Search

Deterministic Networking (DetNet) is a rising technology that offers deterministic delay \& jitter and zero packet loss regardless of failures in large IP networks. In order to support DetNet, we must be able to find a set of low-cost routing paths for a given node pair subject to delay-range constraints. Unfortunately, the \textbf{Delay-Range} Constrained Routing (DRCR) problem is NP-Complete. Existing routing approaches either cannot support the delay-range constraints, or incur extremely high computational complexity. We propose Pulse$+$, a highly scalable and efficient DRCR problem solver. Pulse$+$ adopts a branch-and-bound methodology and optimizes its pruning strategies for higher efficiency. We also integrate Pulse$+$ with a divide-and-conquer approach and propose CoSE-Pulse$+$ to find a pair of active/backup paths that meet DetNet's delay-range and delay-diff constraints. Both Pulse$+$ and CoSE-Pulse$+$ offer optimality guarantee. Notably, although Pulse$+$ and CoSE-Pulse$+$ do not have a polynomial worst-case time complexity, their empirical performance is superior. We evaluate Pulse$+$ and CoSE-Pulse$+$ against the K-Shorst-Path and Lagrangian-dual based algorithms using synthetic test cases generated over networks with thousands of nodes and links. Both Pulse$+$ and CoSE-Pulse$+$ achieve significant speedup. To enable reproduction, we open source our code and test cases at [1].

Farnesoid X receptor (FXR) agonists would be considered as an important therapeutic strategy for several chronic liver and metabolic diseases. Here we have employed an integrated virtual screening by combining ligand-based pharmacophore mapping and molecular docking to identify novel nonsteroidal FXR agonists. Eighteen compounds were selected for in vitro FXR agonistic activity assay, and results showed five compounds exhibiting promising FXR agonistic activity. Among these compounds, compounds F4 and F17 were the most remarkable in vitro activity by using homogeneous time resolved fluorescence (HTRF) assay and the full-length FXR reporter gene assay in HepG2 cells. Real-time PCR assay was performed to measure the expression of FXR target genes. Compounds F4 and F17 increased small heterodimer partner (SHP), in turn, suppress mRNA levels of cholesterol 7-alpha-hydroxylase (CYP7A1). The obtained compounds F4 and F17 from this study may be potential leads for developing novel FXR agonists in the treatment of metabolic diseases.

Takeda G-protein-coupled receptor 5 (TGR5) is emerging as an important and promising target for the development of anti-diabetic drugs. To understand the structural characteristics of TGR5 agonists, the common feature pharmacophore models were generated and molecular docking was performed. The ligand-based virtual screening combined with pharmacophore mapping and molecular docking was performed to identify novel nonsteroidal TGR5 agonists. Finally, 20 compounds were screened for in vitro TGR5 agonistic activity assay, and results showed most compounds exhibiting TGR5 agonistic activity at 40 μM. Among these compounds, V12 and V14 displayed obvious TGR5 agonist activity, with the EC50 values of 19.5 μM and 7.7 μM, respectively. Compounds V12 and V14 could be considered potential TGR5 agonist candidates and also may be used as initial hits for developing novel TGR5 agonists.

Many optical circuit switched data center networks (DCN) have been proposed in the past to attain higher capacity and topology reconfigurability, though commercial adoption of these architectures have been minimal. One major challenge these architectures face is the difficulty of handling uncertain traffic demands using commercial optical circuit switches (OCS) with high switching latency. Prior works have generally focused on developing fast-switching OCS prototypes to quickly react to traffic changes through frequent reconfigurations. This approach, however, adds tremendous complexity to the control plane, and raises the barrier for commercial adoption of optical circuit switched data center networks. We propose COUDER, a robust topology and routing optimization framework for reconfigurable optical circuit switched data centers. COUDER optimizes topology and routing based on a convex set of traffic matrices, and offers strict throughput guarantees for any future traffic matrices bounded by the convex set. For the bursty traffic demands that are unbounded by the convex set, we employ a desensitization technique to reduce performance hit. This enables COUDER to generate topology and routing solutions capable of handling unexpected traffic changes without relying on frequent topology reconfigurations. Our extensive evaluations based on Facebook's production DCN traces show that, even with daily reconfiguration, COUDER achieves about 20\% higher throughput, and about 32\% lower average hop count compared to cost-equivalent static topologies. Our work shows that adoption of reconfigurable topologies in commercial DCNs is feasible even without fast OCSs.

Numerous optical circuit switched data center networks have been proposed over the past decade for higher capacity, though commercial adoption of these architectures have been minimal so far. One major challenge commonly facing these architectures is the difficulty of handling bursty traffic with optical circuit switches (OCS) with high switching latency. Prior works generally rely on fast-switching OCS prototypes to better react to traffic changes via frequent reconfigurations. This approach, unfortunately, adds further complexity to the control plane. We propose METTEOR, an easily deployable solution for optical circuit switched data centers, that is designed for the current capabilities of commercial OCSs. Using multiple predicted traffic matrices, METTEOR designs data center topologies that are less sensitive to traffic changes, thus eliminating the need of frequently reconfiguring OCSs upon traffic changes. Results based on extensive evaluations using production traces show that METTEOR increases the percentage of direct-hop traffic by about 80% over a fat tree at comparable cost, and by about 30% over a uniform mesh, at comparable maximum link utilizations. Compared to ideal solutions that reconfigure OCSs on every traffic matrix, METTEOR achieves close-to-optimal bandwidth utilization even with biweekly reconfiguration. This drastically lowers the controller and management complexity needed to perform METTEOR in commercial settings.

TGR5 is emerging as an important and promising target for the treatment of diabetes, obesity and other metabolic syndromes. A series of novel 1-benzyl-1H-imidazole-5-carboxamide derivatives was designed, synthesized and evaluated in vitro and in vivo. The most potent compounds 19d and 19e exhibited excellent agonistic activities against hTGR5, which was superior to those of the reference drugs INT-777 and LCA. In addition, compounds 19d and 19e exhibited good selectivity against FXR and presented significant glucose-lowering effects in vivo. Compound 19d could stimulate GLP-1 secretion by activating of TGR5.