Spinal cord injury (SCI) causes immune dysfunction, increasing the risk of infectious morbidity and mortality. Since bone marrow hematopoiesis is essential for proper immune function, we hypothesize ...that SCI disrupts bone marrow hematopoiesis. Indeed, SCI causes excessive proliferation of bone marrow hematopoietic stem and progenitor cells (HSPC), but these cells cannot leave the bone marrow, even after challenging the host with a potent inflammatory stimulus. Sequestration of HSPCs in bone marrow after SCI is linked to aberrant chemotactic signaling that can be reversed by post-injury injections of Plerixafor (AMD3100), a small molecule inhibitor of CXCR4. Even though Plerixafor liberates HSPCs and mature immune cells from bone marrow, competitive repopulation assays show that the intrinsic long-term functional capacity of HSPCs is still impaired in SCI mice. Together, our data suggest that SCI causes an acquired bone marrow failure syndrome that may contribute to chronic immune dysfunction.
Summary
Acquired haemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies against human factor VIII (hFVIII). OBI‐1 is an investigational, B‐domain deleted, recombinant FVIII, porcine ...sequence, with low cross‐reactivity to anti‐hFVIII antibodies. Efficacy can be monitored with FVIII activity levels in addition to clinical assessments. This prospective, open label, phase 2/3 study was designed to evaluate the efficacy of OBI‐1 treatment for bleeding episodes in subjects with AHA. After an initial dose of 200 U kg−1, OBI‐1 was titrated to maintain target FVIII activity levels, in correlation with clinical assessments, throughout the treatment phase. All 28 subjects with AHA had a positive response to OBI‐1 treatment 24 h after initiation despite inhibition of FVIII activity levels immediately after infusion in 10 subjects with baseline anti‐porcine FVIII inhibitors. Control of the qualifying bleed was ultimately achieved in 24 of 28 subjects. No related serious adverse events, thrombotic events, allergic reactions or thrombocytopaenia occurred. The results of this study indicate that OBI‐1 is safe and effective in treating bleeding episodes in subjects with AHA. The ability to safely and effectively titrate dosing based on FVIII activity levels in this study demonstrates that OBI‐1 fulfils the unmet medical need to monitor the key coagulation parameter in AHA patients.
High‐resolution inelastic X‐ray scattering is an established technique in the synchrotron community, used to investigate collective low‐frequency responses of materials. When fielded at hard X‐ray ...free‐electron lasers (XFELs) and combined with high‐intensity laser drivers, it becomes a promising technique for investigating matter at high temperatures and high pressures. This technique gives access to important thermodynamic properties of matter at extreme conditions, such as temperature, material sound speed, and viscosity. The successful realization of this method requires the acquisition of many identical laser‐pump/X‐ray‐probe shots, allowing the collection of a sufficient number of photons necessary to perform quantitative analyses. Here, a 2.5‐fold improvement in the energy resolution of the instrument relative to previous works at the Matter in Extreme Conditions (MEC) endstation, Linac Coherent Light Source (LCLS), and the High Energy Density (HED) instrument, European XFEL, is presented. Some aspects of the experimental design that are essential for improving the number of photons detected in each X‐ray shot, making such measurements feasible, are discussed. A careful choice of the energy resolution, the X‐ray beam mode provided by the XFEL, and the position of the analysers used in such experiments can provide a more than ten‐fold improvement in the photometrics. The discussion is supported by experimental data on 10 µm‐thick iron and 50 nm‐thick gold samples collected at the MEC endstation at the LCLS, and by complementary ray‐tracing simulations coupled with thermal diffuse scattering calculations.
High‐resolution inelastic X‐ray scattering measurements at hard X‐ray free‐electron lasers coupled with energetic laser drivers have shown a 2.5‐fold improved energy resolution compared with previous experiments at similar XFEL instruments. Aspects of the experimental design that can be adjusted to improve the number of recorded photons on the detector are discussed.
Several software tools are available that facilitate the use of the NONMEM software and extend its functionality. This tutorial shows how three commonly used and freely available tools, Pirana, PsN, ...and Xpose, form a tightly integrated workbench for modeling and simulation with NONMEM. During the tutorial, we provide some guidance on what diagnostics we consider most useful in pharmacokinetic model development and how to construct them using these tools.
CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e50; doi:10.1038/psp.2013.24; advance online publication 26 June 2013
The Geography of Block Acquisitions KANG, JUN-KOO; KIM, JIN-MO
The Journal of finance (New York),
December 2008, Letnik:
63, Številka:
6
Journal Article
Recenzirano
Using a large sample of partial block acquisitions, we examine the importance of geographic proximity in corporate governance and target returns. We find that block acquirers have a strong preference ...for geographically proximate targets and acquirers that purchase shares in such targets are more likely to engage in post-acquisition target governance activities than are remote block acquirers. Moreover, the targets of these acquirers realize higher announcement returns and better post-acquisition operating performance than do targets of other types of acquirers, particularly when they face greater information asymmetries.
The conversion of light into usable chemical and mechanical energy is pivotal to several biological and chemical processes, many of which occur in solution. To understand the structure–function ...relationships mediating these processes, a technique with high spatial and temporal resolutions is required. Here, we report on the design and commissioning of a liquid-phase mega-electron-volt (MeV) ultrafast electron diffraction instrument for the study of structural dynamics in solution. Limitations posed by the shallow penetration depth of electrons and the resulting information loss due to multiple scattering and the technical challenge of delivering liquids to vacuum were overcome through the use of MeV electrons and a gas-accelerated thin liquid sheet jet. To demonstrate the capabilities of this instrument, the structure of water and its network were resolved up to the
3
rd hydration shell with a spatial resolution of 0.6 Å; preliminary time-resolved experiments demonstrated a temporal resolution of 200 fs.
Recently, there have been reports in the literature on sulfonated carbon catalysts prepared from sugars exhibiting interesting acid catalytic properties. However, to date, little has been reported ...about their activation/deactivation characteristics. For this paper, the activation/deactivation behaviors of such sulfonated carbon catalysts were investigated through the esterification of free fatty acids (acetic acid and caprylic acid) and transesterification of triglycerides (triacetin, tricaprylin and soybean oil) with methanol. The catalytic properties of the sulfonated catalysts were compared with those of Nafion
® SAC-13 and sulfuric acid, other similar Brønsted acid catalysts. For the liquid-phase esterification of acetic acid and transesterification of triacetin with methanol, the sulfonated carbon catalysts exhibited catalytic site activities comparable to those for sulfuric acid, along with higher (by weight) specific catalytic activities but lower initial TOFs compared with Nafion
® SAC-13. Catalyst swelling was critical for catalytic activity of the sulfonated carbon catalysts. Poor swelling in the gas phase of the catalysts led to the appearance of an induction period and inferior catalytic performance in the gas-phase esterification of acetic acid. In the liquid-phase esterification of acetic acid, catalytic activity decreased during the initial reaction batch cycles but reached a plateau after several catalytic cycles at 60 °C. Elemental analysis,
1H NMR results of the liquid reaction mixtures after reaction, and the decreased activity of the catalysts after extensive solvent washing suggest that the initial catalyst deactivation was caused by the leaching of polycyclic aromatic hydrocarbons containing
SO
3H groups. Cycling experiments involving large triglycerides actually showed a cumulative effect of slower catalyst swelling in the less-polar reaction mixtures moderated by deactivation of the catalyst due to leaching, resulting in increased activity in the early cycles followed by a loss of activity in later cycles.
Cannabinoids, including the bioactive constituents of the marijuana plant, their synthetic analogs, and endogenous lipids with cannabinoid-like activity, produce their biological effects by ...interacting with specific receptors. To date, two G protein-coupled cannabinoid receptors have been identified by molecular cloning, CB1 receptors mainly expressed in the brain and mediating most of the neurobehavioral effects of cannabinoids and CB2 receptors expressed by immune and hematopoietic tissues. Recent findings indicate that some cannabinoid effects are not mediated by either CB1 or CB2 receptors, and in some cases there is compelling evidence to implicate additional receptors in these actions. These include transient receptor potential vanilloid 1 (TRPV1) receptors and as-yet-unidentified receptors implicated in the endothelium-dependent vasodilator effect of certain cannabinoids and in the presynaptic inhibition of glutamatergic neurotransmission in the hippocampus. The case for these additional receptors is being reviewed here.
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