Human platelets repurposed as vehicles for in vivo imaging of myeloma xenotransplants.

Human platelets were identified in tumors by Trousseau in 1865, although their roles in tumor microenvironments have only recently attracted the attention of cancer researchers. In this study we exploit and enhance platelet interactions in tumor microenvironments by introducing tumor-targeting and imaging functions. The first step in repurposing human platelets as vehicles for tumor-targeting was to inhibit platelet-aggregation by cytoplasmic-loading of kabiramide (KabC), a potent inhibitor of actin polymerization and membrane protrusion. KabC-Platelets can accumulate high levels of other membrane-permeable cytoxins and probes, including epidoxorubicin, carboxyfluorescein di-ester and chlorin-e6. Finally, mild reaction conditions were developed to couple tumor-targeting proteins and antibodies to KabC-platelets. Fluorescence microscopy studies showed KabC-platelets, surface-coupled with transferrin and Cy5, bind specifically to RPMI8226 and K562 cells, both of which over-express the transferrin receptor. Repurposed platelets circulate for upto 9-days a feature that increases their chance of interacting with target cells. KabC-platelets, surface-coupled with transferrin and Cy7, or chlorin-e6, and injected in immuno-compromised mice were shown to accumulate specifically in sub-cutaneous and intra-cranial myeloma xenotransplants. The high-contrast, in vivo fluorescence images recorded from repurposed platelets within early-stage myeloma is a consequence in part of their large size (φ~2µm), which allows them to transport 100 to 1000-times more targeting-protein and probe molecules respectively. Human platelets can be configured with a plurality of therapeutic and targeting antibodies to help stage tumor environments for an immunotherapy, or with combinations of therapeutic antibodies and therapeutic agents to target and treat cardiovascular and neurologic diseases

Individual IKs channels at the surface of mammalian cells contain two KCNE1 accessory subunits.

KCNE1 (E1) β-subunits assemble with KCNQ1 (Q1) voltage-gated K(+) channel α-subunits to form IKslow (IKs) channels in the heart and ear. The number of E1 subunits in IKs channels has been an issue of ongoing debate. Here, we use single-molecule spectroscopy to demonstrate that surface IKs channels with human subunits contain two E1 and four Q1 subunits. This stoichiometry does not vary. Thus, IKs channels in cells with elevated levels of E1 carry no more than two E1 subunits. Cells with low levels of E1 produce IKs channels with two E1 subunits and Q1 channels with no E1 subunits--channels with one E1 do not appear to form or are restricted from surface expression. The plethora of models of cardiac function, transgenic animals, and drug screens based on variable E1 stoichiometry do not reflect physiology

Charged multiplicity density and number of participant nucleons in relativistic nuclear collisions

The energy and centrality dependences of charged particle pseudorapidity density in relativistic nuclear collisions were studied using a hadron and string cascade model, JPCIAE. Both the relativistic $p+\bar p$ experimental data and the PHOBOS and PHENIX $Au+Au$ data at RHIC energy could be fairly reproduced within the framework of JPCIAE model and without retuning the model parameters. The predictions for $Pb+Pb$ collisions at the LHC energy were also given. We computed the participant nucleon distributions using different methods. It was found that the number of participant nucleons is not a well defined variable both experimentally and theoretically. Thus it may be inappropriate to use the charged particle pseudorapidity density per participant pair as a function of the number of participant nucleons for distinguishing various theoretical models. A discussion for the effect of different definitions in nuclear radius (diffused or sharp) was given.Comment: 15 pages, 7 figure

Hypoxia Produces Pro-arrhythmic Late Sodium Current in Cardiac Myocytes by SUMOylation of NaV1.5 Channels.

Acute cardiac hypoxia produces life-threatening elevations in late sodium current (ILATE) in the human heart. Here, we show the underlying mechanism: hypoxia induces rapid SUMOylation of NaV1.5 channels so they reopen when normally inactive, late in the action potential. NaV1.5 is SUMOylated only on lysine 442, and the mutation of that residue, or application of a deSUMOylating enzyme, prevents hypoxic reopenings. The time course of SUMOylation of single channels in response to hypoxia coincides with the increase in ILATE, a reaction that is complete in under 100 s. In human cardiac myocytes derived from pluripotent stem cells, hypoxia-induced ILATE is confirmed to be SUMO-dependent and to produce action potential prolongation, the pro-arrhythmic change observed in patients

Heavy surface state in a possible topological Kondo insulator: Magneto-thermoelectric transport on the (011)-plane of SmB6_6

Motivated by the high sensitivity to Fermi surface topology and scattering mechanisms in magneto-thermoelectric transport, we have measured the thermopower and Nernst effect on the (011)-plane of the proposed topological Kondo insulator SmB$_6$. These experiments, together with electrical resistivity and Hall effect measurements, demonstrate that the (011)-plane also harbors a metallic surface with the effective mass in the order of 10-10$^2$ $m_0$. The surface and bulk conductances are well distinguished in these measurements and are categorized into metallic and non-degenerate semiconducting regimes, respectively. Electronic correlations play an important role in enhancing scattering and also contribute to the heavy surface state.Comment: 4 figures, 1 tabl

Net charge fluctuation and string fragmentation

We present simulation results of net charge fluctuation in $Au+Au$ collisions at $\sqrt{s_{nn}}$=130 GeV from a dynamic model, JPCIAE. The calculations are done for the quark-gluon phase before hadronization, the pion gas, the resonance pion gas from $\rho$ and $\omega$ decays and so on. The simulations of the charge fluctuation show that the discrepancy exists between the dynamic model and the thermal model for a pion gas and a resonance pion gas from $\rho$ and $\omega$ decays while the simulated charge fluctuation of the quark-gluon phase is close to the thermal model prediction. JPCIAE results of net charge fluctuation in the hardonic phase are nearly 4-5 times larger than one for the quark-gluon phase, which implies that the charge fluctuation in the quark-gluon phase may not survive the hadronization (string fragmentation) as implemented in JPCIAE.Comment: 9 pages, 3 figure