Defective autophagy leads to cancer

AbstractCellular proteins are degraded within two distinct compartments: the proteasome and the lysosome. Alterations in proteasomal degradation can contribute to carcinogenesis. In contrast, alterations in autophagic protein degradation through the lysosome have not been linked to cancer. Now two reports demonstrate that the autophagic gene, Beclin 1, is a haploinsufficient tumor suppressor gene. These new data suggest that autophagic degradation provides an important mechanism to prevent cellular transformation

RAG knockouts deliver a one/two punch

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30119/1/0000495.pd

HIF and c-Myc: Sibling Rivals for Control of Cancer Cell Metabolism and Proliferation

O2 deprivation (hypoxia) and cellular proliferation engage opposite cellular pathways, yet often coexist during tumor growth. The ability of cells to grow during hypoxia results in part from crosstalk between hypoxia-inducible factors (HIFs) and the proto-oncogene c-Myc. Acting alone, HIF and c-Myc partially regulate complex adaptations undertaken by tumor cells growing in low O2. However, acting in concert these transcription factors reprogram metabolism, protein synthesis, and cell cycle progression, to “fine tune” adaptive responses to hypoxic environments

The Pim kinases control rapamycin-resistant T cell survival and activation

Although Pim-1 or Pim-2 can contribute to lymphoid transformation when overexpressed, the physiologic role of these kinases in the immune response is uncertain. We now report that T cells from Pim-1−/−Pim-2−/− animals display an unexpected sensitivity to the immunosuppressant rapamycin. Cytokine-induced Pim-1 and Pim-2 promote the rapamycin-resistant survival of lymphocytes. The endogenous function of the Pim kinases was not restricted to the regulation of cell survival. Like the rapamycin target TOR, the Pim kinases also contribute to the regulation of lymphocyte growth and proliferation. Although rapamycin has a minimal effect on wild-type T cell expansion in vitro and in vivo, it completely suppresses the response of Pim-1−/−Pim-2−/− cells. Thus, endogenous levels of the Pim kinases are required for T cells to mount an immune response in the presence of rapamycin. The existence of a rapamycin-insensitive pathway that regulates T cell growth and survival has important implications for understanding how rapamycin functions as an immunomodulatory drug and for the development of complementary immunotherapeutics

The Implementation of Maximum Likelihood Estimation in Space Launch System Vehicle Design

The Space Launch System uses a Maximum Likelihood Estimation process in conjunction with Design of Experiments to develop statistically representative vehicles for the Block 1 configuration. These vehicles are then used to estimate maximum load conditions for simulating stressing cases in other simulations. This paper discusses the modeling process and how SLS captures manufacturing uncertainty in the launch vehicle design. It also provides an overview of the differences between Block 1 statistical representations. This paper also discusses proper grid choice as well as which uncertainties drive the vehicle design

The Implementation of Maximum Likelihood Estimation in Space Launch System Vehicle Design

As NASAs Space Launch System (SLS) approaches first launch, the design has matured to a point where the manufacturing uncertainty has decreased now that many of the components of the launch vehicle have been manufactured and the flight engines have been successfully tested. Prior to this point, a method was required to qualify and capture the impact of the differences between simulation and reality, as well as any uncertainties in the SLS design. Two primary categories of uncertainty arise during the launch vehicle design process. The first represents flight-day uncertainties including dispersions due to winds and temperatures. These are typically examined by performing a Monte Carlo on 6 Degree of Freedom (6-DOF) simulations. The second category of uncertainties represents any manufacturing variations that are present at the individual component level of the launch vehicle design. These variations are constructed using statistical masses and tend to become better understood and refined as the design cycle matures, finally resulting in the launch vehicle as constructed and tested

Critical function of endogenous XIAP in regulating caspase activation during sympathetic neuronal apoptosis

In sympathetic neurons, unlike most nonneuronal cells, growth factor withdrawal–induced apoptosis requires the development of competence in addition to cytochrome c release to activate caspases. Thus, although most nonneuronal cells die rapidly with cytosolic cytochrome c alone, sympathetic neurons are remarkably resistant unless they develop competence. We have identified endogenous X-linked inhibitor of apoptosis protein (XIAP) as the essential postcytochrome c regulator of caspase activation in these neurons. In contrast to wild-type neurons that are resistant to injection of cytochrome c, XIAP-deficient neurons died rapidly with cytosolic cytochrome c alone. Surprisingly, the release of endogenous Smac was not sufficient to overcome the XIAP resistance in sympathetic neurons. In contrast, the neuronal competence pathway permitted cytochrome c to activate caspases by inducing a marked reduction in XIAP levels in these neurons. Thus, the removal of XIAP inhibition appears both necessary and sufficient for cytochrome c to activate caspases in sympathetic neurons. These data identify a critical function of endogenous XIAP in regulating apoptosis in mammalian cells

IMP Dehydrogenase Inhibitors as Immunomodulators

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74880/1/j.1749-6632.1993.tb35869.x.pd

Large Torque Variations in Two Soft Gamma Repeaters

We have monitored the pulse frequencies of the two soft gamma repeaters SGR 1806-20 and SGR 1900+14 through the beginning of year 2001 using primarily Rossi X-ray Timing Explorer Proportional Counter Array observations. In both sources, we observe large changes in the spin-down torque up to a factor of ~4, which persist for several months. Using long baseline phase-connected timing solutions as well as the overall frequency histories, we construct torque noise power spectra for each SGR. The power spectrum of each source is very red (power-law slope ~-3.5). The torque noise power levels are consistent with some accreting systems on time scales of ~1 year, yet the full power spectrum is much steeper in frequency than any known accreting source. To the best of our knowledge, torque noise power spectra with a comparably steep frequency dependence have only been seen in young, glitching radio pulsars (e.g. Vela). The observed changes in spin-down rate do not correlate with burst activity, therefore, the physical mechanisms behind each phenomenon are also likely unrelated. Within the context of the magnetar model, seismic activity cannot account for both the bursts and the long-term torque changes unless the seismically active regions are decoupled from one another.Comment: 26 pages, 11 figures included, accepted for publication in ApJ, analysis of torque noise power density spectra is revised from previous version and minor text changes were mad