Research of Risk Identify of Accounts Receivable Financing Based on System Dynamics

Based on the analysis of operational mechanism and risk causes, this paper analyzes the financing risk, supply chain operation risk, financing operation risk, legal risk, macro system risk and market risk in six dimensions of SME accounts receivable financing in supply chain. This paper systematically studies the risk characteristics of SME accounts receivable financing, and build SD model of SME accounts receivable financing through the VENSIM simulation software to carry out risk identification, it could identify the risk dimension and risk boundary effectively , and it could dynamic identify the incentive of financing risk through feedback loops analysis of financing process, provides technical support for the further risk measurement and risk prevention of SME accounts receivable financing in supply chain

Repo-Man Controls a Protein Phosphatase 1-Dependent Threshold for DNA Damage Checkpoint Activation

SummaryBackgroundIn response to DNA damage, cells activate checkpoints to halt cell-cycle progression and prevent genomic instability. Checkpoint activation induced by DNA double-strand breaks (DSB) is dependent on the ATM kinase, a master regulator of the DNA damage response (DDR) that is activated through autophosphorylation and monomerization.ResultsHere we show that either protein phosphatase 1 or 2A is sufficient to suppress activation of the DDR and that simultaneous inhibition of both phosphatases fully activates the response. PP1-dependent DDR regulation is mediated by its chromatin-targeting subunit, Repo-Man. Studies in Xenopus egg extracts demonstrate that Repo-Man interacts with ATM and PP1 through distinct domains, leading to PP1-dependent regulation of ATM phosphorylation and activation. Consequently, the level of Repo-Man determines the activation threshold of the DNA damage checkpoint. Repo-Man interacts and extensively colocalizes with ATM in human cells. Expression of wild-type, but not PP1 binding-deficient, Repo-Man attenuates DNA damage-induced ATM activation. Moreover, Repo-Man dissociates from active ATM at DNA damage sites, suggesting that activation of the DDR involves removal of inhibitory regulators. Analysis of primary tumor tissues and cell lines demonstrates that Repo-Man is frequently upregulated in many types of cancers. Elevated Repo-Man expression blunts DDR activation in precancerous cells, whereas knockdown of Repo-Man in malignant cancer cells resensitizes the DDR and restrains growth in soft agar.ConclusionsWe report essential DDR regulation mediated by Repo-Man-PP1 and further delineate underlying mechanisms. Moreover, our evidence suggests that elevated Repo-Man contributes to cancer progression

Adiponectin as a key player in inflammation

Chronic inflammation has recently been proposed to be a key mediator linking obesity to a cluster of cardiometabolic disorders. Obese adipose tissue, infiltrated with activated macrophages and mast cells, is an important source of systemic inflammation, by secreting dozens of the pro-inflammatory adipokines into the blood stream. One the other hand, adiponectin, an abundant adipokine secreted predominantly from adipocytes, is markedly decreased in obesity and associated inflammatory diseases. Adiponectin exerts its anti-inflammatory actions in several target cells by inhibiting the production and activities of tumor necrosis factor-alpha, preventing the activation of nuclear factor-kappa B, and inducing expression of anti-inflammatory cytokines. In animal models, adiponectin treatment alleviates several obesity-associated inflammatory diseases, such as atherosclerosis, nonalcoholic steatohepatitis, asthma and acute myocardial infarction. In humans, circulating levels of adiponectin are inversely correlated with several well-established markers of inflammation, including C-reactive protein and interleukin-6. Furthermore, anti-inflammatory drugs, such as peroxisome proliferator-activated receptor-gamma agonists, can elevate plasma levels of adiponectin. While the majority of clinical and animal data support the role of adiponectin as an anti-inflammatory, anti-atheroscerotic and anti-diabetic adipokine, a number of recent studies have reported its pro-inflammatory actions in certain conditions. Here, we summarize the pathophysiological roles of adiponectin in inflammation-related disorders, and discuss the potential mechanisms involved, also their implications in adiponectin-targeted pharmacotherapy.Biomedical Reviews 2006, 17: 11-22

Development and Validation of a Liquid Chromatography-Tandem Mass Spectrometry Method for the Determination of Temozolomide in Mouse Brain Tissue

Temozolomide is a Food and Drug Administration-approved anticancer drug that has poor drug delivery via oral or intravenous routes. A potential strategy to combat this problem is investigating alternative routes of administration, requiring quantitation of the drug in the brain tissues by liquid chromatography-mass spectrometry. However, current methods used to extract the drug from brain tissues resulted in poor recovery and substantial matrix effects. Herein, we reported a new two-step extraction method that involves the use of Proteinase K to lyse tumor tissues to efficiently release the drug, followed by ethanol protein precipitation. The extracts were then separated on a C18 column and analyzed in positive electrospray ionization, a multiple reaction monitoring mode of the triple quadrupole. We found this new method led to a recovery of 82% with negligible matrix effects. The method has been validated in accordance with Food and Drug Administration guidance for linearity, specificity, selectivity, accuracy, precision, carry-over, stability, and lower limit of quantitation. In conclusion, we have developed and validated a liquid chromatography-mass spectrometry method with a novel sample preparation method that was able to efficiently extract temozolomide from mouse brain tissue with high recovery

Tryptophan-mediated charge-resonance stabilization in the bis-Fe(IV) redox state of MauG

The diheme enzyme MauG catalyzes posttranslational modifications of a methylamine dehydrogenase precursor protein to generate a tryptophan tryptophylquinone cofactor. The MauG-catalyzed reaction proceeds via a bis-Fe(IV) intermediate in which one heme is present as Fe(IV)=O and the other as Fe(IV) with axial histidine and tyrosine ligation. Herein, a unique near-infrared absorption feature exhibited specifically in bis-Fe(IV) MauG is described, and evidence is presented that it results from a charge-resonance-transition phenomenon. As the two hemes are physically separated by 14.5 angstrom, a hole-hopping mechanism is proposed in which a tryptophan residue located between the hemes is reversibly oxidized and reduced to increase the effective electronic coupling element and enhance the rate of reversible electron transfer between the hemes in bis-Fe(IV) MauG. Analysis of the MauG structure reveals that electron transfer via this mechanism is rapid enough to enable a charge-resonance stabilization of the bis-Fe(IV) state without direct contact between the hemes. The finding of the charge-resonance-transition phenomenon explains why the bis-Fe(IV) intermediate is stabilized in MauG and does not permanently oxidize its own aromatic residues

Role of 2-5A-Dependent RNase-L in Senescence and Longevity

Senescence is a permanent growth arrest that restricts the lifespan of primary cells in culture, and represents an in vitro model for aging. Senescence functions as a tumor suppressor mechanism that can be induced independent of replicative crisis by diverse stress stimuli. RNase-L mediates antiproliferative activities and functions as a tumor suppressor in prostate cancer, therefore, we examined a role for RNase-L in cellular senescence and aging. Ectopic expression of RNase-L induced a senescent morphology, a decrease in DNA synthesis, an increase in senescence-associated -galactosidase activity, and accelerated replicative senescence. In contrast, senescence was retarded in RNase-L-null fibroblasts compared with wild-type fibroblasts. Activation of endogenous RNase-L by 2-5A transfection induced distinct senescent and apoptotic responses in parental and Simian virus 40-transformed WI38 fibroblasts, respectively, demonstrating cell type specific differences in the antiproliferative response to RNase-L activation. Replicative senescence is a model for in vivo aging; therefore, genetic disruption of senescence effectors may impact lifespan. RNase-L-/- mice survived 31.7% (P\u3c0.0001) longer than strain-matched RNase-L+/+ mice providing evidence for a physiological role for RNase-L in aging. These findings identify a novel role for RNase-L in senescence that may contribute to its tumor suppressive function and to the enhanced longevity of RNase-L-/- mice

Role of 2-5A-Dependent RNase-L in Senescence and Longevity

Senescence is a permanent growth arrest that restricts the lifespan of primary cells in culture, and represents an in vitro model for aging. Senescence functions as a tumor suppressor mechanism that can be induced independent of replicative crisis by diverse stress stimuli. RNase-L mediates antiproliferative activities and functions as a tumor suppressor in prostate cancer, therefore, we examined a role for RNase-L in cellular senescence and aging. Ectopic expression of RNase-L induced a senescent morphology, a decrease in DNA synthesis, an increase in senescence-associated -galactosidase activity, and accelerated replicative senescence. In contrast, senescence was retarded in RNase-L-null fibroblasts compared with wild-type fibroblasts. Activation of endogenous RNase-L by 2-5A transfection induced distinct senescent and apoptotic responses in parental and Simian virus 40-transformed WI38 fibroblasts, respectively, demonstrating cell type specific differences in the antiproliferative response to RNase-L activation. Replicative senescence is a model for in vivo aging; therefore, genetic disruption of senescence effectors may impact lifespan. RNase-L-/- mice survived 31.7% (P\u3c0.0001) longer than strain-matched RNase-L+/+ mice providing evidence for a physiological role for RNase-L in aging. These findings identify a novel role for RNase-L in senescence that may contribute to its tumor suppressive function and to the enhanced longevity of RNase-L-/- mice

Diradical intermediate within the context of tryptophan tryptophylquinone biosynthesis

Despite the importance of tryptophan (Trp) radicals in biology, very few radicals have been trapped and characterized in a physiologically meaningful context. Here we demonstrate that the diheme enzyme MauG uses Trp radical chemistry to catalyze formation of a Trp-derived tryptophan tryptophylquinone cofactor on its substrate protein, premethylamine dehydrogenase. The unusual six-electron oxidation that results in tryptophan tryptophylquinone formation occurs in three discrete two-electron catalytic steps. Here the exact order of these oxidation steps in the processive six-electron biosynthetic reaction is determined, and reaction intermediates are structurally characterized. The intermediates observed in crystal structures are also verified in solution using mass spectrometry. Furthermore, an unprecedented Trp-derived diradical species on premethylamine dehydrogenase, which is an intermediate in the first two-electron step, is characterized using high-frequency and -field electron paramagnetic resonance spectroscopy and UV-visible absorbance spectroscopy. This work defines a unique mechanism for radical-mediated catalysis of a protein substrate, and has broad implications in the areas of applied biocatalysis and understanding of oxidative protein modification during oxidative stress