Mutant huntingtin enhances activation of dendritic Kv4 K+ channels in striatal spiny projection neurons

Huntington\u27s disease (HD) is initially characterized by an inability to suppress unwanted movements, a deficit attributable to impaired synaptic activation of striatal indirect pathway spiny projection neurons (iSPNs). To better understand the mechanisms underlying this deficit, striatal neurons in ex vivo brain slices from mouse genetic models of HD were studied using electrophysiological, optical and biochemical approaches. Distal dendrites of iSPNs from symptomatic HD mice were hypoexcitable, a change that was attributable to increased association of dendritic Kv4 potassium channels with auxiliary KChIP subunits. This association was negatively modulated by TrkB receptor signaling. Dendritic excitability of HD iSPNs was rescued by knocking-down expression of Kv4 channels, by disrupting KChIP binding, by restoring TrkB receptor signaling or by lowering mutant-Htt (mHtt) levels with a zinc finger protein. Collectively, these studies demonstrate that mHtt induces reversible alterations in the dendritic excitability of iSPNs that could contribute to the motor symptoms of HD

Divergência genética em híbridos de sorgo cultivados sob diferentes níveis de fósforo, em solução nutritiva.

Os objetivos deste trabalho consistiram em identificar a presença de diversidade genética entre acessos de sorgo, em diferentes condições de disponibilidade de P, em solução nutritiva, e determinar quais as características que mais contribuíram para a discriminação dessa divergência. O experimento foi conduzido em casa-de-vegetação, num arranjo fatorial 9x4, sendo nove híbridos de sorgo e quatro doses de P (3, 32, 97 e 129 µM de P.L-1 de solução nutritiva), sob delineamento em blocos ao acaso, com três repetições. Os dados foram submetidos à análise de variância e, posteriormente, ao estudo de dissimilaridade genética, utilizando a matriz de distância generalizada de Mahalanobis e a contribuição relativa das características para a divergência, pelo método de Singh (1981). Concluiu-se que a dose de 3 µM de P.L-1 de solução apresentou valores discrepantes dos demais, sendo desconsiderados seu valores para análise de variância conjunta. Diferenças significativas para todas as características avaliadas foram observadas entre os híbridos, nas doses de P analisadas (32, 97 e 129 µM de P.L-1 de solução nutritiva). A concentração de 97 µM de P.L-1 gerou o maior número de grupos de genótipos. Entretanto, variabilidade genética foi observada também nas demais doses de P. Sob as concentrações de P avaliadas, verificou-se que a característica massa seca total foi a que mais contribuiu para a expressão da dissimilaridade genética entre os híbridos. O híbrido experimental 0735019 apresentou eficiência e responsividade a utilização de P, demonstrando os maiores valores para as características avaliadas nos diferentes níveis de P estudados

Served Through Service: Undergraduate Students’ Experiences in Community Engaged Learning at a Catholic and Marianist University

Students participating in sustained community service at an urban Catholic and Marianist university were volunteer informants in this qualitative exploration of the meaning they make of their service experiences. A PhD student research team (nine members) interviewed fourteen undergraduate students (eleven of whom were seniors). Findings were organized as themes constructed within three domains: background, experience, and meaning. Within “background,” students who had prior work in faith-based service before college deepened their meaning of service. Within “experience,” there were social and cultural dynamics of navigating on and off campus life, including the roles students played as well as the challenge of time management. Within “meaning,” building relationships was central to community service. Students built strong personal relationships with and deep commitments to city residents; the meaning of their own identities grew and developed. Experiencing the roots of social injustice led students both to confirm and to reconsider their life vocations

Outcomes of resection for rectal cancer in India: The impact of the double stapling technique

BACKGROUND: The introduction of circular staplers into colorectal surgery has revolutionized anastomotic techniques stretching the limits of sphincter preservation. Data on the double-stapling technique (DST) has been widely published in the West where the incidence of colorectal cancer is high. However studies using this technique and their results, in the Indian scenario, as well as the rest of Asia, have been few and far between. AIM: To evaluate the feasibility of the DST in Indian patients with low rectal cancers and assess its impact on anastomotic leak rates, covering colostomy rates, level of resection and morbidity in patients undergoing low anterior resection (LAR). METHODS: A comparative analysis was performed between retrospectively acquired data on 78 patients (mean age 53.2 ± 13.5 years) undergoing LAR with the single-stapling technique (SST) (between January 1999 and December 2001) and prospective data acquired on 138 LARs (mean age 50.3 ± 13.9 years) performed using the DST (between January 2003 – December 2005). RESULTS: A total of 77 out of 78 patients in the SST group had Astler Coller B and C disease while the number was 132/138 in the DST group. The mean distance of the tumor from anal verge was 7.6 cm (2.5–15 cm) and 8.0 cm (4–15 cm) in the DST and SST groups, respectively. In the DST group, there were 5 (3.6%) anastomotic failures and 62 (45%) covering stomas compared to 7 (8.9%) anastomotic failures and 51 (65.4%) covering stomas in the SST group. The anastomotic leak rate, though objectively lower in the DST group, did not attain statistical significance (p = 0.12). Covering stoma rates were significantly lower in DST group (p = 0.006). There was 1 death in the DST group due to cardiac causes (unrelated to the anastomosis) and no mortality in the SST group. The LAR and abdominoperineal resection (APR) rates were 40% and 60%, respectively, during 1999–2001. In 2005, these rates were 55% and 45%, respectively. CONCLUSION: This study, perhaps the first from India, demonstrates the feasibility of the DST in a country where the incidence of colorectal cancer is increasing. Since the age at presentation is at least a decade younger than the Western world, consideration of sphincter preservation assumes greater significance. The observed improvement of surgical outcomes with DST needs further studies to significantly prove these findings in a population where the tumors at presentation are predominantly Astler Coller Stage B and C

The UK's Global Health Respiratory Network: Improving respiratory health of the world's poorest through research collaborations.

Respiratory disorders are responsible for considerable morbidity, health care utilisation, societal costs and approximately one in five deaths worldwide [1-4]. Yet, despite this substantial health and societal burden – which particularly affects the world’s poorest populations and as such is a major contributor to global health inequalities – respiratory disorders have historically not received the policy priority they warrant. For example, despite causing an estimated 1000 deaths per day, less than half of the world’s countries collect data on asthma prevalence (http://www.globalasthmareport.org/). This is true for both communicable and non-communicable respiratory disorders, many of which are either amenable to treatment or preventable

Served Through Service: Undergraduate Students’ Experiences in Community Engaged Learning at a Catholic and Marianist University

Students participating in sustained community service at an urban Catholic and Marianist university were volunteer informants in this qualitative exploration of the meaning they make of their service experiences. A PhD student research team (nine members) interviewed fourteen undergraduate students (eleven of whom were seniors). Findings were organized as themes constructed within three domains: background, experience, and meaning. Within “background,” students who had prior work in faith-based service before college deepened their meaning of service. Within “experience,” there were social and cultural dynamics of navigating on and off campus life, including the roles students played as well as the challenge of time management. Within “meaning,” building relationships was central to community service. Students built strong personal relationships with and deep commitments to city residents; the meaning of their own identities grew and developed. Experiencing the roots of social injustice led students both to confirm and to reconsider their life vocations. Estudiantes que participaban en servicios continuados a la comunidad en una universidad católica marianista urbana participaron como encuestados voluntarios de esta exploración cualitativa del significado que le dan a sus experiencias de servicio. Un equipo de investigación de estudiantes (nueve) de doctorado entrevistaron a catorce estudiantes de licenciatura (de los cuales 10 eran de último curso). Los resultados se organizaron en temas englobados en tres dominios: antecedentes, experiencia y significado. En “antecedentes”, los estudiantes que habían realizado trabajo previo en servicios religiosos antes de la universidad profundizaron su significado de servicio. Dentro de “experiencia”, hubo dinámicas sociales y culturales que navegaban dentro y fuera de la vida en el campus, desde el papel de los estudiantes hasta el reto de la gestión del tiempo. En “significado”, la construcción de relaciones resultó central para los servicios a la comunidad. Los estudiantes cultivaron fuertes relaciones personales y compromisos profundos con los residentes de la ciudad. El significado de su propia identidad creció y se desarrolló. Experimentar las raíces de la injusticia social orientó a los estudiantes a confirmar y reconsiderar su vocación y elección de vida. Palabras clave: servicio, aprendizaje a través del servicio, aprendizaje-servicio, aprendizaje comprometido con la comunidad, liderazgo estudiantil, estudiante de licenciatur

Discovery and implementation of transcriptional biomarkers of synthetic LXR agonists in peripheral blood cells

<p>Abstract</p> <p>Background</p> <p>LXRs (Liver X Receptor α and β) are nuclear receptors that act as ligand-activated transcription factors. LXR activation causes upregulation of genes involved in reverse cholesterol transport (RCT), including ABCA1 and ABCG1 transporters, in macrophage and intestine. Anti-atherosclerotic effects of synthetic LXR agonists in murine models suggest clinical utility for such compounds.</p> <p>Objective</p> <p>Blood markers of LXR agonist exposure/activity were sought to support clinical development of novel synthetic LXR modulators.</p> <p>Methods</p> <p>Transcript levels of LXR target genes ABCA1 and ABCG1 were measured using quantitative reverse transcriptase/polymerase chain reaction assays (qRT-PCR) in peripheral blood from mice and rats (following a single oral dose) and monkeys (following 7 daily oral doses) of synthetic LXR agonists. LXRα, LXRβ, ABCA1, and ABCG1 mRNA were measured by qRT-PCR in human peripheral blood mononuclear cells (PBMC), monocytes, T- and B-cells treated <it>ex vivo </it>with WAY-252623 (LXR-623), and protein levels in human PBMC were measured by Western blotting. ABCA1/G1 transcript levels in whole-blood RNA were measured using analytically validated assays in human subjects participating in a Phase 1 SAD (Single Ascending Dose) clinical study of LXR-623.</p> <p>Results</p> <p>A single oral dose of LXR agonists induced ABCA1 and ABCG1 transcription in rodent peripheral blood in a dose- and time-dependent manner. Induction of gene expression in rat peripheral blood correlated with spleen expression, suggesting LXR gene regulation in blood has the potential to function as a marker of tissue gene regulation. Transcriptional response to LXR agonist was confirmed in primates, where peripheral blood ABCA1 and ABCG1 levels increased in a dose-dependent manner following oral treatment with LXR-623. Human PBMC, monocytes, T- and B cells all expressed both LXRα and LXRβ, and all cell types significantly increased ABCA1 and ABCG1 expression upon <it>ex vivo </it>LXR-623 treatment. Peripheral blood from a representative human subject receiving a single oral dose of LXR-623 showed significant time-dependent increases in ABCA1 and ABCG1 transcription.</p> <p>Conclusion</p> <p>Peripheral blood cells express LXRα and LXRβ, and respond to LXR agonist treatment by time- and dose-dependently inducing LXR target genes. Transcript levels of LXR target genes in peripheral blood are relevant and useful biological indicators for clinical development of synthetic LXR modulators.</p

Insights into the function of silver as an oxidation catalyst by ab initio, atomistic thermodynamics

To help understand the high activity of silver as an oxidation catalyst, e.g., for the oxidation of ethylene to epoxide and the dehydrogenation of methanol to formaldehyde, the interaction and stability of oxygen species at the Ag(111) surface has been studied for a wide range of coverages. Through calculation of the free energy, as obtained from density-functional theory and taking into account the temperature and pressure via the oxygen chemical potential, we obtain the phase diagram of O/Ag(111). Our results reveal that a thin surface-oxide structure is most stable for the temperature and pressure range of ethylene epoxidation and we propose it (and possibly other similar structures) contains the species actuating the catalysis. For higher temperatures, low coverages of chemisorbed oxygen are most stable, which could also play a role in oxidation reactions. For temperatures greater than about 775 K there are no stable oxygen species, except for the possibility of O atoms adsorbed at under-coordinated surface sites Our calculations rule out thicker oxide-like structures, as well as bulk dissolved oxygen and molecular ozone-like species, as playing a role in the oxidation reactions.Comment: 15 pages including 9 figures, Related publications can be found at http://www.fhi-berlin.mpg.de/th/paper.htm