An approach to generate damage strategies for inter-domain routing systems based on multi-objective optimization.

Inter-domain routing systems are important complex networks on the Internet. It has been paralyzed several times in recent years. The researchers pay close attention to the damage strategy of inter-domain routing systems and think it is related to the attacker's behavior. The key to the damage strategy is knowing how to select the optimal attack node group. In the process of selecting nodes, the existing research seldom considers the attack cost, and there are some problems, such as an unreasonable definition of attack cost and an unclear optimization effect. To solve the above problems, we designed an algorithm to generate damage strategies for inter-domain routing systems based on multi-objective optimization (PMT). We transformed the damage strategy problem into a double-objective optimization problem and defined the attack cost related to the degree of nonlinearity. In PMT, we proposed an initialization strategy based on a network partition and a node replacement strategy based on partition search. Compared with the existing five algorithms, the experimental results proved the effectiveness and accuracy of PMT.

Sampsonione F suppresses adipogenesis via activating p53 pathway during the mitotic clonal expansion progression of adipocyte differentiation.

The abnormal proliferation and hypertrophy of adipocytes mediate the expansion of adipose tissue and then cause obesity-related diseases. Theoretically, an approach for preventing and curing obesity is to inhibit cell proliferation during the mitotic clonal expansion (MCE) progression of adipocyte differentiation. Polycyclic polyprenylated acylphloroglucinols (PPAPs) are mainly found from Hypericum and Garcinia genus, which have been reported to have various biological activities such as anti-depressant, anti-oxidant, and anti-tumor. Previously, our group has reported that adamantane-type PPAPs exhibited blunting activity in adipogenesis. In this study, another six adamantane PPAPs were screened to investigate their anti-adipogenesis activities and then discussed the structure-activity relationship. Particularly, sampsonione F, one of the PPAPs dramatically suppressed adipogenesis dose-dependently in vitro, along with decreased expressions of C/EBPß, C/EBPα, PPARγ, FABP4, and FAS. Moreover, sampsonione F upregulated the expression of p27 by activating p53 pathway and then downregulated the expressions of key regulators during G1/S phase arrest. Our data support that sampsonione F suppressed adipogenesis by activating p53 pathway, regulating cyclins, and resulting in G1/S phase arrest during the MCE progression of adipogenesis. This work provides a new adamantane-type PPAPs in the regulation of adipogenesis and extends our knowledges on the mechanism of the type PPAPs in regulation of adipogenesis.

Hepatic RACK1 deletion disturbs lipid and glucose homeostasis independently of insulin resistance.

Receptor for activated C kinase 1 (RACK1) is a versatile protein involved in multiple biological processes. In a previous study by Zhao et al., hepatic RACK1 deletion in mice led to an inhibition of autophagy, blocked autophagy-dependent lipolysis, and caused steatosis. Using the same mouse model (RACK1hep-/-), we revealed new roles of RACK1 in maintaining bile acid homeostasis and hepatic glucose uptake, which further affected circulatory lipid and glucose levels. To be specific, even under hepatic steatosis, the plasma lipids were generally reduced in RACK1hep-/- mouse, which was due to the suppression of intestinal lipid absorption. Accordingly, a decrease in total bile acid level was found in RACK1hep-/- livers, gallbladders, and small intestine tissues, and specific decrease of 12-hydroxylated bile acids was detected by liquid chromatography-mass spectrometry. Consistently, reduced expression of CYP8B1 was found. A decrease in hepatic glycogen storage was also observed, which might be due to the inhibited glucose uptake by GLUT2 insufficiency. Interestingly, RACK1-KO-inducing hepatic steatosis did not raise insulin resistance (IR) nor IR-inducing factors like endoplasmic reticulum stress and inflammation. In summary, this study uncovers that hepatic RACK1 might be required in maintaining bile acid homeostasis and glucose uptake in hepatocytes. This study also provides an additional case of hepatic steatosis disassociation with insulin resistance.

Anti-adipogenicadamantane type polycyclic polyprenylated acylphloroglucinols from Hypericum subsessile.

Hypersubones D-H (1-5), five new polycyclic polyprenylated acylphloroglucinols (PPAPs) type metabolites with intriguing adamantane and homo-adamantane skeletons, were characterized from aerial parts of Hypericum subsessile. Compounds 1-2 were elucidated to share an adamantane core with 28,29-expoxide moiety, while 3-5 were homo-adamantane type PPAPs sharing a1,2-dioxepane ring system. Their structures were determined on the basis of comprehensive NMR and MS spectroscopic data.The anti-adipogenesis activities of these isolates were evaluated through employing 3T3-L1 cells as an in vitro system using oil red O staining, and compounds 1, 2 and 5 were able to significant inhibit the adipocyte differentiation, which implied that these compounds possessed anti-adipogenic activity.

Defining and characterizing the critical transition state prior to the type 2 diabetes disease.

BACKGROUND: Type 2 diabetes mellitus (T2DM), with increased risk of serious long-term complications, currently represents 8.3% of the adult population. We hypothesized that a critical transition state prior to the new onset T2DM can be revealed through the longitudinal electronic medical record (EMR) analysis. METHOD: We applied the transition-based network entropy methodology which previously identified a dynamic driver network (DDN) underlying the critical T2DM transition at the tissue molecular biological level. To profile pre-disease phenotypical changes that indicated a critical transition state, a cohort of 7,334 patients was assembled from the Maine State Health Information Exchange (HIE). These patients all had their first confirmative diagnosis of T2DM between January 1, 2013 and June 30, 2013. The cohort's EMRs from the 24 months preceding their date of first T2DM diagnosis were extracted. RESULTS: Analysis of these patients' pre-disease clinical history identified a dynamic driver network (DDN) and an associated critical transition state six months prior to their first confirmative T2DM state. CONCLUSIONS: This 6-month window before the disease state provides an early warning of the impending T2DM, warranting an opportunity to apply proactive interventions to prevent or delay the new onset of T2DM.