Physical and functional interaction between the dopamine transporter and the synaptic vesicle protein synaptogyrin-3.

Uptake through the dopamine transporter (DAT) represents the primary mechanism used to terminate dopaminergic transmission in brain. Although it is well known that dopamine (DA) taken up by the transporter is used to replenish synaptic vesicle stores for subsequent release, the molecular details of this mechanism are not completely understood. Here, we identified the synaptic vesicle protein synaptogyrin-3 as a DAT interacting protein using the split ubiquitin system. This interaction was confirmed through coimmunoprecipitation experiments using heterologous cell lines and mouse brain. DAT and synaptogyrin-3 colocalized at presynaptic terminals from mouse striatum. Using fluorescence resonance energy transfer microscopy, we show that both proteins interact in live neurons. Pull-down assays with GST (glutathione S-transferase) proteins revealed that the cytoplasmic N termini of both DAT and synaptogyrin-3 are sufficient for this interaction. Furthermore, the N terminus of DAT is capable of binding purified synaptic vesicles from brain tissue. Functional assays revealed that synaptogyrin-3 expression correlated with DAT activity in PC12 and MN9D cells, but not in the non-neuronal HEK-293 cells. These changes were not attributed to changes in transporter cell surface levels or to direct effect of the protein-protein interaction. Instead, the synaptogyrin-3 effect on DAT activity was abolished in the presence of the vesicular monoamine transporter-2 (VMAT2) inhibitor reserpine, suggesting a dependence on the vesicular DA storage system. Finally, we provide evidence for a biochemical complex involving DAT, synaptogyrin-3, and VMAT2. Collectively, our data identify a novel interaction between DAT and synaptogyrin-3 and suggest a physical and functional link between DAT and the vesicular DA system

Association Study Among Candidate Genetic Polymorphisms and Chemotherapy-Related Severe Toxicity in Testicular Cancer Patients

Testicular cancer is one of the most commonly occurring malignant tumors in young men with fourfold higher rate of incidence and threefold higher mortality rates in Chile than the average global rates. Surgery is the initial line of treatment for testicular cancers, and is generally followed by chemotherapy, usually with combinations of bleomycin, etoposide, and cisplatin (BEP). However, the adverse effects of chemotherapy vary significantly among individuals; therefore, the present study explored the association of functionally significant allelic variations in genes related to the pharmacokinetics/pharmacodynamics of BEP and DNA repair enzymes with chemotherapy-induced toxicity in BEP-treated testicular cancer patients. We prospectively recruited 119 patients diagnosed with testicular cancer from 2010 to 2017. Genetic polymorphisms were analyzed using PCR and/or qPCR with TaqMan®probes. Toxicity was evaluated based on the Common Terminology Criteria for Adverse Events, v4.03. After univariate analyses to define more relevant genetic variants (p < 0.2) and clinical conditions in relation to severe (III–IV) adverse drug reactions (ADRs), stepwise forward multivariate logistic regression analyses were performed. As expected, the main severe ADRs associated with the non-genetic variables were hematological (neutropenia and leukopenia). Univariate statistical analyses revealed that patients with ERCC2 rs13181 T/G and/or CYP3A4 rs2740574 A/G genotypes are more likely to develop alopecia; patients with ERCC2 rs238406 C/C genotype may develop leukopenia, and patients with GSTT1-null genotype could develop lymphocytopenia (III–IV). Patients with ERCC2 rs1799793 A/A were at risk of developing severe anemia. The BLMH rs1050565 G/G genotype was found to be associated with pain, and the GSTP1 G/G genotype was linked infection (p < 0.05). Multivariate analysis showed an association between specific ERCC1/2 genotypes and cumulative dose of BEP drugs with the appearance of severe leukopenia and/or febrile neutropenia. Grades III–IV vomiting, nausea, and alopecia could be partly explained by the presence of specific ERCC1/2, MDR1, GSTP1, and BLMH genotypes (p < 0.05). Hence, we provide evidence for the usefulness of pharmacogenetics as a tool for predicting severe ADRs in testicular cancer patients treated with BEP chemotherapy

Large-scale patterns of turnover and basal area change in Andean forests

General patterns of forest dynamics and productivity in the Andes Mountains are poorly characterized. Here we present the first large-scale study of Andean forest dynamics using a set of 63 permanent forest plots assembled over the past two decades. In the North-Central Andes tree turnover (mortality and recruitment) and tree growth declined with increasing elevation and decreasing temperature. In addition, basal area increased in Lower Montane Moist Forests but did not change in Higher Montane Humid Forests. However, at higher elevations the lack of net basal area change and excess of mortality over recruitment suggests negative environmental impacts. In North-Western Argentina, forest dynamics appear to be influenced by land use history in addition to environmental variation. Taken together, our results indicate that combinations of abiotic and biotic factors that vary across elevation gradients are important determinants of tree turnover and productivity in the Andes. More extensive and longer-term monitoring and analyses of forest dynamics in permanent plots will be necessary to understand how demographic processes and woody biomass are responding to changing environmental conditions along elevation gradients through this century

Plan piloto "Horticultura responsable". Trabajo conjunto entre INTA y SENASA

Con el objetivo de incentivar a productores de hortalizas en la implementación de buenas prácticas agrícolas, se está llevando adelante un plan piloto en Baradero. La intención fue ayudarlos a posicionar sus productos de una manera más conveniente en los distintos puntos de venta utilizados (ferias, mercados, verdulerías), a través de un logo que identifica las hortalizas provenientes de las quintas donde se está ejecutando el plan. El proyecto se inició en agosto de 2015, y es fruto del trabajo conjunto entre el INTA y el SENASA. Se realizaron capacitaciones a los productores sobre manejo integrado de plagas y enfermedades, manejo del suelo, buenas prácticas agrícolas, normativa vigente en lo referente al uso de agroquímicos, plaguicidas permitidos, desinfección del suelo, seguridad e higiene, etc. Se evaluó el desempeño ambiental de los predios a través del sistema SEPIA (Sistema de Evaluación de Impacto Ambiental Ponderado), el cual permitió elaborar diagnósticos participativos y planificar procesos de mejora. Los productores realizan un registro de las labores y agroquímicos utilizados. Se realizaron monitoreos y análisis de laboratorio para residuos de plaguicidas y contaminación microbiológica por parte del SENASA. Se diseñaron piezas comunicacionales como afiches, volantes y etiquetas para cada productor, siguiendo los requisitos de la normativa. Los productores se inscribieron en el Renspa. La iniciativa contó con el apoyo del Municipio de Baradero, quién realizó difusión en los medios de comunicación y en una Jornada Municipal de Medio Ambiente realizada en mayo del 2017. Además se cuenta con el apoyo del Programa Cambio Rural ya que los productores conformaron el grupo Altiplano en Baradero y de Pro Huerta, a través de un Proyecto Especial aprobado recientemente, y gracias al cual se podrán adquirir bienes necesarios para implementar las mejoras propuestas. Los logros obtenidos son fruto del esfuerzo conjunto de proyectos de investigación y proyectos regionales, así como de distintos organismos del Estado y programas de intervención.EEA San PedroFil: Mitidieri, Mariel Silvina . Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Delprino, María Rosa. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Fortunato, Nicolás. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Fernández, A. Senasa. Servicio Nacional de Sanidad y Calidad Agroalimentaria; ArgentinaFil: Sampietro, Esteban. Senasa. Servicio Nacional de Sanidad y Calidad Agroalimentaria; ArgentinaFil: D´Angelcola, María Elena. Instituto Nacional de Tecnología Agropecuaria (INTA). Gerencia de Control de Gestión; ArgentinaFil: Cuellas, Marisol Virginia. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Área Metropolitana de Buenos Aires; ArgentinaFil: Valenzuela, Osvaldo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Bernardez, Alejandra. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Piris, Estela Beatriz. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Barbieri, Martín Osvaldo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Brambilla, María Virginia. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Del Pardo, Cecilia Karina. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Ciaponi, Mirta Mabel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Taquichiri, E. Actividad privada. Productor hortícola. Baradero; ArgentinaFil: Aricoma, Alfredo. Actividad privada. Productor hortícola. Baradero; ArgentinaFil: Yucra, M. Actividad privada. Productor hortícola. Baradero; ArgentinaFil: Calva, L. Actividad privada. Productor hortícola. Baradero; ArgentinaFil: Sánchez, Florencia. Ministerio de Agroindustria. Unidad de Cambio Rural II; ArgentinaFil: Heguiabeheri, Adolfo Ricardo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Piola, Mariana. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Peña, Lorena Claudina. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; Argentin

The pace of life for forest trees.

Tree growth and longevity trade-offs fundamentally shape the terrestrial carbon balance. Yet, we lack a unified understanding of how such trade-offs vary across the world's forests. By mapping life history traits for a wide range of species across the Americas, we reveal considerable variation in life expectancies from 10 centimeters in diameter (ranging from 1.3 to 3195 years) and show that the pace of life for trees can be accurately classified into four demographic functional types. We found emergent patterns in the strength of trade-offs between growth and longevity across a temperature gradient. Furthermore, we show that the diversity of life history traits varies predictably across forest biomes, giving rise to a positive relationship between trait diversity and productivity. Our pan-latitudinal assessment provides new insights into the demographic mechanisms that govern the carbon turnover rate across forest biomes

Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs

The global abundance of tree palms

Aim Palms are an iconic, diverse and often abundant component of tropical ecosystems that provide many ecosystem services. Being monocots, tree palms are evolutionarily, morphologically and physiologically distinct from other trees, and these differences have important consequences for ecosystem services (e.g., carbon sequestration and storage) and in terms of responses to climate change. We quantified global patterns of tree palm relative abundance to help improve understanding of tropical forests and reduce uncertainty about these ecosystems under climate change. Location Tropical and subtropical moist forests. Time period Current. Major taxa studied Palms (Arecaceae). Methods We assembled a pantropical dataset of 2,548 forest plots (covering 1,191 ha) and quantified tree palm (i.e., ≥10 cm diameter at breast height) abundance relative to co‐occurring non‐palm trees. We compared the relative abundance of tree palms across biogeographical realms and tested for associations with palaeoclimate stability, current climate, edaphic conditions and metrics of forest structure. Results On average, the relative abundance of tree palms was more than five times larger between Neotropical locations and other biogeographical realms. Tree palms were absent in most locations outside the Neotropics but present in >80% of Neotropical locations. The relative abundance of tree palms was more strongly associated with local conditions (e.g., higher mean annual precipitation, lower soil fertility, shallower water table and lower plot mean wood density) than metrics of long‐term climate stability. Life‐form diversity also influenced the patterns; palm assemblages outside the Neotropics comprise many non‐tree (e.g., climbing) palms. Finally, we show that tree palms can influence estimates of above‐ground biomass, but the magnitude and direction of the effect require additional work. Conclusions Tree palms are not only quintessentially tropical, but they are also overwhelmingly Neotropical. Future work to understand the contributions of tree palms to biomass estimates and carbon cycling will be particularly crucial in Neotropical forests

Geographic patterns of tree dispersal modes in Amazonia and their ecological correlates

Aim: To investigate the geographic patterns and ecological correlates in the geographic distribution of the most common tree dispersal modes in Amazonia (endozoochory, synzoochory, anemochory and hydrochory). We examined if the proportional abundance of these dispersal modes could be explained by the availability of dispersal agents (disperser-availability hypothesis) and/or the availability of resources for constructing zoochorous fruits (resource-availability hypothesis). Time period: Tree-inventory plots established between 1934 and 2019. Major taxa studied: Trees with a diameter at breast height (DBH) ≥ 9.55 cm. Location: Amazonia, here defined as the lowland rain forests of the Amazon River basin and the Guiana Shield. Methods: We assigned dispersal modes to a total of 5433 species and morphospecies within 1877 tree-inventory plots across terra-firme, seasonally flooded, and permanently flooded forests. We investigated geographic patterns in the proportional abundance of dispersal modes. We performed an abundance-weighted mean pairwise distance (MPD) test and fit generalized linear models (GLMs) to explain the geographic distribution of dispersal modes. Results: Anemochory was significantly, positively associated with mean annual wind speed, and hydrochory was significantly higher in flooded forests. Dispersal modes did not consistently show significant associations with the availability of resources for constructing zoochorous fruits. A lower dissimilarity in dispersal modes, resulting from a higher dominance of endozoochory, occurred in terra-firme forests (excluding podzols) compared to flooded forests. Main conclusions: The disperser-availability hypothesis was well supported for abiotic dispersal modes (anemochory and hydrochory). The availability of resources for constructing zoochorous fruits seems an unlikely explanation for the distribution of dispersal modes in Amazonia. The association between frugivores and the proportional abundance of zoochory requires further research, as tree recruitment not only depends on dispersal vectors but also on conditions that favour or limit seedling recruitment across forest types

Tree mode of death and mortality risk factors across Amazon forests

AbstractThe carbon sink capacity of tropical forests is substantially affected by tree mortality. However, the main drivers of tropical tree death remain largely unknown. Here we present a pan-Amazonian assessment of how and why trees die, analysing over 120,000 trees representing \u3e 3800 species from 189 long-term RAINFOR forest plots. While tree mortality rates vary greatly Amazon-wide, on average trees are as likely to die standing as they are broken or uprooted—modes of death with different ecological consequences. Species-level growth rate is the single most important predictor of tree death in Amazonia, with faster-growing species being at higher risk. Within species, however, the slowest-growing trees are at greatest risk while the effect of tree size varies across the basin. In the driest Amazonian region species-level bioclimatic distributional patterns also predict the risk of death, suggesting that these forests are experiencing climatic conditions beyond their adaptative limits. These results provide not only a holistic pan-Amazonian picture of tree death but large-scale evidence for the overarching importance of the growth–survival trade-off in driving tropical tree mortality