19 research outputs found
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
Racial Differentials in the Components of Population Change and Neighborhood Transitions in New York City, 1980–2010: The Distinct Role of Asian Net Inflows in the Age of Net Outflows of Whites, Blacks, and Hispanics
La Universidad de Los Andes fija su PosiciĂłn
EditorialEl Silencioso Allanamiento a la Universidad
Rivas, Pedro
Ley de EducaciĂłn Superior
Propuesta de la Cámara de Diputados
Proyecto de Ley de EducaciĂłn Superior
Posiciones Institucionales
Observaciones y Recomendaciones de la Universidad del Zulia
La Universidad de los Andes fija su PosiciĂłn
RodrĂguez LĂłpez, NĂ©stor; Lobo Quintero, William; LĂłpez GuĂ©dez, Horacio; Aguilar, Luis; Pinopascucci; Castillo, Juan Bautista; PĂ©rez Febres, RamĂłn; Silva, Juan; de Ferrero, Ingrid A.
Posiciones de los Académicos
Un Instrumento Innovador
Moros Ghersi, Carlos A.
En Peligro la AutonomĂa Universitaria
RamĂrez, Tulio
La Universidad de Rodillas
VĂvenes, JosĂ©
Amenazas a la Universidad
Moreno, Amado
La Reforma Universitaria
Documento Doctrinario de la AsociaciĂłn Venezolana de Rectores (AVERU)
La Reforma Universitaria:Estrategias de cambio para la EducaciĂłn Superior Venezolana
AsociaciĂłn 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 AsociaciĂłn Venezolana de Rectores
Primer Análisis
MartĂnez Rincones, JosĂ© Francisco; Torres de Dávila, Aura; Cadenas, EvelĂn H.; Moyer, Hugo
Segundo Análisis
Muñoz Lagos, Sergio
VisiĂłn Conceptual
Bonucci, Mario
El Asalto Final a la Universidad Venezolana
Decreto 2.400
Caldera, Rafael
La ComisiĂłn Nacional de EducaciĂłn Superior Informa a la Sociedad Venezolana
Un Decreto de InocenciaA Proposito del Decreto que crea la ComisiĂłn Nacional de Mejoramiento de la EducaciĂłn Superior
Donoso Torres, Roberto
Los Profesores de la UCV Asumen PosiciĂłn Frente al Decreto 2.400
Algunas Secuelas del Asalto Final
Comunicado
Pronunciamiento
Carta Abierta al Ministro de EducaciĂłnNivel analĂticotrimestra
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