Erythropoietin Modulates the Structure of Bone Morphogenetic Protein 2–Engineered Cranial Bone

The ideally engineered bone should have similar structural and functional properties to the native tissue. Although structural integrity is critical for functional bone regeneration, we know less about modulating the structural properties of the engineered bone elicited by bone morphogenetic protein (BMP) than efficacy and safety. Erythropoietin (Epo), a primary erythropoietic hormone, has been used to augment blood transfusion in orthopedic surgery. However, the effects of Epo on bone regeneration are not well known. Here, we determined the role of Epo in BMP2-induced bone regeneration using a cranial defect model. Epo administration improved the quality of BMP2-induced bone and more closely resembled natural cranial bone with a higher bone volume (BV) fraction and lower marrow fraction when compared with BMP2 treatment alone. Epo increased red blood cells (RBCs) in peripheral blood and also increased hematopoietic and mesenchymal stem cell (MSC) populations in bone marrow. Consistent with our previous work, Epo increased osteoclastogenesis both in vitro and in vivo. Results from a metatarsal organ culture assay suggested that Epo-promoted osteoclastogenesis contributed to angiogenesis because angiogenesis was blunted when osteoclastogenesis was blocked by alendronate (ALN) or osteoprotegerin (OPG). Earlier calcification of BMP2-induced temporary chondroid tissue was observed in the Epo+BMP group compared to BMP2 alone. We conclude that Epo significantly enhanced the outcomes of BMP2-induced cranial bone regeneration in part through its actions on osteoclastogenesis and angiogenesis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98479/1/ten%2Etea%2E2011%2E0742.pd

QCD analysis of the diffractive structure function F_2^{D(3)}

The proton diffractive structure function $F_2^{D(3)}$ measured in the H1 and ZEUS experiments at HERA is analyzed in terms of both Regge phenomenology and perturbative QCD evolution. A new method determines the values of the Regge intercepts in ``hard'' diffraction, confirming a higher value of the Pomeron intercept than for soft physics. The data are well described by a QCD analysis in which point-like parton distributions, evolving according to the DGLAP equations, are assigned to the leading and sub-leading Regge exchanges. The gluon distributions are found to be quite different for H1 and ZEUS. A {\it global fit} analysis, where a higher twist component is taken from models, allows us to use data in the whole available range in diffractive mass and gives a stable answer for the leading twist contribution. We give sets of quark and gluon parton distributions for the Pomeron, and predictions for the charm and the longitudinal proton diffractive structure function from the QCD fit. An extrapolation to the Tevatron range is compared with CDF data on single diffraction. Conclusions on factorization breaking depend critically whether H1 (strong violation) or ZEUS (compatibility at low $\beta$) fits are taken into account.Comment: 24 page

Flavor symmetry breaking and scaling for improved staggered actions in quenched QCD

We present a study of the flavor symmetry breaking in the pion spectrum for various improved staggered fermion actions. To study the effects of link fattening and tadpole improvement, we use three different variants of the p4 action - p4fat3, p4fat7, and p4fat7tad. These are compared to Asqtad and also to naive staggered. To study the pattern of symmetry breaking, we measure all 15 meson masses in the 4-flavor staggered theory. The measurements are done on a quenched gauge background, generated using a one-loop improved Symanzik action with $\beta=10/g^2 = 7.40, 7.75,$ and 8.00, corresponding to lattice spacings of approximately a = .31 fm., .21 fm., and .14 fm. We also study how the lattice scale set by the $\rho$ mass on each of these ensembles compares to one set by the static quark potential.Comment: 18 pages, 6 figure

3-Fluoro-4-hydroxyprolines:Synthesis, conformational analysis and stereoselective recognition by the VHL E3 ubiquitin ligase for targeted protein degradation

Hydroxylation and fluorination of proline alters the pyrrolidine ring pucker and the trans:cis amide bond ratio in a stereochemistry-dependent fashion, affecting molecular recognition of proline-containing molecules by biological systems. While hydroxyprolines and fluoroprolines are common motifs in medicinal and biological chemistry, the synthesis and molecular properties of prolines containing both modifications, i.e., fluoro-hydroxyprolines, have not been described. Here we present a practical and facile synthesis of all four diastereoisomers of 3-fluoro-4-hydroxyprolines (F-Hyps), starting from readily available 4-oxo-l-proline derivatives. Small-molecule X-ray crystallography, NMR spectroscopy, and quantum mechanical calculations are consistent with fluorination at C³ having negligible effects on the hydrogen bond donor capacity of the C⁴ hydroxyl, but inverting the natural preference of Hyp from C⁴-exo to C⁴-endo pucker. In spite of this, F-Hyps still bind to the von Hippel–Lindau (VHL) E3 ligase, which naturally recognizes C⁴-exo Hyp in a stereoselective fashion. Co-crystal structures and electrostatic potential calculations support and rationalize the observed preferential recognition for (3<i>R</i>,4<i>S</i>)-F-Hyp over the corresponding (3<i>S</i>,4<i>S</i>) epimer by VHL. We show that (3<i>R</i>,4<i>S</i>)-F-Hyp provides bioisosteric Hyp substitution in both hypoxia-inducible factor 1 alpha (HIF-1α) substrate peptides and peptidomimetic ligands that form part of PROTAC (proteolysis targeting chimera) conjugates for targeted protein degradation. Despite a weakened affinity, Hyp substitution with (3<i>S</i>,4<i>S</i>)-F-Hyp within the PROTAC MZ1 led to Brd4-selective cellular degradation at concentrations >100-fold lower than the binary <i>K</i>_d for VHL. We anticipate that the disclosed chemistry of 3-fluoro-4-hydroxyprolines and their application as VHL ligands for targeted protein degradation will be of wide interest to medicinal organic chemists, chemical biologists, and drug discoverers alike

Transformation of in-plane ρ(T)\rho (T) in YBa2Cu3O7−δYBa_{2}Cu_{3}O_{7-\delta} at fixed oxygen content

This paper reveals the origin of variation in the magnitude and temperature dependence of the normal state resistivity frequently observed in different YBCO single crystal or thin film samples with the same $T_{c}$. We investigated temperature dependence of resistivity in $YBa_{2}Cu_{3}O_{7-\delta}$ thin films with 7- $\delta = 6.95$ and 6.90, which were subjected to annealing in argon at 400-420 K ($120-140^{o}C$). Before annealing these films exhibited a non-linear $\rho_{ab}(T)$, with a flattening below 230 K, similar to $\rho_{b}(T)$ and $\rho_{ab}(T)$ observed in untwinned and twinned YBCO crystals, respectively. For all films the annealing causes an increase of resistivity and a transformation of $\rho_{ab}(T)$ from a non-linear dependence towards a more linear one (less flattening). In films with 7- $\delta = 6.90$ the increase of resistivity is also associated with an increase in $T_{c}$. We proposed the model that provides an explanation of these phenomena in terms of thermally activated redistribution of residual O(5) oxygens in the chain-layer of YBCO. Good agreement between the experimental data for $\rho_{ab}(t,T)$, where t is the annealing time, and numerical calculations was obtained.Comment: 8 pages, 9 figures, submitted to PR

Periodic Orbits and Escapes in Dynamical Systems

We study the periodic orbits and the escapes in two different dynamical systems, namely (1) a classical system of two coupled oscillators, and (2) the Manko-Novikov metric (1992) which is a perturbation of the Kerr metric (a general relativistic system). We find their simple periodic orbits, their characteristics and their stability. Then we find their ordered and chaotic domains. As the energy goes beyond the escape energy, most chaotic orbits escape. In the first case we consider escapes to infinity, while in the second case we emphasize escapes to the central "bumpy" black hole. When the energy reaches its escape value a particular family of periodic orbits reaches an infinite period and then the family disappears (the orbit escapes). As this family approaches termination it undergoes an infinity of equal period and double period bifurcations at transitions from stability to instability and vice versa. The bifurcating families continue to exist beyond the escape energy. We study the forms of the phase space for various energies, and the statistics of the chaotic and escaping orbits. The proportion of these orbits increases abruptly as the energy goes beyond the escape energy.Comment: 28 pages, 23 figures, accepted in "Celestial Mechanics and Dynamical Astronomy

Specific Heat Study of the Magnetic Superconductor HoNi2B2C

The complex magnetic transitions and superconductivity of HoNi2B2C were studied via the dependence of the heat capacity on temperature and in-plane field angle. We provide an extended, comprehensive magnetic phase diagram for B // [100] and B // [110] based on the thermodynamic measurements. Three magnetic transitions and the superconducting transition were clearly observed. The 5.2 K transition (T_{N}) shows a hysteresis with temperature, indicating the first order nature of the transition at B=0 T. The 6 K transition (T_{M}), namely the onset of the long-range ordering, displays a dramatic in-plane anisotropy: T_{M} increases with increasing magnetic field for B // [100] while it decreases with increasing field for B // [110]. The anomalous anisotropy in T_{M} indicates that the transition is related to the a-axis spiral structure. The 5.5 K transition (T^{*}) shows similar behavior to the 5.2 K transition, i.e., a small in-plane anisotropy and scaling with Ising model. This last transition is ascribed to the change from a^{*} dominant phase to c^{*} dominant phase.Comment: 9 pages, 11 figure

SRAO CO Observation of 11 Supernova Remnants in l = 70 to 190 deg

We present the results of 12CO J = 1-0 line observations of eleven Galactic supernova remnants (SNRs) obtained using the Seoul Radio Astronomy Observatory (SRAO) 6-m radio telescope. The observation was made as a part of the SRAO CO survey of SNRs between l = 70 and 190 deg, which is intended to identify SNRs interacting with molecular clouds. The mapping areas for the individual SNRs are determined to cover their full extent in the radio continuum. We used halfbeam grid spacing (60") for 9 SNRs and full-beam grid spacing (120") for the rest. We detected CO emission towards most of the remnants. In six SNRs, molecular clouds showed a good spatial relation with their radio morphology, although no direct evidence for the interaction was detected. Two SNRs are particularly interesting: G85.4+0.7, where there is a filamentary molecular cloud along the radio shell, and 3C434.1, where a large molecular cloud appears to block the western half of the remnant. We briefly summarize the results obtained for individual SNRs.Comment: Accepted for publication in Astrophysics & Space Science. 12 pages, 12 figures, and 3 table

GPIHBP1 expression in gliomas promotes utilization of lipoprotein-derived nutrients

GPIHBP1, a GPI-anchored protein of capillary endothelial cells, binds lipoprotein lipase (LPL) within the subendothelial spaces and shuttles it to the capillary lumen. The GPIHBP1-bound LPL is essential for the margination of triglyceride-rich lipoproteins (TRLs) along capillaries, allowing the lipolytic processing of TRLs to proceed. In peripheral tissues, the intravascular processing of TRLs by the GPIHBP1-LPL complex is crucial for generating lipid nutrients for adjacent parenchymal cells. GPIHBP1 is absent in capillaries of the brain, which uses glucose for fuel; however, GPIHBP1 is expressed in capillaries of mouse and human gliomas. Importantly, the GPIHBP1 in glioma capillaries captures locally produced LPL. We document, by NanoSIMS imaging, that TRLs marginate along glioma capillaries and that there is uptake of TRL-derived lipid nutrients by surrounding glioma cells. Thus, GPIHBP1 expression in gliomas facilitates TRL processing and provides a source of lipid nutrients for glioma cells