Hamster-to-rat heart and liver xenotransplantation with FK506 plus antiproliferative drugs

Heterotopic hamster hearts transplanted to unmodified LEW rats underwent humoral rejection in 3 days. Survival was prolonged to a median of 4 days with 2 mg/kg/day FK506. As monotherapy, 15 mg/kg/day cyclophosphamide greatly prolonged graft survival-far more than could be accomplished with RS-61443, brequinar (BQR), mizoribine, methotrexate, or deoxyspergualin. However, when FK506 treatment, which was ineffective alone, was combined with a short induction course (14 or 30 days) of subtherapeutic BQR, RS-61443, or cyclophosphamide, routine survival of heart xenografts was possible for as long as the daily FK506 was continued. In addition, a single large dose of 80 mg/kg cyclophosphamide 10 days preoperatively allowed routine cardiac xenograft survival under FK506. The ability of these antimetabolites to unmask the therapeutic potential of FK506 correlated, although imperfectly, with the prevention of rises of preformed heterospecific cytotoxic antibodies immediately postoperatively. As an adjunct to FK506, azathioprine was of marginal value, whereas mizoribine, methotrexate, and deoxyspergualin (DSPG) were of intermediate efficacy. After orthotopic hepatic xenotransplantation, the perioperative survival of the liver with its well-known resistance to antibodies was less dependent than the heart on the antimetabolite component of the combined drug therapy, but the unsatisfactory results with monotherapy of FK506, BQR, RS-61443, or cyclophosphamide were changed to routine success by combining continuous FK506 with a short course of any of the other drugs. Thus, by breaking down the antibody barrier to xenotransplantation with these so-called antiproliferative drugs, it has been possible with FK506 to transplant heart and liver xenografts with consistent long-term survival of healthy recipients

Self-modulation of nonlinear waves in a weakly magnetized relativistic electron-positron plasma with temperature

We develop a nonlinear theory for self-modulation of a circularly polarized electromagnetic wave in a relativistic hot weakly magnetized electron-positron plasma. The case of parallel propagation along an ambient magnetic field is considered. A nonlinear Schrodinger equation is derived for the complex wave amplitude of a self-modulated wave packet. We show that the maximum growth rate of the modulational instability decreases as the temperature of the pair plasma increases. Depending on the initial conditions, the unstable wave envelope can evolve nonlinearly to either periodic wave trains or solitary waves. This theory has application to high-energy astrophysics and high-power laser physics.CONICyTFONDECyT 1110135 1080658Brazilian agency CNPqBrazilian agency FAPESPMarie Curie International Incoming Fellowshiphospitality of Paris ObservatoryInstitute for Fusion Studie

Self-modulation of nonlinear Alfven waves in a strongly magnetized relativistic electron-positron plasma

We study the self-modulation of a circularly polarized Alfven wave in a strongly magnetized relativistic electron-positron plasma with finite temperature. This nonlinear wave corresponds to an exact solution of the equations, with a dispersion relation that has two branches. For a large magnetic field, the Alfven branch has two different zones, which we call the normal dispersion zone (where d omega/dk > 0) and the anomalous dispersion zone (where d omega/dk < 0). A nonlinear Schrodinger equation is derived in the normal dispersion zone of the Alfven wave, where the wave envelope can evolve as a periodic wave train or as a solitary wave, depending on the initial condition. The maximum growth rate of the modulational instability decreases as the temperature is increased. We also study the Alfven wave propagation in the anomalous dispersion zone, where a nonlinear wave equation is obtained. However, in this zone the wave envelope can evolve only as a periodic wave train.CONICyT 21100839 74110049FONDECyT 1110135 1110729 1080658 1121144CNPqEuropean Commission for a Marie Curie International Incoming FellowshipInstitute for Fusion Studie

Curie Temperatures and Emplacement Conditions of Pyroclastic Deposits From Popocatépetl Volcano, Mexico

Most pyroclastic deposits of Popocatépetl volcano were emplaced at high temperatures and have similar mafic to more evolved compositions, suggesting a long-lived, interconnected magma environment. We performed a magnetic and microscopic study on different eruptive sequences <14 ky in age and found that temperature and field dependence of magnetic susceptibility are suited to separate eruption phases. We observed homogeneous titanomagnetite with Curie temperatures (T$_{C}$) of 50–200°C and 200–400°C, together with different amounts of oxy-exsolved titanomagnetite with T$_{C}$ ∼ 570°C. Some block-and-ash flow deposits show remarkably irreversible T$_{C}$ in heating and cooling branches with a positive ΔT$_{C}$ (T$_{C}$ $_{heating}$ –T$_{C}$ $_{cooling}$) of up to 130°C in the center. The central part of this sequence is characterized by decreasing magnetic susceptibility and low field dependence of magnetic susceptibility (<10%), which is atypical for ulvöspinel-rich titanomagnetite. The nonreversibility of heating and cooling runs measured with rates of around 10 K/min is probably related to vacancy-enhanced nanoscale chemical clustering, which seems to occur preferentially during rapid quenching, possibly combined with subtle maghemitization. In contrast, pumice layers have the highest field dependence (∼20%) and contain Ti-rich and intermediate titanomagnetite with T$_{C}$ < 100 and ∼300°C, which are in line with mafic and more evolved magma composition. In intermediate phases, irreversibility of T$_{C}$ is more common but with a relatively low ΔT$_{C}$ of ±20°C. We suggest that magneto-mineralogy in pyroclastic density currents is complex but offers a complementary tool to the paleomagnetic directional analysis for emplacement temperature and contribute information on the volcanic material history and their emplacement conditions

STING-dependent recognition of cyclic di-AMP mediates type I interferon responses during Chlamydia trachomatis infection.

UnlabelledSTING (stimulator of interferon [IFN] genes) initiates type I IFN responses in mammalian cells through the detection of microbial nucleic acids. The membrane-bound obligate intracellular bacterium Chlamydia trachomatis induces a STING-dependent type I IFN response in infected cells, yet the IFN-inducing ligand remains unknown. In this report, we provide evidence that Chlamydia synthesizes cyclic di-AMP (c-di-AMP), a nucleic acid metabolite not previously identified in Gram-negative bacteria, and that this metabolite is a prominent ligand for STING-mediated activation of IFN responses during infection. We used primary mouse lung fibroblasts and HEK293T cells to compare IFN-β responses to Chlamydia infection, c-di-AMP, and other type I IFN-inducing stimuli. Chlamydia infection and c-di-AMP treatment induced type I IFN responses in cells expressing STING but not in cells expressing STING variants that cannot sense cyclic dinucleotides but still respond to cytoplasmic DNA. The failure to induce a type I IFN response to Chlamydia and c-di-AMP correlated with the inability of STING to relocalize from the endoplasmic reticulum to cytoplasmic punctate signaling complexes required for IFN activation. We conclude that Chlamydia induces STING-mediated IFN responses through the detection of c-di-AMP in the host cell cytosol and propose that c-di-AMP is the ligand predominantly responsible for inducing such a response in Chlamydia-infected cells.ImportanceThis study shows that the Gram-negative obligate pathogen Chlamydia trachomatis, a major cause of pelvic inflammatory disease and infertility, synthesizes cyclic di-AMP (c-di-AMP), a nucleic acid metabolite that thus far has been described only in Gram-positive bacteria. We further provide evidence that the host cell employs an endoplasmic reticulum (ER)-localized cytoplasmic sensor, STING (stimulator of interferon [IFN] genes), to detect c-di-AMP synthesized by Chlamydia and induce a protective IFN response. This detection occurs even though Chlamydia is confined to a membrane-bound vacuole. This raises the possibility that the ER, an organelle that innervates the entire cytoplasm, is equipped with pattern recognition receptors that can directly survey membrane-bound pathogen-containing vacuoles for leaking microbe-specific metabolites to mount type I IFN responses required to control microbial infections

The Chlamydia trachomatis Type III Secretion Chaperone Slc1 Engages Multiple Early Effectors, Including TepP, a Tyrosine-phosphorylated Protein Required for the Recruitment of CrkI-II to Nascent Inclusions and Innate Immune Signaling

Chlamydia trachomatis, the causative agent of trachoma and sexually transmitted infections, employs a type III secretion (T3S) system to deliver effector proteins into host epithelial cells to establish a replicative vacuole. Aside from the phosphoprotein TARP, a Chlamydia effector that promotes actin re-arrangements, very few factors mediating bacterial entry and early inclusion establishment have been characterized. Like many T3S effectors, TARP requires a chaperone (Slc1) for efficient translocation into host cells. In this study, we defined proteins that associate with Slc1 in invasive C. trachomatis elementary bodies (EB) by immunoprecipitation coupled with mass spectrometry. We identified Ct875, a new Slc1 client protein and T3S effector, which we renamed TepP (Translocated early phosphoprotein). We provide evidence that T3S effectors form large molecular weight complexes with Scl1 in vitro and that Slc1 enhances their T3S-dependent secretion in a heterologous Yersinia T3S system. We demonstrate that TepP is translocated early during bacterial entry into epithelial cells and is phosphorylated at tyrosine residues by host kinases. However, TepP phosphorylation occurs later than TARP, which together with the finding that Slc1 preferentially engages TARP in EBs leads us to postulate that these effectors are translocated into the host cell at different stages during C.trachomatis invasion. TepP co-immunoprecipitated with the scaffolding proteins CrkI-II during infection and Crk was recruited to EBs at entry sites where it remained associated with nascent inclusions. Importantly, C. trachomatis mutants lacking TepP failed to recruit CrkI-II to inclusions, providing genetic confirmation of a direct role for this effector in the recruitment of a host factor. Finally, endocervical epithelial cells infected with a tepP mutant showed altered expression of a subset of genes associated with innate immune responses. We propose a model wherein TepP acts downstream of TARP to recruit scaffolding proteins at entry sites to initiate and amplify signaling cascades important for the regulation of innate immune responses to Chlamydia.Fil: Chen, Yi-Shan. University of Duke; Estados UnidosFil: Bastidas, Robert J.. University of Duke; Estados UnidosFil: Saka, Hector Alex. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. University of Duke; Estados UnidosFil: Carpenter, Victoria K.. Duke University Medical Center; . University of Duke; Estados UnidosFil: Richards, Kristian L.. Miami University; Estados UnidosFil: Plano, Gregory V.. Miami University; Estados UnidosFil: Valdivia, Raphael H.. University of Duke; Estados Unido

Stability of axially symmetric magnetic fields in stars

The magnetic fields observed in Ap-stars, white dwarfs, and neutron stars are known to be stable for long times. However, the physical conditions inside the stellar interiors that allow these states are still a matter of research. It has been formally demonstrated that both purely toroidal and purely poloidal magnetic fields develop instabilities at some point in the star. On the other hand, numerical simulations have proved the stability of roughly axisymmetric magnetic field configurations inside stably stratified stars. These configurations consist of mutually stabilizing toroidal and poloidal components in a twisted torus shape. Previous studies have proposed rough upper and lower bounds on the ratio of the magnetic energy in the toroidal and poloidal components of the magnetic field. With the purpose of mapping out the parameter space under which such configurations remain stable, we used the Pencil Code to perform 3D magnetohydrodynamic simulations of the evolution of the magnetic field in non-rotating, non-degenerate stars in which viscosity is the only dissipation mechanism, both for stars with a uniform (barotropic) and radially increasing (stably stratified) specific entropy. Furthermore, we considered different conditions regarding the degree of stable stratification and the magnetic energy in each component, roughly confirming the previously suggested stability boundaries for the magnetic field.Comment: 9 pages, 9 figure