One More Weight is Enough: Toward the Optimal Traffic Engineering with OSPF

Traffic Engineering (TE) leverages information of network traffic to generate a routing scheme optimizing the traffic distribution so as to advance network performance. However, optimize the link weights for OSPF to the offered traffic is an known NP-hard problem. In this paper, motivated by the fairness concept of congestion control, we firstly propose a new generic objective function, where various interests of providers can be extracted with different parameter settings. And then, we model the optimal TE as the utility maximization of multi-commodity flows with the generic objective function and theoretically show that any given set of optimal routes corresponding to a particular objective function can be converted to shortest paths with respect to a set of positive link weights. This can be directly configured on OSPF-based protocols. On these bases, we employ the Network Entropy Maximization(NEM) framework and develop a new OSPF-based routing protocol, SPEF, to realize a flexible way to split traffic over shortest paths in a distributed fashion. Actually, comparing to OSPF, SPEF only needs one more weight for each link and provably achieves optimal TE. Numerical experiments have been done to compare SPEF with the current version of OSPF, showing the effectiveness of SPEF in terms of link utilization and network load distribution

Interferon-β-induced miR-155 inhibits osteoclast differentiation by targeting SOCS1 and MITF

AbstractIFN-β is induced via a c-fos dependent mechanism that is present downstream of the receptor activator of NF-κB ligand (RANKL)-RANK signal transduction cascade during osteoclast differentiation. Increased production of IFN-β in turn inhibits osteoclastogenesis. However, the mechanism by which IFN-β exerts its suppressive function remains unclear. In the present study, we found that miR-155, an IFN-β-induced miRNA, mediated the suppressive effect of IFN-β on osteoclast differentiation by targeting SOCS1 and MITF, two essential regulators of osteoclastogenesis. These findings have not only demonstrated that miR-155 inhibits osteoclast differentiation, but also provided a new therapeutic target for treatment of osteoclast-mediated diseases

Recruitment of Endophilin to Clathrin-Coated Pit Necks Is Required for Efficient Vesicle Uncoating after Fission

SummaryEndophilin is a membrane-binding protein with curvature-generating and -sensing properties that participates in clathrin-dependent endocytosis of synaptic vesicle membranes. Endophilin also binds the GTPase dynamin and the phosphoinositide phosphatase synaptojanin and is thought to coordinate constriction of coated pits with membrane fission (via dynamin) and subsequent uncoating (via synaptojanin). We show that although synaptojanin is recruited by endophilin at bud necks before fission, the knockout of all three mouse endophilins results in the accumulation of clathrin-coated vesicles, but not of clathrin-coated pits, at synapses. The absence of endophilin impairs but does not abolish synaptic transmission and results in perinatal lethality, whereas partial endophilin absence causes severe neurological defects, including epilepsy and neurodegeneration. Our data support a model in which endophilin recruitment to coated pit necks, because of its curvature-sensing properties, primes vesicle buds for subsequent uncoating after membrane fission, without being critically required for the fission reaction itself

Modelling small block aperture in an in-house developed GPU-accelerated Monte Carlo-based dose engine for pencil beam scanning proton therapy

Purpose: To enhance an in-house graphic-processing-unit (GPU) accelerated virtual particle (VP)-based Monte Carlo (MC) proton dose engine (VPMC) to model aperture blocks in both dose calculation and optimization for pencil beam scanning proton therapy (PBSPT)-based stereotactic radiosurgery (SRS). Methods and Materials: A block aperture module was integrated into VPMC. VPMC was validated by an opensource code, MCsquare, in eight water phantom simulations with 3cm thick brass apertures: four were with aperture openings of 1, 2, 3, and 4cm without a range shifter, while the other four were with same aperture opening configurations with a range shifter of 45mm water equivalent thickness. VPMC was benchmarked with MCsquare and RayStation MC for 10 patients with small targets (average volume 8.4 cc). Finally, 3 patients were selected for robust optimization with aperture blocks using VPMC. Results: In the water phantoms, 3D gamma passing rate (2%/2mm/10%) between VPMC and MCsquare were 99.71$\pm$0.23%. In the patient geometries, 3D gamma passing rates (3%/2mm/10%) between VPMC/MCsquare and RayStation MC were 97.79$\pm$2.21%/97.78$\pm$1.97%, respectively. The calculation time was greatly decreased from 112.45$\pm$114.08 seconds (MCsquare) to 8.20$\pm$6.42 seconds (VPMC), both having statistical uncertainties of about 0.5%. The robustly optimized plans met all the dose-volume-constraints (DVCs) for the targets and OARs per our institutional protocols. The mean calculation time for 13 influence matrices in robust optimization by VPMC was 41.6 seconds. Conclusion: VPMC has been successfully enhanced to model aperture blocks in dose calculation and optimization for the PBSPT-based SRS.Comment: 3 tables, 3 figure

Neuronal ablation of GHSR mitigates diet-induced depression and memory impairment via AMPK-autophagy signaling-mediated inflammation

Obesity is associated with chronic inflammation in the central nervous system (CNS), and neuroinflammation has been shown to have detrimental effects on mood and cognition. The growth hormone secretagogue receptor (GHSR), the biologically relevant receptor of the orexigenic hormone ghrelin, is primarily expressed in the brain. Our previous study showed that neuronal GHSR deletion prevents high-fat diet-induced obesity (DIO). Here, we investigated the effect of neuronal GHSR deletion on emotional and cognitive functions in DIO. The neuron-specific GHSR-deficient mice exhibited reduced depression and improved spatial memory compared to littermate controls under DIO. We further examined the cortex and hippocampus, the major regions regulating cognitive and emotional behaviors, and found that the neuronal deletion of GHSR reduced DIO-induced neuroinflammation by suppressing proinflammatory chemokines/cytokines and decreasing microglial activation. Furthermore, our data showed that neuronal GHSR deletion suppresses neuroinflammation by downregulating AMPK-autophagy signaling in neurons. In conclusion, our data reveal that neuronal GHSR inhibition protects against DIO-induced depressive-like behavior and spatial cognitive dysfunction, at least in part, through AMPK-autophagy signaling-mediated neuroinflammation

The Mechanism of (R,R) ZX-5 on Increasing NO Release

(R,R) ZX-5 has been proven to have positive effects on choroidal blood flow without affecting the sclera and ciliary bodies in New Zealand white rabbits. This study was designed to investigate the mechanisms of (R,R) ZX-5 on improving the choroidal blood flow and promoting NO production. HUVECs (human umbilical vein endothelial cells) were used to determine the production of eNOS, p-eNOS, AKT and Erk1/2 by Western blot analysis. iNOS and eNOS mRNA levels were investigated by RT-PCR and the effect of (R,R) ZX-5 on NO production were determined by eNOS activity assay. We found (R,R) ZX-5 upregulated protein expression of eNOS and iNOS, increased NO production, and reduced ERK and Akt protein level. Therefore, (R,R) ZX-5 may promote the choroidal blood flow in New Zealand white rabbits without affecting the blood flow in the iris or ciliary bodies via increasing NO production. These results suggest that (R,R) ZX-5 may function to cure and prevent Age-related macular degeneration (AMD)

Epstein-Barr-Virus-Induced One-Carbon Metabolism Drives B Cell Transformation.

Epstein-Barr virus (EBV) causes Burkitt, Hodgkin, and post-transplant B cell lymphomas. How EBV remodels metabolic pathways to support rapid B cell outgrowth remains largely unknown. To gain insights, primary human B cells were profiled by tandem-mass-tag-based proteomics at rest and at nine time points after infection; >8,000 host and 29 viral proteins were quantified, revealing mitochondrial remodeling and induction of one-carbon (1C) metabolism. EBV-encoded EBNA2 and its target MYC were required for upregulation of the central mitochondrial 1C enzyme MTHFD2, which played key roles in EBV-driven B cell growth and survival. MTHFD2 was critical for maintaining elevated NADPH levels in infected cells, and oxidation of mitochondrial NADPH diminished B cell proliferation. Tracing studies underscored contributions of 1C to nucleotide synthesis, NADPH production, and redox defense. EBV upregulated import and synthesis of serine to augment 1C flux. Our results highlight EBV-induced 1C as a potential therapeutic target and provide a new paradigm for viral onco-metabolism