Channel gating of the glycine receptor changes accessibility to residues implicated in receptor potentiation by alcohols and anesthetics.

Abstract The glycine receptor is a target for both alcohols and anesthetics, and certain amino acids in the α1 subunit transmembrane segments (TM) are critical for drug effects. Introducing larger amino acids at these positions increases the potency of glycine, suggesting that introducing larger residues, or drug molecules, into the drug-binding cavity facilitates channel opening. A possible mechanism for these actions is that the volume of the cavity expands and contracts during channel opening and closing. To investigate this hypothesis, mutations for amino acids in TM1 (I229C) and TM2 (G256C, T259C, V260C, M263C, T264C, S267C, S270C) and TM3 (A288C) were individually expressed in Xenopus laevis oocytes. The ability of sulfhydryl-specific alkyl methanethiosulfonate (MTS) compounds of different lengths to covalently react with introduced cysteines in both the closed and open states of the receptor was determined. S267C was accessible to short chain (C3–C8) MTS in both open and closed states, but was only accessible to longer chain (C10–C16) MTS compounds in the open state. Reaction with S267C was faster in the open state. I229C and A288C showed state-dependent reaction with MTS only in the presence of agonist. M263C and S270C were also accessible to MTS labeling. Mutated residues more intracellular than M263C did not react, indicating a floor of the cavity. These data demonstrate that the conformational changes accompanying channel gating increase accessibility to amino acids critical for drug action in TM1, TM2, and TM3, which may provide a mechanism by which alcohols and anesthetics can act on glycine (and likely other) receptors

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY challenge

Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups

Party rules, party resources, and the politics of parliamentary democracies: how parties organize in the 21st Century

This article introduces the first findings of the Political Party Database (PPDB) project, a major survey of party organizations in parliamentary and semi-presidential democracies. The project’s first round of data covers 122 parties in 19 countries. In this paper we describe the scope of the database, then investigate what it tells us about contemporary party organization in these countries, focussing on parties’ resources, structures and internal decision-making. We examine organizational patterns by country and party family, and where possible we make temporal comparisons with older datasets. Our analyses suggest a remarkable coexistence of uniformity and diversity. In terms of the major organizational resources on which parties can draw, such as members, staff and finance, the new evidence largely confirms the continuation of trends identified in previous research: i.e., declining membership, but enhanced financial resources and more paid staff. We also find remarkable uniformity regarding the core architecture of party organizations. At the same time, however, we find substantial variation between countries and party families in terms of their internal processes, with particular regard to how internally democratic they are, and in the forms that this democratization takes

Role of nucleus accumbens core but not shell in incubation of methamphetamine craving after voluntary abstinence

We recently introduced an animal model to study incubation of drug craving after prolonged voluntary abstinence, mimicking the human condition of relapse after successful contingency management treatment. Here we studied the role of the nucleus accumbens (NAc) in this model. We trained rats to self-administer a palatable solution (sucrose+maltodextrin 1%, 6 h/day, 6 days) and methamphetamine (6 h/day, 12 days). We then evaluated relapse to methamphetamine seeking after 1 and 15 days of voluntary abstinence, achieved via a discrete choice procedure between the palatable solution and methamphetamine (14 days). We used RNAscope in-situ hybridization to quantify the co-labeling of the neuronal activity marker Fos, and dopamine Drd1- and Drd2-expressing medium spiny neurons (MSNs) in NAc core and shell during the incubation tests. Next, we determined the effect of pharmacological inactivation of NAc core and shell by either GABAA and GABAB agonists (muscimol+baclofen, 50+50 ng/side), Drd1-Drd2 antagonist (flupenthixol, 10 µg/side) or the selective Drd1 or Drd2 antagonists (SCH39166 1.0 µg/side or raclopride 1.0 µg/side) during the relapse tests. Incubated methamphetamine seeking after voluntary abstinence was associated with a selective increase of Fos expression in the NAc core, but not shell, and Fos was co-labeled with both Drd1- and Drd2-MSNs. NAc core, but not shell, injections of muscimol+baclofen, flupenthixol, SCH39166, and raclopride reduced methamphetamine seeking after 15 days of abstinence. Together, our results suggest that dopamine transmission through Drd1 and Drd2 in NAc core is critical to the incubation of methamphetamine craving after voluntary abstinence

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. RESULTS: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. CONCLUSIONS: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups

Physiological and Molecular Responses of Woody Plants Exposed to Future Atmospheric CO2 Levels under Abiotic Stresses

Climate change is mainly driven by the accumulation of carbon dioxide (CO2) in the atmosphere in the last century. Plant growth is constantly challenged by environmental fluctuations including heat waves, severe drought and salinity, along with ozone accumulation in the atmosphere. Food security is at risk in an increasing world population, and it is necessary to face the current and the expected effects of global warming. The effects of the predicted environment scenario of elevated CO2 concentration (e[CO2]) and more severe abiotic stresses have been scarcely investigated in woody plants, and an integrated view involving physiological, biochemical and molecular data is missing. This review highlights the effects of elevated CO2 in the metabolism of woody plants and the main findings of its interaction with abiotic stresses, including a molecular point of view, aiming to improve the understanding of how woody plants will face the predicted environmental conditions. Overall, e[CO2] stimulates photosynthesis and growth and attenuates mild to moderate abiotic stress in woody plants if root growth and nutrients are not limited. Moreover, e[CO2] does not induce acclimation in most tree species. Some high-throughput analyses involving omics techniques were conducted to better understand how these processes are regulated. Finally, knowledge gaps in the understanding of how the predicted climate condition will affect woody plant metabolism were identified, with the aim of improving the growth and production of this plant species

La Universidad de Los Andes fija su Posición

EditorialEl Silencioso Allanamiento a la Universidad Rivas, Pedro Ley de Educación Superior Propuesta de la Cámara de Diputados Proyecto de Ley de Educación Superior Posiciones Institucionales Observaciones y Recomendaciones de la Universidad del Zulia La Universidad de los Andes fija su Posición Rodríguez López, Néstor; Lobo Quintero, William; López Guédez, Horacio; Aguilar, Luis; Pinopascucci; Castillo, Juan Bautista; Pérez Febres, Ramón; Silva, Juan; de Ferrero, Ingrid A. Posiciones de los Académicos Un Instrumento Innovador Moros Ghersi, Carlos A. En Peligro la Autonomía Universitaria Ramírez, Tulio La Universidad de Rodillas Vívenes, José Amenazas a la Universidad Moreno, Amado La Reforma Universitaria Documento Doctrinario de la Asociación Venezolana de Rectores (AVERU) La Reforma Universitaria:Estrategias de cambio para la Educación Superior Venezolana Asociación Venezolana de Rectores (AVERU) Propuesta de Acuerdo que presenta la AVERU al Consejo Nacional de Universidades sobre la Reforma Universitaria Acosta, Humberto; Mosquera, Genaro; Quevedo, Rafael Isidro La Universidad de los Andes frente a la propuesta de la Asociación Venezolana de Rectores Primer Análisis Martínez Rincones, José Francisco; Torres de Dávila, Aura; Cadenas, Evelín H.; Moyer, Hugo Segundo Análisis Muñoz Lagos, Sergio Visión Conceptual Bonucci, Mario El Asalto Final a la Universidad Venezolana Decreto 2.400 Caldera, Rafael La Comisión Nacional de Educación Superior Informa a la Sociedad Venezolana Un Decreto de InocenciaA Proposito del Decreto que crea la Comisión Nacional de Mejoramiento de la Educación Superior Donoso Torres, Roberto Los Profesores de la UCV Asumen Posición Frente al Decreto 2.400 Algunas Secuelas del Asalto Final Comunicado Pronunciamiento Carta Abierta al Ministro de EducaciónNivel analíticotrimestra

Elevated [CO2] Mitigates Drought Effects and Increases Leaf 5-O-Caffeoylquinic Acid and Caffeine Concentrations During the Early Growth of Coffea Arabica Plants

Increasing atmospheric [CO 2] is thought to contribute to changes in precipitation patterns, increasing heatwaves and severe drought scenarios. However, how the combination of elevated [CO 2] and progressive drought affect plant metabolism is poorly understood. Aiming to investigate the effects of this environmental condition on photosynthesis and specialized metabolites in leaves of Coffea arabica during the early growth, plants fertilized with ambient (a[CO 2]-400 ppm) and elevated (e[CO 2]-800 ppm) [CO 2] were exposed to well-watered (WW) or water-deficit (WD) regimes for 40 days. Over the 40-day-water-withdrawal, soil moisture, and leaf water potential decreased compared to WW-condition. Elevated [CO 2] stimulates CO 2 assimilation (A) and intrinsic water use efficiency (iWUE) even under WD. Drought condition slightly changed stomatal conductance, transpiration rate and maximum quantum efficiency of photosystem II (PSII) regardless of [CO 2] compared to WW-plants. Total soluble amino acid concentration did not change significantly, while total phenolic compounds concentration decreased under e[CO 2] regardless of water regimes. The combination of e[CO 2]+WD increased the 5-O-caffeoylquinic acid (5-CQA) and caffeine amounts by 40-day when compared to a[CO 2]+WD plants. Altogether, these results suggest that e[CO 2] buffers mild-drought stress in young C. arabica by increasing A, iWUE and stimulating changes in the leaf contents of 5-CQA and caffeine