This document presents a set of requirements for Traffic Engineering over Multiprotocol Label Switching (MPLS). It identifies the functional capabilities required to implement policies that facilitate efficient and reliable network operations in an MPLS domain. These capabilities can be used to optimize the utilization of network resources and to enhance traffic oriented performance characteristics.
Inflammation and oxidative stress are pathogenic mediators of many diseases, but therapeutic targets remain elusive. In the vasculature, abdominal aortic aneurysm (AAA) formation critically involves inflammaton and matrix degradation. Cyclophilin A (CyPA, encoded by Ppia) is highly expressed in vascular smooth muscle cells (VSMC), is secreted in response to reactive oxygen species (ROS), and promotes inflammation. Using the angiotensin II (AngII)-induced AAA model in Apoe−/− mice, we show that Apoe−/−Ppia−/− mice were completely protected from AngII–induced AAA formation, in contrast to Apoe−/−Ppia+/+ mice. Apoe−/−Ppia−/− mice showed decreased inflammatory cytokine expression, elastic lamina degradation, and aortic expansion. These features were not altered by reconstitution of bone marrow cells from Ppia+/+ mice. Mechanistic studies demonstrated that VSMC-derived intracellular and extracellular CyPA were required for ROS generation and matrix metalloproteinase-2 activation. These data define a novel role for CyPA in AAA formation and suggest CyPA is a new target for cardiovascular therapies.
Meiotic crossovers (COs) are nonrandomly distributed along chromosomes such that two COs seldom occur close together, a phenomenon known as CO interference. We have used genetic and cytological methods to investigate interference mechanisms in budding yeast. Assembly of the synaptonemal complex (SC) initiates at a few sites along each chromosome, triggered by a complex of proteins (including Zip2 and Zip3) called the synapsis initiation complex (SIC). We found that SICs, like COs, display interference, supporting the hypothesis that COs occur at synapsis initiation sites. Unexpectedly, we found that SICs show interference in mutants in which CO interference is abolished; one explanation is that these same mutations eliminate the subset of COs that normally occur at SICs. Since SICs are assembled in advance of SC and they are properly positioned even in the absence of SC formation, these data clearly demonstrate an aspect of interference that is independent of synapsis.
Transgenic Petunia plants with a chsA coding sequence under the control of a 35S promoter sometimes lose endogene and transgene chalcone synthase activity and purple flower pigment through posttranscriptional chsA RNA degradation. In these plants, shorter poly(A)+ and poly(A)- chsA RNAs are found, and a 3' end-specific RNA fragment from the endogene is more resistant to degradation. The termini of this RNA fragment are located in a region of complementarity between the chsA 3' coding region and its 3' untranslated region. Equivalent chsA RNA fragments remain in the white flower tissue of a nontransgenic Petunia variety. We present a model involving cycles of RNA-RNA pairing between complementary sequences followed by endonucleolytic RNA cleavages to describe how RNA degradation is likely to be promoted.
Intrahepatic cholangiocarcinoma (IHCC) is a primary cancer of the liver with a rising incidence and poor prognosis. Preclinical studies of the etiology and treatment of this disease are hampered by the relatively small number of available IHCC cell lines or genetically faithful animal models. Here we report the development of a genetically engineered mouse model of IHCC that incorporates two of the most common mutations in human IHCC, activating mutations of Kras (KrasG12D) and deletion of p53. Tissue-specific activation of KrasG12D alone resulted in the development of invasive IHCC with low penetrance and long latency. Latency was shortened by combining KrasG12D activation with heterozygous or homozygous deletion of p53 (mean survival of 56 weeks versus 19 weeks, respectively), which also resulted in widespread local and distant metastasis. Serial analysis showed that the murine models closely recapitulated the multistage histopathologic progression of the human disease, including the development of stroma-rich tumors and the pre-malignant biliary lesions, intraductal papillary biliary neoplasms (IPBN) and Von Meyenburg complexes (VMC; also known as biliary hamartomas). These findings establish a new genetically and histopathologically faithful model of IHCC and lend experimental support to the hypothesis that IPBN and VMC are precursors to invasive cancers.
Cyclophilin A promotes atherosclerosis in part by inducing reactive oxygen species and promoting endothelial cell apoptosis and macrophage recruitment into lesions.
Background— Oxidative stress, generated by excessive reactive oxygen species, promotes cardiovascular disease. Cyclophilin A (CyPA) is a 20-kDa chaperone protein secreted from vascular smooth muscle cells (VSMCs) in response to reactive oxygen species that stimulates VSMC proliferation and inflammatory cell migration in vitro; however, the role CyPA plays in vascular function in vivo remains unknown. Methods and Results— We tested the hypothesis that CyPA contributes to vascular remodeling by analyzing the response to complete carotid ligation in CyPA knockout mice, wild-type mice, and mice that overexpress CyPA in VSMC (VSMC-Tg). After carotid ligation, CyPA expression in vessels of wild-type mice increased dramatically and was significantly greater in VSMC-Tg mice. Reactive oxygen species–induced secretion of CyPA from mouse VSMCs correlated significantly with intracellular CyPA expression. Intimal and medial hyperplasia correlated significantly with CyPA expression after 2 weeks of carotid ligation, with marked decreases in CyPA knockout mice and increases in VSMC-Tg mice. Inflammatory cell migration into the intima was significantly reduced in CyPA knockout mice and increased in VSMC-Tg mice. Additionally, VSMC proliferation assessed by Ki67 + cells was significantly less in CyPA knockout mice and was increased in VSMC-Tg mice. The importance of CyPA for intimal and medial thickening was shown by strong correlations between CyPA expression and the number of both inflammatory cells and proliferating VSMCs in vivo and in vitro. Conclusions— In response to low flow, CyPA plays a crucial role in VSMC migration and proliferation, as well as inflammatory cell accumulation, thereby regulating flow-mediated vascular remodeling and intima formation.
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