The Physics of the B Factories

This work is on the Physics of the B Factories. Part A of this book contains a brief description of the SLAC and KEK B Factories as well as their detectors, BaBar and Belle, and data taking related issues. Part B discusses tools and methods used by the experiments in order to obtain results. The results themselves can be found in Part C

hTID-1 defines a novel regulator of c-Met Receptor signaling in renal cell carcinomas

The c-Met receptor tyrosine kinase (MetR) is frequently overexpressed and constitutively phosphorylated in a number of human malignancies. Activation of the receptor by its ligand, hepatocyte growth factor (HGF), leads to increased cell proliferation, motility, survival and disruption of adherens junctions. In this study, we show that hTid-1, a DNAJ/Hsp40 chaperone, represents a novel modulator of the MetR signaling pathway. hTid-1 is a co-chaperone of the Hsp70 family of proteins, and has been shown to regulate a number of cellular signaling proteins including several involved in tumorigenic and apoptotic pathways. In this study we demonstrate that hTid-1 binds to unphosphorylated MetR and becomes dissociated from the receptor upon HGF stimulation. Overexpression of the short form of hTid-1 (hTid-1S) in 786-0 renal clear cell carcinomas (RCCs) enhances MetR kinase activity leading to an increase in HGF-mediated cell migration with no discernible effect on cell proliferation. By contrast, knockdown of hTid-1 markedly impairs both the onset and amplitude of MetR phosphorylation in response to HGF without altering receptor protein levels. hTid-1-depleted cells display defective migratory properties, coincident with inhibition of ERK/MAP kinase and STAT3 pathways. Taken together, our findings denote hTid-1S as an essential regulatory component of MetR signaling. We propose that the binding of hTid-1S to MetR may stabilize the receptor in a ligand-competent state and this stabilizing function may influence conformational changes that take place during the catalytic cycle that promote kinase activation. Given the prevalence of HGF/MetR pathway activation in human cancers, targeted inhibition of hTid-1 may be a useful therapeutic in the management of MetR-dependent malignancies

Extracellular Administration of BCL2 Protein Reduces Apoptosis and Improves Survival in a Murine Model of Sepsis

Severe sepsis and septic shock are major causes of morbidity and mortality worldwide. In experimental sepsis there is prominent apoptosis of various cell types, and genetic manipulation of death and survival pathways has been shown to modulate organ injury and survival.We investigated the effect of extracellular administration of two anti-apoptotic members of the BCL2 (B-cell lymphoma 2) family of intracellular regulators of cell death in a murine model of sepsis induced by cecal ligation and puncture (CLP). We show that intraperitoneal injection of picomole range doses of recombinant human (rh) BCL2 or rhBCL2A1 protein markedly improved survival as assessed by surrogate markers of death. Treatment with rhBCL2 or rhBCL2A1 protein significantly reduced the number of apoptotic cells in the intestine and heart following CLP, and this was accompanied by increased expression of endogenous mouse BCL2 protein. Further, mice treated with rhBCL2A1 protein showed an increase in the total number of neutrophils in the peritoneum following CLP with reduced neutrophil apoptosis. Finally, although neither BCL2 nor BCL2A1 are a direct TLR2 ligand, TLR2-null mice were not protected by rhBCL2A1 protein, indicating that TLR2 signaling was required for the protective activity of extracellularly adminsitered BCL2A1 protein in vivo.Treatment with rhBCL2A1 or rhBCL2 protein protects mice from sepsis by reducing apoptosis in multiple target tissues, demonstrating an unexpected, potent activity of extracellularly administered BCL2 BH4-domain proteins

Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection

Macrophages display flexible activation states that range between pro-inflammatory (classical activation) and anti-inflammatory (alternative activation). These macrophage polarization states contribute to a variety of organismal phenotypes such as tissue remodeling and susceptibility to infectious and inflammatory diseases. Several macrophage- or immune-related genes have been shown to modulate infectious and inflammatory disease pathogenesis. However, the potential role that differences in macrophage activation phenotypes play in modulating differences in susceptibility to infectious and inflammatory disease is just emerging. We integrated transcriptional profiling and linkage analyses to determine the genetic basis for the differential murine macrophage response to inflammatory stimuli and to infection with the obligate intracellular parasite Toxoplasma gondii. We show that specific transcriptional programs, defined by distinct genomic loci, modulate macrophage activation phenotypes. In addition, we show that the difference between AJ and C57BL/6J macrophages in controlling Toxoplasma growth after stimulation with interferon gamma and tumor necrosis factor alpha mapped to chromosome 3, proximal to the Guanylate binding protein (Gbp) locus that is known to modulate the murine macrophage response to Toxoplasma. Using an shRNA-knockdown strategy, we show that the transcript levels of an RNA helicase, Ddx1, regulates strain differences in the amount of nitric oxide produced by macrophage after stimulation with interferon gamma and tumor necrosis factor. Our results provide a template for discovering candidate genes that modulate macrophage-mediated complex traits