Inhibiting CDK4/6 in pancreatic ductal adenocarcinoma via microRNA-21

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a 5-year survival rate of 5–10 %. The high mortality rate is due to the asymptomatic progression of clinical features in metastatic stages of the disease, which renders standard therapeutic options futile. PDAC is characterised by alterations in several genes that drive carcinogenesis and limit therapeutic response. The two most common genetic aberrations in PDAC are the mutational activation of KRAS and loss of the tumour suppressor CDK inhibitor 2A (CDKN2A), which culminate the activation of the cyclin-dependent kinase 4 and 6 (CDK4/6), that promote G1 cell cycle progression. Therapeutic strategies focusing on the CDK4/6 inhibitors such as palbociclib (PD-0332991) may potentially improve outcomes in this malignancy. MicroRNAs (miRs/miRNAs) are small endogenous non-coding RNA molecules associated with cellular proliferation, invasion, apoptosis, and cell cycle. Primarily, miR-21 promotes cell proliferation and a higher proportion of PDAC cells in the S phase, while knockdown of miR-21 has been linked to cell cycle arrest at the G2/M phase and inhibition of cell proliferation. In this study, using a CRISPR/Cas9 loss-of-function screen, we individually silenced the expression of miR-21 in two PDAC cell lines and in combination with PD-0332991 treatment, we examined the synergetic mechanisms of CDK4/6 inhibitors and miR-21 knockouts (KOs) on cell survival and death. This combination reduced cell proliferation, cell viability, increased apoptosis and G1 arrest in vitro. We further analysed the mitochondrial respiration and glycolysis of PDAC cells; then assessed the protein content of these cells and revealed numerous Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with PD-0332991 treatment and miR-21 knocking out. Our results demonstrate that combined targeting of CDK4/6 and silencing of miR-21 represents a novel therapeutic strategy in PDAC

A rich, nearby galaxy cluster in Sagittarius

We report on the existence of a rich, heavily obscured galaxy cluster (or a set of clusters) in Sagittarius, centered near l_(II) ≃ 359°, b_(II) ≃ 8°. About 30 objects, originally identified by Terzan and his collaborators, were imaged and followed up spectroscopically. We present here redshifts for 21 galaxies found among them. There is a pronounced concentration at cz ≃ 8600 km/s (containing 14 out of the 21 galaxies), and another possible concentration near cz ≃ 11 340 km/s (five out of 21). This putative Sagittarius cluster is probably part of a larger system, involving the Ophiuchus cluster at l_(II) ≃ 1°, b_(II) ≃ 9°, cz ≃ 8400 km/s, previously identified by Johnston et al. and Wakamatsu and Malkan. The heavy extinction on this line of sight (we estimate A_v ~ 5^m from the observed Balmer decrements) suggests that there is a much larger, as yet undetected number of galaxies in this direction. We propose that the Sagittarius-Ophiuchus concentration may be a massive cluster, or even a supercluster, comparable in richness to the Coma-A 1367 system, and at a comparable distance. The existence of this concentration serves as a reminder that some possibly dynamically important constituents of the local large-scale structure may be absent from the galaxy .catalogs available now, and the dynamical analyses based on them

Cosmological Model Predictions for Weak Lensing: Linear and Nonlinear Regimes

Weak lensing by large scale structure induces correlated ellipticities in the images of distant galaxies. The two-point correlation is determined by the matter power spectrum along the line of sight. We use the fully nonlinear evolution of the power spectrum to compute the predicted ellipticity correlation. We present results for different measures of the second moment for angular scales \theta \simeq 1'-3 degrees and for alternative normalizations of the power spectrum, in order to explore the best strategy for constraining the cosmological parameters. Normalizing to observed cluster abundance the rms amplitude of ellipticity within a 15' radius is \simeq 0.01 z_s^{0.6}, almost independent of the cosmological model, with z_s being the median redshift of background galaxies. Nonlinear effects in the evolution of the power spectrum significantly enhance the ellipticity for \theta < 10' -- on 1' the rms ellipticity is \simeq 0.05, which is nearly twice the linear prediction. This enhancement means that the signal to noise for the ellipticity is only weakly increasing with angle for 2'< \theta < 2 degrees, unlike the expectation from linear theory that it is strongly peaked on degree scales. The scaling with cosmological parameters also changes due to nonlinear effects. By measuring the correlations on small (nonlinear) and large (linear) angular scales, different cosmological parameters can be independently constrained to obtain a model independent estimate of both power spectrum amplitude and matter density \Omega_m. Nonlinear effects also modify the probability distribution of the ellipticity. Using second order perturbation theory we find that over most of the range of interest there are significant deviations from a normal distribution.Comment: 38 pages, 11 figures included. Extended discussion of observational prospects, matches accepted version to appear in Ap

The Extragalactic Distance Scale Key Project XXVII. A Derivation of the Hubble Constant Using the Fundamental Plane and Dn-Sigma Relations in Leo I, Virgo, and Fornax

Using published photometry and spectroscopy, we construct the fundamental plane and D_n-Sigma relations in Leo I, Virgo and Fornax. The published Cepheid P-L relations to spirals in these clusters fixes the relation between angular size and metric distance for both the fundamental plane and D_n-Sigma relations. Using the locally calibrated fundamental plane, we infer distances to a sample of clusters with a mean redshift of cz \approx 6000 \kms, and derive a value of H_0=78+- 5+- 9 km/s/Mpc (random, systematic) for the local expansion rate. This value includes a correction for depth effects in the Cepheid distances to the nearby clusters, which decreased the deduced value of the expansion rate by 5% +- 5%. If one further adopts the metallicity correction to the Cepheid PL relation, as derived by the Key Project, the value of the Hubble constant would decrease by a further 6%+- 4%. These two sources of systematic error, when combined with a +- 6% error due to the uncertainty in the distance to the Large Magellanic Cloud, a +- 4% error due to uncertainties in the WFPC2 calibration, and several small sources of uncertainty in the fundamental plane analysis, combine to yield a total systematic uncertainty of +- 11%. We find that the values obtained using either the CMB, or a flow-field model, for the reference frame of the distant clusters, agree to within 1%. The Dn-Sigma relation also produces similar results, as expected from the correlated nature of the two scaling relations. A complete discussion of the sources of random and systematic error in this determination of the Hubble constant is also given, in order to facilitate comparison with the other secondary indicators being used by the Key Project.Comment: 21 pages, 3 figures, Accepted for publication in Ap

The disruption of nearby galaxies by the Milky Way

Interactions between galaxies are common and are an important factor in determining their physical properties such as position along the Hubble sequence and star-formation rate. There are many possible galaxy interaction mechanisms, including merging, ram-pressure stripping, gas compression, gravitational interaction and cluster tides. The relative importance of these mechanisms is often not clear, as their strength depends on poorly known parameters such as the density, extent and nature of the massive dark halos that surround galaxies. A nearby example of a galaxy interaction where the mechanism is controversial is that between our own Galaxy and two of its neighbours -- the Large and Small Magellanic Clouds. Here we present the first results of a new HI survey which provides a spectacular view of this interaction. In addition to the previously known Magellanic Stream, which trails 100 degrees behind the Clouds, the new data reveal a counter-stream which lies in the opposite direction and leads the motion of the Clouds. This result supports the gravitational model in which leading and trailing streams are tidally torn from the body of the Magellanic Clouds.Comment: 17 pages with 5 figures in gif format, scheduled for publication in the August 20th, 1998 issue of Natur

Optical and Radio Observations of the Afterglow from GRB990510: Evidence for a Jet

We present multi-color optical and two-frequency radio observations of the bright SAX event, GRB 990510. The well-sampled optical decay, together with the radio observations are inconsistent with simple spherical afterglow models. The achromatic optical steepening and the decay of the radio afterglow both occuring at $t \sim 1$ day are evidence for hydrodynamical evolution of the source, and can be most easily interpreted by models where the GRB ejecta are collimated in a jet. Employing a simple jet model to interpret the observations, we derive a jet opening angle of $\theta_o = 0.08$, reducing the isotropic gamma-ray emission of $2.9 \times 10^{53}$ erg by a factor $\sim 300$. If the jet interpretation is correct, we conclude that GRB observations to-date are consistent with an energy for the central source of E \lsim 10^{52} erg.Comment: 12 pages, 2 figures. Version accepted for publication in ApJ Letter

The Protean Challenge of Game Collections at Academic Libraries

The rise of game development and game studies on university campuses prompts academic libraries to consider how to support teaching and research in this area. This article examines current issues and challenges in the development of game collections at academic libraries. The gaming ecosystem has become more complex and libraries may need to move beyond collections largely based on console video games. This article will advance the discussion by considering emerging issues to support access to the full range of games. The article will use examples from Carleton University Library, Ottawa, which has been developing a game collection since 2008

Ray Tracing Simulations of Weak Lensing by Large-Scale Structure

We investigate weak lensing by large-scale structure using ray tracing through N-body simulations. Photon trajectories are followed through high resolution simulations of structure formation to make simulated maps of shear and convergence on the sky. Tests with varying numerical parameters are used to calibrate the accuracy of computed lensing statistics on angular scales from about 1 arcminute to a few degrees. Various aspects of the weak lensing approximation are also tested. For fields a few degrees on a side the shear power spectrum is almost entirely in the nonlinear regime and agrees well with nonlinear analytical predictions. Sampling fluctuations in power spectrum estimates are investigated by comparing several ray tracing realizations of a given model. For survey areas smaller than a degree on a side the main source of scatter is nonlinear coupling to modes larger than the survey. We develop a method which uses this effect to estimate the mass density parameter Omega from the scatter in power spectrum estimates for subregions of a larger survey. We show that the power spectrum can be measured accurately from realistically noisy data on scales corresponding to 1-10 Mpc/h. Non-Gaussian features in the one point distribution function of the weak lensing convergence (reconstructed from the shear) are also sensitive to Omega. We suggest several techniques for estimating Omega in the presence of noise and compare their statistical power, robustness and simplicity. With realistic noise Omega can be determined to within 0.1-0.2 from a deep survey of several square degrees.Comment: 59 pages, 22 figures included. Matches version accepted for Ap