Triune Synergy in Biomedical Research: Uniting Pharmaceutical Companies, University Researchers, and the NIH through the Drug Repurposing Project at NCATS

The drug discovery process is long, expensive, and prone to failure. The average cost of developing an approved drug is increasing exponentially. Exacerbating the problem is the fact that, instead of being translated into medical therapies, basic scientific discoveries are languishing without further development. This phenomenon, known as the “Valley of Death,” has become a concern of the National Institutes of Health (NIH), which is the main funder of biomedical research in the United States. In an attempt to build bridges across the Valley of Death, the NIH created the National Center for Advancing Translational Sciences (NCATS) in December 2011. NCATS’ first project was the Discovering New Therapeutic Uses for Existing Molecules Program (the “Repurposing Project”). The linchpin for getting the Repurposing Project off the ground was convincing the pharmaceutical companies to allow outside researchers to experiment with their patented drugs. If an outside researcher were to be successful in finding a new use for the drug, the company’s intellectual property (IP) ownership over the drug would be diluted. This, in turn, would limit the company’s ability to profit from the drug. In a break from their normally secretive business practices, the eight participating pharmaceutical companies published Collaborative Research Agreements (CRAs) on the NIH’s website that outline the intellectual property rights they were willing to give up in order to participate in the project. This Note discusses the content of the CRAs developed for the Repurposing Project, examines the IP provisions that each of the eight participating companies incorporated into its CRA, and argues that the Repurposing Project aligns the skills and interests of three of the most important entities in biomedical research, thereby promoting a triune synergy unique to the biomedical research field

Oblique propagation of arbitrary amplitude electron acoustic solitary waves in magnetized kappa-distributed plasmas

The linear and nonlinear properties of large amplitude electron-acoustic waves are investigated in a magnetized plasma comprising two distinct electron populations (hot and cold) and immobile ions. The hot electrons are assumed to be in a non-Maxwellian state, characterized by an excess of superthermal particles, here modelled by a kappa-type long-tailed distribution function. Waves are assumed to propagate obliquely to the ambient magnetic field. Two types of electrostatic modes are shown to exist in the linear regime, and their properties are briefly analyzed. A nonlinear pseudopotential type analysis reveals the existence of large amplitude electrostatic solitary waves and allows for an investigation of their propagation characteristics and existence domain, in terms of the soliton speed (Mach number). The effects of the key plasma configuration parameters, namely, the superthermality index and the cold electron density, on the soliton characteristics and existence domain, are studied. The role of obliqueness and magnetic field are discussed.Comment: Submitted to Plasma Physics and Controlled Fusio

New Seiberg Dualities from N=2 Dualities

We propose a number of new Seiberg dualities of N=1 quiver gauge theories. The new Seiberg dualities originate in new S-dualities of N=2 superconformal field theories recently proposed by Gaiotto. N=2 S-dual theories deformed by suitable mass terms flow to our N=1 Seiberg dual theories. We show that the number of exactly marginal operators is universal for these Seiberg dual theories and the 't Hooft anomaly matching holds for these theories. These provide strong evidence for the new Seiberg dualities. Furthermore, we study in detail the Klebanov-Witten type theory and its dual as a concrete example. We show that chiral operators and their non-linear relations match between these theories. These arguments also give non-trivial consistency checks for our proposal.Comment: 31 pages, 7 figures. v2:version to appear in JHE

Targeting cellular calcium homeostasis to prevent cytokine-mediated beta cell death

AbstractPro-inflammatory cytokines are important mediators of islet inflammation, leading to beta cell death in type 1 diabetes. Although alterations in both endoplasmic reticulum (ER) and cytosolic free calcium levels are known to play a role in cytokine-mediated beta cell death, there are currently no treatments targeting cellular calcium homeostasis to combat type 1 diabetes. Here we show that modulation of cellular calcium homeostasis can mitigate cytokine- and ER stress-mediated beta cell death. The calcium modulating compounds, dantrolene and sitagliptin, both prevent cytokine and ER stress-induced activation of the pro-apoptotic calcium-dependent enzyme, calpain, and partly suppress beta cell death in INS1E cells and human primary islets. These agents are also able to restore cytokine-mediated suppression of functional ER calcium release. In addition, sitagliptin preserves function of the ER calcium pump, sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), and decreases levels of the pro-apoptotic protein thioredoxin-interacting protein (TXNIP). Supporting the role of TXNIP in cytokine-mediated cell death, knock down of TXNIP in INS1-E cells prevents cytokine-mediated beta cell death. Our findings demonstrate that modulation of dynamic cellular calcium homeostasis and TXNIP suppression present viable pharmacologic targets to prevent cytokine-mediated beta cell loss in diabetes.</jats:p

Stop-and-go kinetics in amyloid fibrillation

Many human diseases are associated with protein aggregation and fibrillation. Using glucagon as a model system for protein fibrillation we show that fibrils grow in an intermittent fashion, with periods of growth followed by long pauses. Remarkably, even if the intrinsic transition rates vary considerably in each experiment, the probability of being in the growing (stopping) state is very close to 1/4 (3/4), suggesting the presence of 4 independent conformations of the fibril tip. We discuss this possibility in terms of existing structural knowledge

Space-time evolution of bulk QCD matter

We introduce a combined fully three-dimensional macroscopic/microscopic transport approach employing relativistic 3D-hydrodynamics for the early, dense, deconfined stage of the reaction and a microscopic non-equilibrium model for the later hadronic stage where the equilibrium assumptions are not valid anymore. Within this approach we study the dynamics of hot, bulk QCD matter, which is being created in ultra-relativistic heavy ion collisions at RHIC. Our approach is capable of self-consistently calculating the freezeout of the hadronic system, while accounting for the collective flow on the hadronization hypersurface generated by the QGP expansion. In particular, we perform a detailed analysis of the reaction dynamics, hadronic freezeout, and transverse flow.Comment: 24 pages, 27 figure

Discovery of New Dwarf Galaxy near The Isolated Spiral Galaxy NGC 6503

We report the discovery of a new dwarf galaxy (NGC6503-d1) during the Subaru extended ultraviolet (XUV) disk survey. It is a likely companion of the spiral galaxy NGC6503. The resolved images, in B, V, R, i, and Halpha, show an irregular appearance due to bright stars with underlying, smooth and unresolved stellar emission. It is classified as the transition type (dIrr/dSph). Its structural properties are similar to those of the dwarfs in the Local Group, with a V absolute magnitude ~ -10.5, half-light radius ~400 pc, and central surface brightness ~25.2. Despite the low stellar surface brightness environment, one HII region was detected, though its Halpha luminosity is low, indicating an absence of any appreciable O-stars at the current epoch. The presence of multiple stellar populations is indicated by the color-magnitude diagram of ~300 bright resolved stars and the total colors of the dwarf, with the majority of its total stellar mass ~4x10^6 Msun in an old stellar population.Comment: Published in ApJL (ApJ, 802, L24). 7 pages, 4 figure

The Universal Initial Mass Function In The XUV Disk of M83

We report deep Subaru Halpha observations of the XUV disk of M83. These new observations enable the first complete census of very young stellar clusters over the entire XUV disk. Combining Subaru and GALEX data with a stellar population synthesis model, we find that (1) the standard, but stochastically-sampled, initial mass function (IMF) is preferred over the truncated IMF, because there are low mass stellar clusters (10^{2-3}Msun) that host massive O-type stars; that (2) the standard Salpeter IMF and a simple aging effect explain the counts of FUV-bright and Halpha-bright clusters with masses >10^3Msun; and that (3) the Halpha to FUV flux ratio over the XUV disk supports the standard IMF. The Subaru Prime Focus Camera (Suprime-Cam) covers a large area even outside the XUV disk -- far beyond the detection limit of the HI gas. This enables us to statistically separate the stellar clusters in the disk from background contamination. The new data, model, and previous spectroscopic studies provide overall consistent results with respect to the internal dust extinction (Av~0.1 mag) and low metallicity (~0.2Zsun) using the dust extinction curve of SMC.Comment: 11 pages, 8 figures. Accepted for publication in Ap

Subaru Deep Survey VI. A Census of Lyman Break Galaxies at z=4 and 5 in the Subaru Deep Fields: Clustering Properties

We investigate the clustering properties of 2,600 Lyman Break Galaxies (LBGs) at z=3.5-5.2 in two large blank fields, the Subaru Deep Field and the Subaru/XMM Deep Field (600arcmin^2 each). The angular correlation functions of these LBGs show a clear clustering at both z~4 and 5. The correlation lengths are r_0= 4.1^{+0.2}_{-0.2} and 5.9^{+1.3}_{-1.7} h_{100}^{-1} Mpc (r_0= 5.1^{+1.0}_{-1.1} and 5.9^{+1.3}_{-1.7} h_{100}^{-1} Mpc) for all the detected LBGs (for L>L* LBGs) at z~4 and 5, respectively. These correlation lengths correspond to galaxy-dark matter biases of b_g= 2.9^{+0.1}_{-0.1} and 4.6^{+0.9}_{-1.2} (b_g=3.5^{+0.6}_{-0.7} and 4.6^{+0.9}_{-1.2}), for all the detected LBGs (for L>L^* LBGs) at z~4 and 5, respectively. These results, combined with estimates for z~3 LBGs in the literature, show that the correlation length of L>L^* LBGs is almost constant, ~5 h_{100}^{-1} Mpc, over z~3-5, while the bias monotonically increases with redshift at z>3. We also find that for LBGs at z~4 the clustering amplitude increases with UV-continuum luminosity and with the amount of dust extinction. We estimate the mass of dark halos hosting various kinds of high-z galaxies including LBGs with the analytic model given by Sheth & Tormen (1999). We find that the typical mass of dark halos hosting L>L^* LBGs is about 1x10^{12} h_{70}^{-1}Msol over z~3-5, which is comparable to that of the Milky Way Galaxy. A single dark halo with ~10^{12} h_{70}^{-1} Msol is found to host 0.1-0.3 LBG on average but host about four K-band selected galaxies.Comment: 33 pages, 12 figures, ApJ in press. Paper with high resolution figures is available at http://hikari.astron.s.u-tokyo.ac.jp/~ouchi/work/astroph/SDS_V_VI/SDS_VI.pdf (PDF) (The abstract was reduced by the revision.

The Halpha Luminosity Function of the Galaxy Cluster Abell 521 at z = 0.25

We present an optical multicolor-imaging study of the galaxy cluster Abell 521 at $z = 0.25$, using Suprime-Cam on the Subaru Telescope, covering an area of $32 \times 20$ arcmin$^2$ ($9.4 \times 5.8 h_{50}^{-2}$ Mpc$^2$ at $z = 0.25$). Our imaging data taken with both a narrow-band filter, $NB816$ ($\lambda_0 = 8150$\AA and $\Delta \lambda = 120$\AA), and broad-band filters, $B,V,R_{\rm C}, i^\prime$, and $z^\prime$ allow us to find 165 H$\alpha$ emitters. We obtain the H$\alpha$ luminosity function (LF) for the cluster galaxies within 2 Mpc; the Schechter parameters are $\alpha = -0.75 \pm 0.23$, $\phi^\star = 10^{-0.25 \pm 0.20}$ Mpc$^{-3}$, and $L^\star = 10^{42.03 \pm 0.17}$ erg s$^{-1}$. Although the faint end slope, $\alpha$, is consistent with that of the local cluster H$\alpha$ LFs, the characteristic luminosity, $L^\star$, is about 6 times (or $\approx 2$ mag) brighter. This strong evolution implies that Abell 521 contains more active star-forming galaxies than the local clusters, being consistent with the observed Butcher-Oemler effect. However, the bright $L^\star$ of Abell 521 may be, at least in part, due to the dynamical condition of this cluster.Comment: 21 pages, 7 figures, ApJ, Part 1, in pres