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Ramulus Mori (Sangzhi) alkaloids (SZ-A) derived from twigs of mulberry (Morus alba L., genus Morus in the Moraceae family) was approved by the National Medical Products Administration in 2020 for the treatment of type 2 diabetes mellitus. In addition to excellent hypoglycemic effect, increasing evidence has confirmed that SZ-A exerts multiple pharmacological effects, such as protecting pancreatic ß-cell function, stimulating adiponectin expression, and alleviating hepatic steatosis. Importantly, a specific distribution of SZ-A in target tissues following oral absorption into the blood is essential for the induction of multiple pharmacological effects. However, there is a lack of studies thoroughly exploring the pharmacokinetic profiles and tissue distribution of SZ-A following oral absorption into the blood, particularly dose-linear pharmacokinetics and target tissue distribution associated with glycolipid metabolic diseases. In the present study, we systematically investigated the pharmacokinetics and tissue distribution of SZ-A and its metabolites in human and rat liver microsomes, and rat plasma, as well as its effects on the activity of hepatic cytochrome P450 enzymes (CYP450s). The results revealed that SZ-A was rapidly absorbed into the blood, exhibited linear pharmacokinetic characteristics in the dose range of 25–200 mg/kg, and was broadly distributed in glycolipid metabolism-related tissues. The highest SZ-A concentrations were observed in the kidney, liver, and aortic vessels, followed by the brown and subcutaneous adipose tissues, and the heart, spleen, lung, muscle, pancreas, and brain. Except for the trace oxidation products produced by fagomine, other phase I or phase II metabolites were not detected. SZ-A had no inhibitory or activating effects on major CYP450s. Conclusively, SZ-A is rapidly and widely distributed in target tissues, with good metabolic stability and a low risk of triggering drug-drug interactions. This study provides a framework for deciphering the material basis of the multiple pharmacological functions of SZ-A, its rational clinical use, and the expansion of its indications.

The popularity of Contrastive Language-Image Pre-training (CLIP) has propelled its application to diverse downstream vision tasks. To improve its capacity on downstream tasks, few-shot learning has become a widely-adopted technique. However, existing methods either exhibit limited performance or suffer from excessive learnable parameters. In this paper, we propose APE, an Adaptive Prior rEfinement method for CLIP's pre-trained knowledge, which achieves superior accuracy with high computational efficiency. Via a prior refinement module, we analyze the inter-class disparity in the downstream data and decouple the domain-specific knowledge from the CLIP-extracted cache model. On top of that, we introduce two model variants, a training-free APE and a training-required APE-T. We explore the trilateral affinities between the test image, prior cache model, and textual representations, and only enable a lightweight category-residual module to be trained. For the average accuracy over 11 benchmarks, both APE and APE-T attain state-of-the-art and respectively outperform the second-best by +1.59% and +1.99% under 16 shots with x30 less learnable parameters., Comment: Code is available at https://github.com/yangyangyang127/APE

While training an end-to-end navigation network in the real world is usually of high cost, simulation provides a safe and cheap environment in this training stage. However, training neural network models in simulation brings up the problem of how to effectively transfer the model from simulation to the real world (sim-to-real). In this work, we regard the environment representation as a crucial element in this transfer process and propose a visual information pyramid (VIP) model to systematically investigate a practical environment representation. A novel representation composed of spatial and semantic information synthesis is then established accordingly, where noise model embedding is particularly considered. To explore the effectiveness of this representation, we compared the performance with representations popularly used in the literature in both simulated and real-world scenarios. Results suggest that our environment representation stands out. Furthermore, an analysis on the feature map is implemented to investigate the effectiveness through inner reaction, which could be irradiative for future researches on end-to-end navigation., Comment: 10 pages, 11 figures

Proceedings Of The 7Th Graz Brain-Computer Interface Conference 2017, From Vision To Reality, September 18-22, 2017 Graz University Of Technology, Austria

Proceedings Of The 6Th International Bci Meeting: Bci Past, Present, And Future

Proceedings Of The 6Th International Bci Meeting: Bci Past, Present, And Future

Objective To analyze the levels of interleukin-33 (IL-33) in the serum of patients with rheumatoid arthritis (RA) and investigated its possible pathophysiological importance. Methods The concentrations of IL-33 and matrix metalloproteinase (MMP)-3 were measured by enzyme-linked immunosorbent assay (ELISA) in the serum of 121 patients with RA and 47 controls. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), and anticyclic citrullinated peptide (anti-CCP) were measured by standard laboratory techniques. Interstitial lung disease (ILD) was identified on high-resolution computed tomography. Disease activity in RA was scored with the Disease Activity Score 28 based on C-reactive protein levels (DAS28-CRP). The bone erosion of RA patients was evaluated by modified Sharp Score (MSS). Results Serum levels of IL-33 and MMP-3 were significantly higher in RA patients than in healthy controls. Significant higher levels of IL-33 were found in CCP-positive group and in patients with ILD. There was positive correlation between the levels of IL-33 and RF. Moreover, there was also positive correlation between IL-33 and MMP-3, MSS. Conclusion These data support the hypothesis that IL-33 may be involved in RA pathogenesis and it may partly contribute to the bone erosion in RA patients.

Background Costimulatory molecule pair CD40-CD40L plays a central role not only in immune cell interactions but also in immune-non immune cell activation. Targeting this pathway has generated great interest but early attempts to target CD40L failed mainly due to thrombotic complications observed in the clinic. In addition, developing a potent truly antagonistic CD40 antibody has proven to be challenging. Objectives Here we describe the preclinical characterization of BI 655064, an anti-human CD40 mAb that is being developed for the treatment of autoimmune disorders. BI 655064 is engineered as a human IgG1 molecule with a mutated Fc region to abrogate effector function. Methods Binding of BI 655064 to CD40 expressed on primary B cells was measured by flow cytometry. The ability of BI 655064 to block CD40L-induced B cell proliferation in vitro was measured by tritium uptake, while blockade of endothelial and DC activation was measured by inhibition of cytokine release. A subcutaneous PK/PD study in the cynomolgus monkey was performed to establish correlations between BI 655064 exposure, target coverage using a receptor occupancy assay and pharmacodynamic effects using an ex vivo CD54-induction assay. In vivo blockade of B cell function was also tested in a human-peripheral blood lymphocyte (huPBL) induced SCID mouse model of graft-versus-host disease (GvHD) and in cynomolgus monkeys immunized with keyhole limpet hemocyanin (KLH). Results In human whole blood, BI 655064 binds to CD40 on B cells (EC 90 of 6.85 nM ±0.74). Blockade of CD40L-induced B cell proliferation was observed at an average IC 50 of 0.4 nM. Inhibition of CD40L mediated cytokine release was observed in DCs (IC 50 =0.25 nM and 0.59 nM for TNFα and IL12/23p40, respectively) and to verify effects beyond immune cells, BI655064 was tested in CD40L stimulated endothelial cell cultures. Binding of BI 655064 to human platelets did not induce or augment platelet activation as determined by in vitro induction of CD62P. In the PK/PD study, cynomolgus monkeys dosed with greater than 1 mg/kg of BI 655064 exhibited complete blockade of ex vivo CD54 upregulation corresponding to full CD40 target coverage on B cells. In vivo , BI 655064 demonstrated clear effects on B cell function in the GvHD model where both human IgM and IgG responses were completely abrogated. As part of a repeat dose tolerability study, BI 655064 given to cynomolgus monkeys prior to immunization with KLH resulted in inhibition of KLH-specific IgM and IgG antibody responses. At doses of 5 mg/kg and above, germinal center size was decreased microscopically in Peyer9s patches, lymph nodes, spleens and tonsils in treated monkeys. Evaluation of platelet function in cynomolgus monkeys dosed with BI 655064 did not reveal any effects on ex vivo platelet activation or aggregation. Conclusions BI 655064 is a humanized antagonistic anti-CD40 mAb which is to be tested in human clinical trials for autoimmune disorders to establish safety and efficacy. BI 655064 demonstrated relevant pharmacologic in vitro and in vivo activity, blocking CD40-related functions at clinical dosing levels of >1 mg/kg in animal models. Disclosure of Interest K. Ralph Employee of: Boehringer Ingelheim Pharmaceuticals, A. Nicoletti Employee of: Boehringer Ingelheim Pharmaceuticals, E. Musvasva Employee of: Boehringer Ingelheim Pharmaceuticals, S. Cannan Employee of: Boehringer Ingelheim Pharmaceuticals, S. VanTongeren Employee of: Boehringer Ingelheim Pharmaceuticals, D. Blanset Employee of: Boehringer Ingelheim Pharmaceuticals, S. Brodeur Employee of: Boehringer Ingelheim Pharmaceuticals, J. Ahlberg Employee of: Boehringer Ingelheim Pharmaceuticals, H. Li Employee of: Boehringer Ingelheim Pharmaceuticals, S. Fogal Employee of: Boehringer Ingelheim Pharmaceuticals, S. Desai Employee of: Boehringer Ingelheim Pharmaceuticals, K. O9Shea Employee of: Boehringer Ingelheim Pharmaceuticals, R. Kroe-Barrett Employee of: Boehringer Ingelheim Pharmaceuticals, E. Mainolfi Employee of: Boehringer Ingelheim Pharmaceuticals, G. Nabozny: None declared, H. Wu Employee of: Boehringer Ingelheim Pharmaceuticals, G. Hansen Employee of: Boehringer Ingelheim Pharmaceuticals, K. Canada Employee of: Boehringer Ingelheim Pharmaceuticals, S. Singh Employee of: Boehringer Ingelheim Pharmaceuticals, X. Zhu Employee of: Boehringer Ingelheim Pharmaceuticals, M. Ramanujam Employee of: Boehringer Ingelheim Pharmaceuticals, C. Grimaldi Employee of: Boehringer Ingelheim Pharmaceuticals

The logic design on FPGAs of the ATM SAR function in broadband access networks is studied. AAL which adapts services to the ATM cell is the adaptation layer between the ATM layer and the high layer. FR and Ethernet data services should adapt the ATM cell with AAL5. Segmentation, reassembly process and traffic control issues are also discussed.

The fast and accurate collision detection and distance calculation between geometric models is fundamental in robotics, manufacturing and computer-simulated environments. This paper surveys the state of the art in the theory and algorithms of distance and pseudo distance functions between convex sets. An overview on the existing results, including fast algorithms for distance calculation, definitions and properties of various pseudo distance functions (the J-function, the growth distance, and the pseudo minimum translational distance), is presented. The distance and pseudo distance functions are versatile in a wide range of areas. Their applications in robot motion planning, grasp analysis/synthesis, form error evaluation, and engineering optimization is demonstrated.