces uncontrolled proliferation and fails to stimulate the beneficial immunomodulatory effects of testosterone in prostatic cells, becoming necessary to investigate if genomic signaling mediates homeostatic effects of testosterone. However, the lack of specific modulators for genomic androgen signaling has delayed the understanding of this mechanism. In this article, we demonstrate that monosialoganglioside (GM1) micelles are capable of delivering testosterone into the cytoplasm to specifically activate genomic signaling. Stimulation with testosterone-loaded GM1 micelles led to the activation of androgen response element (ARE)-regulated genes in vitro as well as to the recovery of normal prostate size and histology after castration in mice. In addition, these micelles avoided MIAS, as demonstrated by the absence of rapid signaling pathway activation and the inability to induce uncontrolled cell proliferation. In conclusion, our results validate a novel tool for the specific activation of genomic androgen signaling and demonstrate the importance of selective pathway activation in androgen-mediated proliferation.

Cancer immunotherapy–related adverse events: causes and challenges Blidner, Ada Gabriela; Choi, Jennifer Ailen; Cooksley, Tim; Dougan, Michael; Glezerman, Ilya; Ginex, Pamela; Girotra, Monica; Gupta, Dipti; Johnson, Douglas; Shannon, Vickie R.; Suarez Almazor, Maria; Rapoport, Bernardo L.; Anderson, Ronald Despite the success and ongoing promise of monoclonal antibody–targeted immune checkpoint inhibitor immunotherapy of advanced malignancies, in particular, antibodies directed against CTLA-4 and PD-1/PD-L1, the development of immune-related adverse events (irAEs) remains a constraint of this type of therapy. Although rarely fatal, the occurrence of irAEs may necessitate discontinuation of immunotherapy, as well as administration of corticosteroids or other immunosuppressive therapies that may not only compromise efficacy but also predispose for development of opportunistic infection. Clearly, retention of efficacy of immune checkpoint–targeted therapies with concurrent attenuation of immune-mediated toxicity represents a formidable challenge. In this context, the current brief review examines mechanistic relationships between these events, as well as recent insights into immunopathogenesis, and strategies which may contribute to resolving this issue. These sections are preceded by brief overviews of the discovery and functions of CTLA-4 and PD-1, as well as the chronology of the development of immunotherapeutic monoclonal antibodies which target these immune checkpoint inhibitors.

A plausible extension of standard penalty, streamline upwind and immersed boundary techniques to the improved element-free Galerkin-based solution of incompressible Navier–Stokes equations Álvarez Hostos, Juan Carlos; Cruchaga, Marcela A.; Fachinotti, Victor Daniel; Zambrano Carrillo, Javier Alexander; Zamora Ramirez, Esteban Alonso The present work has been conducted in order to propose the extension of standard penalty and stabilization techniques to the improved element-free Galerkin (IEFG) method, for the numerical solution of incompressible fluid flow problems. In principle, the numerical procedures to be implemented in this communication have been conceived for finite element method (FEM)-based solutions, and these include the reduced integration penalty method (RIPM), the streamline upwind Petrov–Galerkin (SUPG) scheme, and a penalty-based immersed boundary method (PBIBM) for the imposition of essential boundary conditions along internal fluid–solid interfaces. The linear momentum balance and mass conservation equations have been coupled via the RIPM, in order to obtain a global weak formulation where the IEFG model is entirely developed in terms of improved moving least squares (IMLS) approximations of the velocity field. A detailed explanation concerning the appropriate extension of both the RIPM and SUPG procedures to the context of IEFG formulations, has also been provided. The resulting formulation has been applied to the solution of two well-known benchmark problems: i) Lid-driven square cavity flow, and ii) Flow past a fixed cylinder. Regarding the flow past a fixed cylinder benchmark problem, the fluid–solid interaction has been imposed as an internal immersed boundary condition via the PBIBM. The feasibility and reliability of implementing the RIPM, SUPG and PBIBM procedures in the IEFG formulation, have been proven by comparison with experimental and mesh-based numerical results reported in the literature. The results obtained in this study have revealed that a proper extension of the aforementioned penalty and stabilization techniques to the IEFG formulation, allows the achievement of accurate and stable numerical results during the solution of incompressible fluid-dynamics problems.

From town to town: Predicting the taxonomic, functional and phylogenetic diversity of birds using NDVI Leveau, Lucas Matias; Isla, Federico Ignacio; Bellocq, Maria Isabel Biodiversity mapping in urban areas is imperative for their conservation. Remote sensors produce environmental information, such as the Normalized Difference Vegetation Index (NDVI), an indicator of vegetation cover in urban areas. NDVI can be used to predict the taxonomic, functional and phylogenetic bird diversity in urban areas. Moreover, a predictive model constructed in one city can be used to predict the bird diversity in other cities. The objectives of this study were: 1) to construct and evaluate predictive models between NDVI and taxonomic, functional and phylogenetic diversity of birds in Mar del Plata city, Argentina; and 2) to extrapolate these models to two other cities in the region: Balcarce and Miramar. Generalized additive models were applied to relate bird diversity variations to NDVI. In Mar del Plata, the taxonomic and functional diversity increased with increasing NDVI values, and the predictive models explained 64–81% of the taxonomic and functional diversity variation. The models correctly predicted taxonomic and functional diversity values in additional transects not included in the models, although they had a low predictive power of phylogenetic diversity. The models constructed in Mar del Plata adequately predicted the spatial variation of species diversity (Shannon index) in Balcarce and Miramar, the spatial variation of species richness in Balcarce, and the variation of functional diversity in Miramar. Our analysis revealed that a predictive model of bird diversity based on NDVI patterns created in one city can also depict the expected species diversity in other cities, being a time-saving and cost-effective method to create a tool for urban biodiversity conservation.

Entre el plan nacional de inclusión digital educativa (PNIDE) y el plan aprender conectados (PAC): las voces de los actores territoriales y escolares; Between the national plan for digital inclusion in education (PNIDE) and the plan learn connected: the voices of territorial and school actors Quintana, Rocío; Mamani, Gonzalo Ricardo En este artículo nos proponemos indagar en una primera parte, las rupturas y las continuidades en la dimensión programática de dos políticas públicas educativas que marcaron el fin y el comienzo de proyectos políticos diferentes en nuestro país: el Plan Nacional de Inclusión Digital Educativa (en adelante PNIDE), lanzado en 2015 durante el gobierno de Cristina Fernández de Kirchner, y el Plan Aprender Conectados, lanzado en 2018 durante el gobierno nacional de Mauricio Macri. En una segunda parte, describir las voces de los diferentes actores territoriales y escolares que intervienen en la implementación de la política públicas en las instituciones educativas.; In this article we propose to investigate, in the first part, the ruptures and continuities in the programmatic dimension of two public educational policies that marked the end and the beginning of different political projects in our country: the National Plan for Educational Digital Inclusion, launched in 2015 during the government of Cristina Fernández de Kirchner, and the Plan Learn Connected, launched in 2018 during the national government of Mauricio Macri. In a second part, we will explore the voices of the different territorial and school actors that intervene in the implementation of public policies in educational institutions.

Effects of agricultural pesticides on the reproductive system of aquatic wildlife species, with crocodilians as sentinel species Tavalieri, Yamil Ezequiel; Galoppo, Germán Hugo; Canesini, Guillermina; Luque, Enrique Hugo; Muñoz de Toro, Monica Milagros Agricultural pesticides represent a significant class of endocrine-disrupting chemicals (EDCs) to which non-target organisms around the world are constantly exposed. Laboratory studies have found strong evidence showing the endocrine-disruptive potential of these pesticides at environmentally relevant exposure levels. Since the field of endocrine disruption continues to grow in richness and complexity, this review aims to provide an update on the effects of two agricultural pesticides that act as EDCs: atrazine and endosulfan. We will focus mainly on the effects on crocodilians due to their worldwide occurrence in tropical and sub-tropical wetland ecosystems and their ecological and physiological features, which render them vulnerable to exposure to pesticides with endocrine-disrupting action at all life stages. The results here reviewed provide important insights into the effects of hormonally active agricultural pesticides at cellular, tissue, and organ levels in the reproductive system of crocodiles. A better understanding of the effects of exposure to environmentally relevant doses of EDCs on the reproductive system of crocodilians will contribute to protect and improve the health of both wildlife species and humans.

Perinatal exposure to Bisphenol A disturbs the early differentiation of male germ cells Pagotto, Romina María del Luján; Santamaría, Clarisa Guillermina; Harreguy, María Belén; Abud, Julián Elías; Zenclussen, Maria Laura; Kass, Laura; Crispo, Martina; Muñoz de Toro, Monica Milagros; Rodriguez, Horacio Adolfo; Bollati Fogolín, Mariela Understanding the effects of Bisphenol A (BPA) on early germ cell differentiation and their consequences in adult life is an area of growing interest in the field of endocrine disruption. Herein, we investigate whether perinatal exposure to BPA affects the differentiation of male germ cells in early life using a transgenic mouse expressing the GFP reporter protein under the Oct4 promoter. In this model, the expression of GFP reflects the expression of the Oct4 gene. This pluripotency gene is required to maintain the spermatogonial stem cells in an undifferentiated stage. Thus, GFP expression was used as a parameter to evaluate the effect of BPA on early germ cell development. Female pregnant transgenic mice were exposed to BPA by oral gavage, from embryonic day 5.5 to postnatal day 7 (PND7). The effects of BPA on male germ cell differentiation were evaluated at PND7, while sperm quality, testicular morphology, and protein expression of androgen receptor and proliferating cell nuclear antigen were studied at PND130. We found that perinatal/lactational exposure to BPA up-regulates the expression of Oct4-driven GFP in testicular cells at PND7. This finding suggests a higher proportion of undifferentiated spermatogonia in BPA-treated animals compared with non-exposed mice. Moreover, in adulthood, the number of spermatozoa per epididymis was reduced in those animals perinatally exposed to BPA. This work shows that developmental exposure to BPA disturbed the normal differentiation of male germ cells early in life, mainly by altering the expression of Oct4 and exerted long-lasting sequelae at the adult stage, affecting sperm count and testis.

Bisphenol A and benzophenone-3 exposure alters milk protein expression and its transcriptional regulation during functional differentiation of the mammary gland in vitro Altamirano, Gabriela Anahí; Gomez, Ayelen Luciana; Schierano Marotti, Gonzalo; Muñoz de Toro, Monica Milagros; Rodriguez, Horacio Adolfo; Kass, Laura The plastic monomer and plasticizer bisphenol A (BPA), and the UV-filter benzophenone-3 (BP3) have been shown to have estrogenic activities that could alter mammary gland development. Our aim was to analyze whether BPA or BP3 direct exposure affects the functional differentiation of the mammary gland using an in vitro model. Mammary organoids were obtained and isolated from 8 week-old virgin female C57BL/6 mice and were differentiated on Matrigel with medium containing lactogenic hormones and exposed to: a) vehicle (0.01% ethanol); b) 1 × 10−9 M or 1 × 10−6 M BPA; or c) 1 × 10−12 M, 1 × 10−9 M or 1 × 10−6 M BP3 for 72 h. The mRNA and protein expression of estrogen receptor alpha (ESR1) and progesterone receptor (PR) were assessed. In addition, mRNA levels of PR-B isoform, glucocorticoid receptor (GR), prolactin receptor (PRLR) and Stat5a, and protein expression of pStat5a/b were evaluated at 72 h. The mRNA and protein expression of milk proteins and their DNA methylation status were also analyzed. Although mRNA level of PRLR and GR was similar between treatments, mRNA expression of ESR1, total PR, PR-B and Stat5a was increased in organoids exposed to 1 × 10−9 M BPA and 1 × 10−12 M BP3. Total PR expression was also increased with 1 × 10−6 M BPA. Nuclear ESR1 and PR expression was observed in all treated organoids; whereas nuclear pStat5a/b alveolar cells was observed only in organoids exposed to 1 × 10−9 M BPA and 1 × 10−12 M BP3. The beta-casein mRNA level was increased in both BPA concentrations and 1 × 10−12 M BP3, which was associated with hypomethylation of its promoter. The beta-casein protein expression was only increased with 1 × 10−9 M BPA or 1 × 10−12 M BP3. In contrast, BPA exposure decreased alpha-lactalbumin mRNA expression and increased DNA methylation level in different methylation-sensitive sites of the gene. Also, 1 × 10−9 M BPA decreased alpha-lactalbumin protein expression. Our results demonstrate that BPA or BP3 exposure alters milk protein synthesis and its transcriptional regulation during mammary gland differentiation in vitro.

Preparation and evaluation of caffeine bioadhesive emulgels for cosmetic applications based on formulation design using QbD tools de Lafuente, Yanina; Ochoa-Andrade, A.; Parente, M. E.; Palena, María Celeste; Jimenez Kairuz, Alvaro Federico The aim of the present study was to evaluate the influence of the incorporation of caffeine as a model active ingredient on the quality attributes of a bioadhesive emulgel formulation previously optimized by Quality by Design (QbD) tools. Emulgels are emerging topical drug delivery systems for cosmetic or pharmaceutical uses, which combine the advantages of both emulsions and gels. Methods: In this work, the observed and predicted values for spreadability, phase separation by centrifugation and detachment forces performed by texturometer were compared with those of the control and active-containing emulgel formulations. In addition, rheological properties, release of caffeine and comparative in vitro/ex vivo bioadhesion properties were evaluated using human skin. Results: The flow curves of emulgel formulations showed the typical pseudoplastic and no thixotropic flow with yield stress. The incorporation of active ingredient did not produce significant changes. All emulgels were uniformly spread and no significant differences in spreadability values between control and caffeine containing formulations and neither respect to those predicted values from experimental design optimization were found. Emulgel formulations showed appropriate detachment forces values and no significant differences between caffeine loading and control emulgel formulations were observed. Conclusion: Caffeine was successfully vehiculized in this optimized bioadhesive emulgel formulation, which showed high robustness regarding the process variability. There were no significant changes in the critical quality attributes after the incorporation of the active ingredient and a promising stability was observed for at least one year. Results suggested that the optimized emulgel is an interesting topical biodhesive delivery system for cosmetic applications, including agents for skin conditioning, not present in gels formulations.

Differentiation of non-aureus staphylococci species isolated from bovine mastitis by PCR-RFLP of groEL and gap genes in comparison to MALDI-TOF mass spectrometry Conesa, Agustin; Dieser, Silvana Andrea; Barberis, Claudia; Bonetto, Cesar; Lasagno, Mirta; Vay, Carlos; Odierno, Liliana; Porporatto, Carina; Raspanti, Claudia Intramammary infections (IMI) cause serious economic losses for farmers and the dairy industry. Cases of subclinical mastitis are commonly the result of infection by minor pathogens such as non-aureus staphylococci (NAS), so their correct identification is important for appropriate therapeutic intervention and management. The aim of this study was to assess the reliability of PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) of the groEL and gap genes to discriminate between bovine-associated NAS species, using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) as the reference method. MALDI-TOF MS was able to correctly identify 112 NAS isolates from bovine IMI at species level out of a total of 115 (97.4%). These results were considered definitive and thus compared with those from the PCR-RFLP analyses. Only 50% (56/112) of the samples classified through groEL PCR-RFLP matched the molecular identity determined by MALDI-TOF MS, whereas coincidence rose to 96.4% (108/112) when comparing results from gap PCRRFLP and the spectral analysis. This study demonstrates that gap PCR-RFLP is a useful and reliable tool for the identification of NAS species isolated from bovine mastitis.

Cluster analysis for granular mechanics simulations using machine learning algorithms; Análisis de clústeres para simulaciones de mecánica granular mediante algoritmos de aprendizaje automático Rim, Daniela Noemí; Millán, Emmanuel Nicolás; Planes, María Belén; Bringa, Eduardo Marcial; Moyano, Luis Gregorio Las simulaciones de dinámica molecular (MD) en colisiones de granos permiten incorporar propiedades complejas de interacciones de polvo. Realizamos simulaciones de colisiones de granos porosos, cada uno con muchas partículas, utilizando el software LAMMPS de MD. Las simulaciones consistieron en un grano de proyectil que golpeó un grano objetivo inmóvil más grande, con diferentes velocidades de impacto. La desventaja de este método es el gran costo computacional debido a que se modela una gran cantidad de partículas. Machine Learning (ML) tiene el poder de manipular grandes datos y construir modelos predictivos que podrían reducir los tiempos de simulación MD. Usando algoritmos ML (Support Vector Machine y Random Forest) podemos predecir el resultado de las simulaciones MD con respecto a la formación de fragmentos, después de varios pasos más pequeños que en las simulaciones MD habituales. Logramos una reducción de tiempo de al menos un 46%, para una precisión del 90%. Estos resultados muestran que SVM y RF pueden ser herramientas poderosas pero simples para reducir el costo computacional en simulaciones de fragmentación de colisiones.; Molecular Dynamics (MD) simulations on grain collisions allow to incorporate complex properties of dust interactions. We performed simulations of collisions of porous grains, each with many particles, using the MD software LAMMPS. The simulations consisted of a projectile grain striking a larger immobile target grain, with different impact velocities. The disadvantage of this method is the large computational cost due to a large number of particles being modeled. Machine Learning (ML) has the power to manipulate large data and build predictive models that could reduce MD simulation times. Using ML algorithms (Support Vector Machine and Random Forest), we are able to predict the outcome of MD simulations regarding fragment formation after a number of steps smaller than in usual MD simulations. We achieved a time reduction of at least 46%, for 90% accuracy. These results show that SVM and RF can be powerful yet simple tools to reduce computational cost in collision fragmentation simulations.