Adaptive Optics Imaging of IRAS 18276-1431: a bipolar pre-planetary nebula with circumstellar "searchlight beams" and "arcs"

We present high-angular resolution images of the post-AGB nebula IRAS18276-1431 (also known as OH17.7-2.0) obtained with the Keck II Adaptive Optics (AO) system in its Natural Guide Star (NGS) mode in the Kp, Lp, and Ms near-infrared bands. We also present supporting optical F606W and F814W HST images as well as interferometric observations of the 12CO(J=1-0), 13CO(J=1-0), and 2.6mm continuum emission with OVRO. The envelope of IRAS18276-1431 displays a clear bipolar morphology in our optical and NIR images with two lobes separated by a dark waist and surrounded by a faint 4.5"x3.4" halo. Our Kp-band image reveals two pairs of radial ``searchlight beams'' emerging from the nebula center and several intersecting, arc-like features. From our CO data we derive a mass of M>0.38[D/3kpc]^2 Msun and an expansion velocity v_exp=17km/s for the molecular envelope. The density in the halo follows a radial power-law proportional to r^-3, which is consistent with a mass-loss rate increasing with time. Analysis of the NIR colors indicates the presence of a compact central source of ~300-500K dust illuminating the nebula in addition to the central star. Modeling of the thermal IR suggests a two-shell structure in the dust envelope: 1) an outer shell with inner and outer radius R_in~1.6E16cm and R_out>~1.25E17cm, dust temperature T_d~105-50K, and a mean mass-loss rate of Mdot~1E-3Msun/yr; and 2) an inner shell with R_in~6.3E14cm, T_dust~500-105K, and Mdot~3E-5Msun/yr. An additional population of big dust grains (radius a>~0.4mm) with T_dust=150-20K and mass M_dust=(0.16-1.6)E-3 [D/3kpc]^2 Msun can account for the observed sub-mm and mm flux excess. The mass of the envelope enclosed within R_out=1.25E17cm derived from SED modeling is ~1[D/3kpc]^2 Msun.Comment: 46 pages, 14 figures, 3 tables, accepted for publication in ApJ. Figures 12 & 13 in low resolution. Full resolution versions are available upon request to the first autho

Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism

By analyzing and simulating inactive conformations of the highly-homologous dopamine D2 and D3 receptors (D2R and D3R), we find that eticlopride binds D2R in a pose very similar to that in the D3R/eticlopride structure but incompatible with the D2R/risperidone structure. In addition, risperidone occupies a sub-pocket near the Na+ binding site, whereas eticlopride does not. Based on these findings and our experimental results, we propose that the divergent receptor conformations stabilized by Na+-sensitive eticlopride and Na+-insensitive risperidone correspond to different degrees of inverse agonism. Moreover, our simulations reveal that the extracellular loops are highly dynamic, with spontaneous transitions of extracellular loop 2 from the helical conformation in the D2R/risperidone structure to an extended conformation similar to that in the D3R/eticlopride structure. Our results reveal previously unappreciated diversity and dynamics in the inactive conformations of D2R. These findings are critical for rational drug discovery, as limiting a virtual screen to a single conformation will miss relevant ligands

Evaluation of public and animal health risks in case of a delayed post-mortem inspection in ungulates

The potential effects of a 24 or 72-h delay in post-mortem inspection (PMI) of ungulates on public health and monitoring of animal health and welfare was evaluated. The assessment used a survey of meat inspectors, expert opinion, literature search and a stochastic model for Salmonella detection sensitivity. Disease detection sensitivity at a delayed PMI is expected to reduce detection sensitivity to a variable extent, depending on the hazard and on the signs/lesions and organs involved. No reduction is expected for Trichinella detection in meat from susceptible animal species and any decrease in detection of transmissible spongiform encephalopathies (TSEs) will not exceed the current tolerance for fallen stock. A 24-h delay in PMI could result in a small reduction in sensitivity of detection for tuberculosis, echinococcosis and cysticercosis. A greater reduction is expected for the detection of pyaemia and Rift valley fever. For the detection of Salmonella, the median model estimates are a reduction of sensitivity of 66.5% (90% probability interval (PI) 0.08–99.75%) after 24-h delay and 94% (90% PI 0.83–100%) after 72-h delay of PMI. Laboratory testing for tuberculosis following a sampling delay of 24–72 h could result in no, or a moderate, decrease in detection depending on the method of confirmation used (PCR, culture, histopathology). For chemical contaminants, a delay in meat inspection of 24 or 72 h is expected to have no impact on the effectiveness of detection of persistent organic pollutants and metals. However, for certain pharmacologically active substances, there will be a reduced effectiveness to detect some of these substances due to potential degradation in the available matrices (tissues and organs) and the non-availability of specific preferred matrices of choice

Abordagem por Competências no Currículo Escolar em Cabo Verde: Desfazendo Equívocos para uma Mudança Significativa nas Políticas e Práxis Educacionais

A abordagem curricular por competências, enquanto fenómeno recente no discurso educativo em Cabo Verde, corre o risco de não passar de mero modismo, sem se traduzir numa inovação efectiva ao nível das práxis educacionais, se não for correctamente compreendida pelos diversos actores envolvidos na obra educativa e, em particular, nos processos de deliberação, gestão e realização dos currículos escolares. O presente artigo procura esclarecer alguns equívocos que em Cabo Verde, como em outras latitudes, acompanham a defesa da pedagogia por competências. Assim, importa elucidar que a abordagem curricular por competências vem aprofundar, entre outras, as abordagens por conteúdos e por objectivos e não, pura e simplesmente, substituí-las, por serem, alegadamente, tradicionais. Outrossim, no contexto da educação escolar, as competências não devem ser encaradas numa perspectiva redutora, focalizada na transferibilidade de conhecimentos para o mercado de trabalho, mas, fundamentalmente, no sentido da mobilização do conhecimento escolar para a resolução dos problemas nos diversos contextos ou situações da vida, que não se esgota no mercado

Low intrinsic efficacy for G protein activation can explain the improved side-effect profile of new opioid agonists

Biased agonism at G protein–coupled receptors describes the phenomenon whereby some drugs can activate some downstream signaling activities to the relative exclusion of others. Descriptions of biased agonism focusing on the differential engagement of G proteins versus β-arrestins are commonly limited by the small response windows obtained in pathways that are not amplified or are less effectively coupled to receptor engagement, such as β-arrestin recruitment. At the μ-opioid receptor (MOR), G protein–biased ligands have been proposed to induce less constipation and respiratory depressant side effects than opioids commonly used to treat pain. However, it is unclear whether these improved safety profiles are due to a reduction in β-arrestin–mediated signaling or, alternatively, to their low intrinsic efficacy in all signaling pathways. Here, we systematically evaluated the most recent and promising MOR-biased ligands and assessed their pharmacological profile against existing opioid analgesics in assays not confounded by limited signal windows. We found that oliceridine, PZM21, and SR-17018 had low intrinsic efficacy. We also demonstrated a strong correlation between measures of efficacy for receptor activation, G protein coupling, and β-arrestin recruitment for all tested ligands. By measuring the antinociceptive and respiratory depressant effects of these ligands, we showed that the low intrinsic efficacy of opioid ligands can explain an improved side effect profile. Our results suggest a possible alternative mechanism underlying the improved therapeutic windows described for new opioid ligands, which should be taken into account for future descriptions of ligand action at this important therapeutic target

Rapid Assessment of Octocoral Diversity and Habitat on Saba Bank, Netherlands Antilles

Saba Bank is a large submerged platform (∼2200 km2), average depth 30 m, located 4 km southwest of Saba Island in Netherlands Antilles, Caribbean Sea. Ships traveling to and from oil terminals on nearby St. Eustatius routinely anchor on the Bank, damaging benthic megafauna. Gorgonian octocorals are vulnerable to anchor damage, and they are common and conspicuous in shallow water (15–50 m) around the banks. This prompted a rapid assessment of octocoral habitat and diversity. The primary objectives were to estimate total species richness and to characterize habitats vis a vis gorgonians. Landsat imagery and multibeam bathymetry were employed to identify random sites for quantitative transects. A Seabotix LBV200L remotely operated vehicle (ROV) and SCUBA were used to collect and survey to 130 m. A total of 14 scuba dives and 3 ROV dives were completed in 10 days. During that time, 48 octocoral species were collected, including two likely undescribed species in the genera Pterogorgia and Lytreia. Gorgonian richness was exceptional, but not all species were collected, because the species accumulation curve remained steeply inclined after all surveys. Two shallow-water gorgonian habitat types were identified using multidimensional scaling and hierarchical cluster analyses: 1) a high diversity, high density fore-reef environment characterized by Eunicea spp., Gorgonia spp., and Pseudopterogorgia spp. and 2) a low diversity, low density plateau environment characterized by Pseudopterogorgia acerosa, Pterogorgia guadalupensis, and Gorgonia mariae. The analyses support hypotheses of broad (∼15 km) habitat homogeneity (ANOSIM, P>0.05), but a significant difference between fore-reef and plateau environments (ANOSIM, P<0.05). However, there was some indication of habitat heterogeneity along the 15 km study section of the 50 km platform edge along the southeast rim. Our results highlight the complexity and biodiversity of the Saba Bank, and emphasize the need for more scientific exploration

Thermochronologic constraints on the late Cenozoic exhumation history of the Gurla Mandhata metamorphic core complex, Southwestern Tibet

This is the publisher's version, also available electronically from http://onlinelibrary.wiley.com/doi/10.1002/2013TC003302/abstractHow the Tibetan plateau is geodynamically linked to the Himalayas is a topic receiving considerable attention. The Karakoram fault plays key roles in describing the structural relationship between southern Tibet and the Himalayas. In particular, considerable debate exists at the southeastern end of the Karakoram fault, where its role is interpreted in two different ways. One interpretation states that slip along the dextral Karakoram fault extends eastward along the Indus-Yalu suture zone, bypassing the Himalayas. The other interprets that fault slip is fed southward into the Himalayan thrust belt along the Gurla Mandhata detachment (GMD). To evaluate these competing models, the late Miocene history of the GMD was reconstructed from thermokinematic modeling of zircon (U-Th)/He data. Three east-west transects reveal rapid cooling of the GMD footwall from 8.0 ± 1.3 Ma to 2.6 ± 0.7 Ma. Model simulations show a southward decrease in slip magnitude and rate along the GMD. In the north, initiation of the GMD range between 14 and 11 Ma with a mean fault slip rate of 5.0 ± 0.9 mm/yr. The central transect shows an initiation age from 14 to 11 Ma with a mean fault slip rate of 3.3 ± 0.6 mm/yr. In the south, initiation began between 15 and 8 Ma with a mean fault slip rate of 3.2 ± 1.6 mm/yr. The initiation ages and slip rates match the Karakoram fault across several timescales, supporting the idea that the two are kinematically linked. Specifically, the data are consistent with the GMD acting as an extensional stepover, with slip transferred southward into the Himalayas of western Nepal

Aberrant overexpression of an epithelial marker, 14-3-3σ, in a subset of hematological malignancies

<p>Abstract</p> <p>Background</p> <p>14-3-3σ is a p53-mediated cell-cycle inhibitor in epithelial cells. The expression of 14-3-3σ is frequently altered in cancers of epithelial origin associated with altered DNA methylation. Since its involvement in a non-epithelial tumor is unknown, we examined 14-3-3σ expression in patients with haematological malignancies.</p> <p>Methods</p> <p>We analyzed 41 hematopoietic cell lines and 129 patients with a variety of hematological malignancies for 14-3-3σ expression with real-time RT-PCR. We also examined protein levels by Western blot analysis and DNA methylation status of the 14-3-3σ gene by methylation-specific PCR analysis of bisulfite-treated DNA. In addition, mutations of p53 gene were identified by RT-PCR-SSCP analysis and the expression levels of 14-3-3σ were compared with those of other cell-cycle inhibitor genes, CDKN2A and ARF.</p> <p>Results</p> <p>The expression levels of 14-3-3σ mRNA in almost all cell lines were low and comparable to those in normal hematopoietic cells except for 2 B-cell lines. On the contrary, 14-3-3σ mRNA was aberrantly overexpressed frequently in mature lymphoid malignancies (30 of 93, 32.3%) and rarely in acute leukemia (3 of 35, 8.6%). 14-3-3σ protein was readily detectable and roughly reflected the mRNA level. In contrast to epithelial tumors, methylation status of the 14-3-3σ gene was not associated with expression in hematological malignancies. Mutations of p53 were identified in 12 patients and associated with lower expression of 14-3-3σ. The expression levels of 14-3-3σ, CDKN2A and ARF were not correlated with but rather reciprocal to one another, suggesting that simultaneous overexpression of any two of them is incompatible with tumor growth.</p> <p>Conclusion</p> <p>14-3-3σ, an epithelial cell marker, was overexpressed significantly in a subset of mature lymphoid malignancies. This is the first report of aberrant 14-3-3σ expression in non-epithelial tumors <it>in vivo</it>. Since the significance of 14-3-3σ overexpression is unknown even in epithelial tumors such as pancreatic cancers, further analysis of regulation and function of the 14-3-3σ gene in non-epithelial as well as epithelial tumors is warranted.</p

Identification of DNA hypermethylation of SOX9 in association with bladder cancer progression using CpG microarrays

CpG island arrays represent a high-throughput epigenomic discovery platform to identify global disease-specific promoter hypermethylation candidates along bladder cancer progression. DNA obtained from 10 pairs of invasive bladder tumours were profiled vs their respective normal urothelium using differential methylation hybridisation on custom-made CpG arrays (n=12 288 clones). Promoter hypermethylation of 84 clones was simultaneously shown in at least 70% of the tumours. SOX9 was selected for further validation by bisulphite genomic sequencing and methylation-specific polymerase chain reaction in bladder cancer cells (n=11) and primary bladder tumours (n=101). Hypermethylation was observed in bladder cancer cells and associated with lack of gene expression, being restored in vitro by a demethylating agent. In primary bladder tumours, SOX9 hypermethylation was present in 56.4% of the cases. Moreover, SOX9 hypermethylation was significantly associated with tumour grade and overall survival. Thus, this high-throughput epigenomic strategy has served to identify novel hypermethylated candidates in bladder cancer. In vitro analyses supported the role of methylation in silencing SOX9 gene. The association of SOX9 hypermethylation with tumour progression and clinical outcome suggests its relevant clinical implications at stratifying patients affected with bladder cancer