Development of an ALK2-Biased BMP Type I Receptor Kinase Inhibitor

The bone morphogenetic protein (BMP) signaling pathway has essential functions in development, homeostasis, and the normal and pathophysiologic remodeling of tissues. Small molecule inhibitors of the BMP receptor kinase family have been useful for probing physiologic functions of BMP signaling in vitro and in vivo and may have roles in the treatment of BMP-mediated diseases. Here we describe the development of a selective and potent inhibitor of the BMP type I receptor kinases, LDN-212854, which in contrast to previously described BMP receptor kinase inhibitors exhibits nearly 4 orders of selectivity for BMP versus the closely related TGF-? and Activin type I receptors. In vitro, LDN-212854 exhibits some selectivity for ALK2 in preference to other BMP type I receptors, ALK1 and ALK3, which may permit the interrogation of ALK2-mediated signaling, transcriptional activity, and function. LDN-212854 potently inhibits heterotopic ossification in an inducible transgenic mutant ALK2 mouse model of fibrodysplasia ossificans progressiva. These findings represent a significant step toward developing selective inhibitors targeting individual members of the highly homologous BMP type I receptor family. Such inhibitors would provide greater resolution as probes of physiologic function and improved selectivity against therapeutic targets

Klein-Gordon Solutions on Non-Globally Hyperbolic Standard Static Spacetimes

We construct a class of solutions to the Cauchy problem of the Klein-Gordon equation on any standard static spacetime. Specifically, we have constructed solutions to the Cauchy problem based on any self-adjoint extension (satisfying a technical condition: "acceptability") of (some variant of) the Laplace-Beltrami operator defined on test functions in an $L^2$-space of the static hypersurface. The proof of the existence of this construction completes and extends work originally done by Wald. Further results include the uniqueness of these solutions, their support properties, the construction of the space of solutions and the energy and symplectic form on this space, an analysis of certain symmetries on the space of solutions and of various examples of this method, including the construction of a non-bounded below acceptable self-adjoint extension generating the dynamics

Canonical Decompositions of n-qubit Quantum Computations and Concurrence

The two-qubit canonical decomposition SU(4) = [SU(2) \otimes SU(2)] Delta [SU(2) \otimes SU(2)] writes any two-qubit quantum computation as a composition of a local unitary, a relative phasing of Bell states, and a second local unitary. Using Lie theory, we generalize this to an n-qubit decomposition, the concurrence canonical decomposition (C.C.D.) SU(2^n)=KAK. The group K fixes a bilinear form related to the concurrence, and in particular any computation in K preserves the tangle ||^2 for n even. Thus, the C.C.D. shows that any n-qubit quantum computation is a composition of a computation preserving this n-tangle, a computation in A which applies relative phases to a set of GHZ states, and a second computation which preserves it. As an application, we study the extent to which a large, random unitary may change concurrence. The result states that for a randomly chosen a in A within SU(2^{2p}), the probability that a carries a state of tangle 0 to a state of maximum tangle approaches 1 as the even number of qubits approaches infinity. Any v=k_1 a k_2 for such an a \in A has the same property. Finally, although ||^2 vanishes identically when the number of qubits is odd, we show that a more complicated C.C.D. still exists in which K is a symplectic group.Comment: v2 corrects odd qubit CCD misstatements, reference chapter for KAK v3 notation change to coincide with sequel, typos. 20 pages, 0 figure

Confronting the Minimal Supersymmetric Standard Model with the Study of Scalar Leptons at Future Linear e+e- Colliders

Sleptons can easily be found at future linear e+e- colliders if kinematically accessible. Measurements of their masses and decay distributions would then determine MSSM parameters. This paper presents a detailed MC study of the production and decay of the lighter scalar tau lepton, stau1. We found that mstau1 and the left-right mixing angle of stau would be measured within an error of a few percent. tanbeta is determinable in some region of the parameter space through simultaneous studies of stau1-and selectron-pair production: the polarization measurement of the tau leptons from stau1 decays and the M1, mchi1 determination using selectron pair production and decay. We also point out the possibility to determine bino-selectron-e coupling through the measurement of the angular distribution of the selectron-pair production. The error on the coupling is expected to be comparable to its typical SUSY radiative correction, which is proportional to log(msquark/mslepton). The radiative correction affects M1 and tanbeta determination, necessitating the full 1-loop radiative correction to the selectron production processes. The implication of these measurements of the MSSM parameters on selecting models of the origin of supersymmetry breaking is also discussed.Comment: 35 pages. REVTEX(gzip compressed and uuencoded). Figure are not included. Text and 15 Figures are available at http://jlcux1.kek.jp/subg/susy/index-e.html#librar

Strong Influence of the diffuse component on the lattice dynamics in Pb(Mg1/3_{1/3}Nb2/3_{2/3})O3_{3}

The temperature and zone dependence of the lattice dynamics in Pb(Mg$_{1/3}$Nb$_{2/3}$)O$_{3}$ is characterized using neutron inelastic scattering. A strong correlation between the diffuse and phonon scattering is measured. The lattice dynamics in Brillouin zones where the diffuse scattering is strong is observed to display qualitatively different behavior than those zones where the diffuse scattering is weak. In the (220) and (200) zones, where there is a weak diffuse component, the dynamics are well described by coupled harmonic oscillators. Compared with SrTiO$_{3}$, the coupling is weak and isotropic, resulting in only a small transfer of spectral weight from one mode to another. A comparison of the scattering in these zones to the (110) zone, where a strong diffuse component is present, reveals a strong coupling of the diffuse (or central) component to the acoustic mode. We speculate that the coupling to the central peak is the reason for several recent conflicting interpretations of the lattice dynamics based on data from zones with a strong diffuse component.Comment: 7 pages, 7 figure

Primordial black hole constraints in cosmologies with early matter domination

Moduli fields, a natural prediction of any supergravity and superstring-inspired supersymmetry theory, may lead to a prolonged period of matter domination in the early Universe. This can be observationally viable provided the moduli decay early enough to avoid harming nucleosynthesis. If primordial black holes form, they would be expected to do so before or during this matter dominated era. We examine the extent to which the standard primordial black hole constraints are weakened in such a cosmology. Permitted mass fractions of black holes at formation are of order $10^{-8}$, rather than the usual $10^{-20}$ or so. If the black holes form from density perturbations with a power-law spectrum, its spectral index is limited to $n \lesssim 1.3$, rather than the $n \lesssim 1.25$ obtained in the standard cosmology.Comment: 7 pages RevTeX file with four figures incorporated (uses RevTeX and epsf). Also available by e-mailing ARL, or by WWW at http://star-www.maps.susx.ac.uk/papers/infcos_papers.htm

Dynamical effects of the nanometer-sized polarized domains in Pb(Zn1/3Nb2/3)O3

Recent neutron scattering measurements performed on the relaxor ferroelectric Pb[(Zn1/3Nb2/3)0.92Ti0.08]O3 (PZN-8%PT) in its cubic phase at 500 K, have revealed an anomalous ridge of inelastic scattering centered ~0.2 A-1 from the zone center (Gehring et al., Phys. Rev. Lett. 84, 5216 (2000)). This ridge of scattering resembles a waterfall when plotted as a phonon dispersion diagram, and extends vertically from the transverse acoustic (TA) branch near 4 meV to the transverse optic (TO) branch near 9 meV. No zone center optic mode was found. We report new results from an extensive neutron scattering study of pure PZN that exhibits the same waterfall feature. We are able to model the dynamics of the waterfall using a simple coupled-mode model that assumes a strongly q-dependent optic mode linewidth Gamma1(q) that increases sharply near 0.2 A-1 as one approaches the zone center. This model was motivated by the results of Burns and Dacol in 1983, who observed the formation of a randomly-oriented local polarization in PZN at temperatures far above its ferroelectric phase transition temperature. The dramatic increase in Gamma1 is believed to occur when the wavelength of the optic mode becomes comparable to the size of the small polarized micro-regions (PMR) associated with this randomly-oriented local polarization, with the consequence that longer wavelength optic modes cannot propagate and become overdamped. Below Tc=410 K, the intensity of the waterfall diminishes. At lowest temperatures ~30 K the waterfall is absent, and we observe the recovery of a zone center transverse optic mode near 10.5 meV.Comment: 8 pages, 9 figures (one color). Submitted to Physical Review

Misogyny, racism, and Islamophobia: street harassment at the intersections

Veiled Muslim women are at an increased risk of street harassment in the current political and economic climate. Their visibility, combined with their popular portrayal as culturally dangerous or threatening means that they are vulnerable to receiving verbal and physical threats, which can be misogynistic and Islamophobic in nature. Drawing on 60 individual and 20 focus group interviews with Muslim women in the United Kingdom who wear the niqab (face veil) and had experienced harassment in public, this qualitative study details their lived experiences. It argues that an intersectional analysis is crucial to understanding the nuances of their lived experiences and the impact street harassment has on their lives. The findings demonstrate that street harassment can produce a hostile environment for veiled Muslim women, which can have a terrorizing effect, limiting their full participation in the public sphere

Recurrent Clostridium difficile infection associates with distinct bile acid and microbiome profiles

Background: The healthy microbiome protects against the development of Clostridium difficile infection (CDI), which typically develops following antibiotics. The microbiome metabolises primary to secondary bile acids, a process if disrupted by antibiotics, may be critical for the initiation of CDI. Aim: To assess the levels of primary and secondary bile acids associated with CDI and associated microbial changes. Methods: Stool and serum were collected from patients with (i) first CDI (fCDI), (ii) recurrent CDI (rCDI) and (iii) healthy controls. 16S rRNA sequencing and bile salt metabolomics were performed. Random forest regression models were constructed to predict disease status. PICRUSt analyses were used to test for associations between predicted bacterial bile salt hydrolase (BSH) gene abundances and bile acid levels. Results: Sixty patients (20 fCDI, 19 rCDI and 21 controls) were enrolled. Secondary bile acids in stool were significantly elevated in controls compared to rCDI and fCDI (P < 0.0001 and P = 0.0007 respectively). Primary bile acids in stool were significantly elevated in rCDI compared to controls (P < 0.0001) and in rCDI compared to fCDI (P = 0.02). Using random forest regression, we distinguished rCDI and fCDI patients 84.2% of the time using bile acid ratios. Stool deoxycholate to glycoursodeoxycholate ratio was the single best predictor. PICRUSt analyses found significant differences in predicted abundances of bacterial BSH genes in stool samples across the groups. Conclusions: Primary and secondary bile acid composition in stool was different in those with rCDI, fCDI and controls. The ratio of stool deoxycholate to glycoursodeoxycholate was the single best predictor of disease state and may be a potential biomarker for recurrence.American College of Gastroenterology (Clinical Research Award ACGJR-017-2015