The Polycomb protein, Bmi1, regulates insulin sensitivity

Objective: The Polycomb Repressive Complexes (PRC) 1 and 2 function to epigenetically repress target genes. The PRC1 component, Bmi1, plays a crucial role in maintenance of glucose homeostasis and beta cell mass through repression of the Ink4a/Arf locus. Here we have explored the role of Bmi1 in regulating glucose homeostasis in the adult animal, which had not been previously reported due to poor postnatal survival of Bmi1−/− mice. Methods: The metabolic phenotype of Bmi1+/− mice was characterized, both in vivo and ex vivo. Glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps were performed. The insulin signaling pathway was assessed at the protein and transcript level. Results: Here we report a negative correlation between Bmi1 levels and insulin sensitivity in two models of insulin resistance, aging and liver-specific insulin receptor deficiency. Further, heterozygous loss of Bmi1 results in increased insulin sensitivity in adult mice, with no impact on body weight or composition. Hyperinsulinemic-euglycemic clamp reveals increased suppression of hepatic glucose production and increased glucose disposal rate, indicating elevated glucose uptake to peripheral tissues, in Bmi1+/− mice. Enhancement of insulin signaling, specifically an increase in Akt phosphorylation, in liver and, to a lesser extent, in muscle appears to contribute to this phenotype. Conclusions: Together, these data define a new role for Bmi1 in regulating insulin sensitivity via enhancement of Akt phosphorylation

CHARIS Science: Performance Simulations for the Subaru Telescope's Third-Generation of Exoplanet Imaging Instrumentation

We describe the expected scientific capabilities of CHARIS, a high-contrast integral-field spectrograph (IFS) currently under construction for the Subaru telescope. CHARIS is part of a new generation of instruments, enabled by extreme adaptive optics (AO) systems (including SCExAO at Subaru), that promise greatly improved contrasts at small angular separation thanks to their ability to use spectral information to distinguish planets from quasistatic speckles in the stellar point-spread function (PSF). CHARIS is similar in concept to GPI and SPHERE, on Gemini South and the Very Large Telescope, respectively, but will be unique in its ability to simultaneously cover the entire near-infrared $J$, $H$, and $K$ bands with a low-resolution mode. This extraordinarily broad wavelength coverage will enable spectral differential imaging down to angular separations of a few $\lambda/D$, corresponding to $\sim$0.\!\!''1. SCExAO will also offer contrast approaching $10^{-5}$ at similar separations, $\sim$0.\!\!''1--0.\!\!''2. The discovery yield of a CHARIS survey will depend on the exoplanet distribution function at around 10 AU. If the distribution of planets discovered by radial velocity surveys extends unchanged to $\sim$20 AU, observations of $\sim$200 mostly young, nearby stars targeted by existing high-contrast instruments might find $\sim$1--3 planets. Carefully optimizing the target sample could improve this yield by a factor of a few, while an upturn in frequency at a few AU could also increase the number of detections. CHARIS, with a higher spectral resolution mode of $R \sim 75$, will also be among the best instruments to characterize planets and brown dwarfs like HR 8799 cde and $\kappa$ And b.Comment: 13 pages, 7 figures, proceedings from SPIE Montrea

Scientific Design of a High Contrast Integral Field Spectrograph for the Subaru Telescope

Ground-based telescopes equipped with adaptive-optics (AO) systems and specialized science cameras are now capable of directly detecting extrasolar planets. We present the expected scientific capabilities of CHARIS, the Coronagraphic High Angular Resolution Imaging Spectrograph, which is being built for the Subaru 8.2 m telescope of the National Astronomical Observatory of Japan. CHARIS will be implemented behind the new extreme adaptive optics system at Subaru, SCExAO, and the existing 188-actuator system AO188. CHARIS will offer three observing modes over near-infrared wavelengths from 0.9 to 2.4 microns (the y-, J-, H-, and K-bands), including a low-spectral-resolution mode covering this entire wavelength range and a high-resolution mode within a single band. With these capabilities, CHARIS will offer exceptional sensitivity for discovering giant exoplanets, and will enable detailed characterization of their atmospheres. CHARIS, the only planned high-contrast integral field spectrograph on an 8m-class telescope in the Northern Hemisphere, will complement the similar instruments such as Project 1640 at Palomar, and GPI and SPHERE in Chile.Comment: 10 pages, 7 figures, SPIE Astronomical Telescopes and Instrumentation 201

Detection of Daytime Arctic Clouds Using MISR and MODIS Data

Amongst the 36 spectral radiances available on the Moderate Resolution Imaging Spectroradiometer (MODIS) seven of them are used operationally for detection of clouds in daytime polar regions. While the information content of clouds inherent in spectral radiances is familiar, the information content of clouds contained in angular radiances (i.e., radiances emanating to space from the same object but in di#erent directions) is not. The Multi-angle Imaging Spectroradiometer (MISR) measures angular radiances to space and its collocation on the NASA Terra satellite with MODIS allows for a comparative analysis of its cloud detection capabilities with those of MODIS

Pcif1 modulates Pdx1 protein stability and pancreatic β cell function and survival in mice

The homeodomain transcription factor pancreatic duodenal homeobox 1 (Pdx1) is a major mediator of insulin transcription and a key regulator of the β cell phenotype. Heterozygous mutations in PDX1 are associated with the development of diabetes in humans. Understanding how Pdx1 expression levels are controlled is therefore of intense interest in the study and treatment of diabetes. Pdx1 C terminus–interacting factor-1 (Pcif1, also known as SPOP) is a nuclear protein that inhibits Pdx1 transactivation. Here, we show that Pcif1 targets Pdx1 for ubiquitination and proteasomal degradation. Silencing of Pcif1 increased Pdx1 protein levels in cultured mouse β cells, and Pcif1 heterozygosity normalized Pdx1 protein levels in Pdx1+/– mouse islets, thereby increasing expression of key Pdx1 transcriptional targets. Remarkably, Pcif1 heterozygosity improved glucose homeostasis and β cell function and normalized β cell mass in Pdx1+/– mice by modulating β cell survival. These findings indicate that in adult mouse β cells, Pcif1 limits Pdx1 protein accumulation and thus the expression of insulin and other gene targets important in the maintenance of β cell mass and function. They also provide evidence that targeting the turnover of a pancreatic transcription factor in vivo can improve glucose homeostasis

Pcif1 modulates Pdx1 protein stability and pancreatic beta cell function and survival in mice

The homeodomain transcription factor pancreatic duodenal homeobox 1 (Pdx1) is a major mediator of insulin transcription and a key regulator of the β cell phenotype. Heterozygous mutations in PDX1 are associated with the development of diabetes in humans. Understanding how Pdx1 expression levels are controlled is therefore of intense interest in the study and treatment of diabetes. Pdx1 C terminus-interacting factor-1 (Pcif1, also known as SPOP) is a nuclear protein that inhibits Pdx1 transactivation. Here, we show that Pcif1 targets Pdx1 for ubiquitination and proteasomal degradation. Silencing of Pcif1 increased Pdx1 protein levels in cultured mouse β cells, and Pcif1 heterozygosity normalized Pdx1 protein levels in Pdx1 +/-mouse islets, thereby increasing expression of key Pdx1 transcriptional targets. Remarkably, Pcif1 heterozygosity improved glucose homeostasis and β cell function and normalized β cell mass in Pdx1 +/-mice by modulating β cell survival. These findings indicate that in adult mouse β cells, Pcif1 limits Pdx1 protein accumulation and thus the expression of insulin and other gene targets important in the maintenance of β cell mass and function. They also provide evidence that targeting the turnover of a pancreatic transcription factor in vivo can improve glucose homeostasis

Improved estimates of strength and stiffness in pathologic vertebrae with bone metastases using CT-derived bone density compared with radiographic bone lesion quality classification.

OBJECTIVE The aim of this study was to compare the ability of 1) CT-derived bone lesion quality (classification of vertebral bone metastases [BM]) and 2) computed CT-measured volumetric bone mineral density (vBMD) for evaluating the strength and stiffness of cadaver vertebrae from donors with metastatic spinal disease. METHODS Forty-five thoracic and lumbar vertebrae were obtained from cadaver spines of 11 donors with breast, esophageal, kidney, lung, or prostate cancer. Each vertebra was imaged using microCT (21.4 μm), vBMD, and bone volume to total volume were computed, and compressive strength and stiffness experimentally measured. The microCT images were reconstructed at 1-mm voxel size to simulate axial and sagittal clinical CT images. Five expert clinicians blindly classified the images according to bone lesion quality (osteolytic, osteoblastic, mixed, or healthy). Fleiss' kappa test was used to test agreement among 5 clinical raters for classifying bone lesion quality. Kruskal-Wallis ANOVA was used to test the difference in vertebral strength and stiffness based on bone lesion quality. Multivariable regression analysis was used to test the independent contribution of bone lesion quality, computed vBMD, age, gender, and race for predicting vertebral strength and stiffness. RESULTS A low interrater agreement was found for bone lesion quality (κ = 0.19). Although the osteoblastic vertebrae showed significantly higher strength than osteolytic vertebrae (p = 0.0148), the multivariable analysis showed that bone lesion quality explained 19% of the variability in vertebral strength and 13% in vertebral stiffness. The computed vBMD explained 75% of vertebral strength (p < 0.0001) and 48% of stiffness (p < 0.0001) variability. The type of BM affected vBMD-based estimates of vertebral strength, explaining 75% of strength variability in osteoblastic vertebrae (R2 = 0.75, p < 0.0001) but only 41% in vertebrae with mixed bone metastasis (R2 = 0.41, p = 0.0168), and 39% in osteolytic vertebrae (R2 = 0.39, p = 0.0381). For vertebral stiffness, vBMD was only associated with that of osteoblastic vertebrae (R2 = 0.44, p = 0.0024). Age and race inconsistently affected the model's strength and stiffness predictions. CONCLUSIONS Pathologic vertebral fracture occurs when the metastatic lesion degrades vertebral strength, rendering it unable to carry daily loads. This study demonstrated the limitation of qualitative clinical classification of bone lesion quality for predicting pathologic vertebral strength and stiffness. Computed CT-derived vBMD more reliably estimated vertebral strength and stiffness. Replacing the qualitative clinical classification with computed vBMD estimates may improve the prediction of vertebral fracture risk