Synthetic glycan-based TLR4 agonists targeting caspase-4/11 for the development of adjuvants and immunotherapeutics

Gram-negative bacterial lipopolysaccharide (LPS)-induced Toll-like receptor 4 (TLR4) mediated pro-inflammatory signaling plays a key role in immunoprotection against infectious challenges and boosts adaptive immunity, whereas the activation of the cytosolic LPS receptor caspase-4/11 leads to cell death by pyroptosis and is deeply implicated in the development of sepsis. Despite tremendous advances in the understanding of the LPS-TLR4 interaction, predictably regulated TLR4 activation has not yet been achieved. The structural basis for the induction of caspase-4/11 protease activity by LPS is currently unknown. The modulation of innate and adaptive immune responses through the controlled induction of TLR4 signaling without triggering caspase-4/11 activity would open novel perspectives in the development of safe vaccine adjuvants and immunotherapeutics. We report the discovery of highly potent glycan-based immunostimulants with picomolar affinity for TLR4 which interact with caspase-4/11 and promote caspase-4/11 oligomerization while abolishing caspase-11 protease activity. The rigidity and twisted molecular shape of the alpha,alpha-(1 1')-linked disaccharide core of synthetic LPS mimicking anionic glycolipids accounted for both species-independent and adjustable TLR4-mediated NF-kappa B signaling and the modulation of caspase-4/11 activation. By the use of crystal structure based design and advanced synthetic chemistry we created a set of versatile probes for studying the structural basis of caspase-4/11 activation and established a chemical strategy for controllable TLR4 mediated cytokine release which is dissociable from the induction of caspase-11 protease activity

The Spatiotemporal Variations of Runoff in the Yangtze River Basin under Climate Change

A better understanding of the runoff variations contributes to a better utilization of water resources and water conservancy planning. In this paper, we analyzed the runoff changes in the Yangtze River Basin (YRB) including the spatiotemporal characteristics of intra-annual variation, the trend, the mutation point, and the period of annual runoff using various statistical methods. We also investigated how changes in the precipitation and temperature could impact on runoff. We found that the intra-annual runoff shows a decreasing trend from 1954 to 2008 and from upper stream to lower stream. On the annual runoff sequence, the upstream runoff has a high consistency and shows an increasing diversity from upper stream to lower stream. The mutation points of the annual runoff in the YRB are years 1961 and 2004. Annual runoff presents multitime scales for dry and abundance changes. Hurst values show that the runoffs at the main control stations all have Hurst phenomenon (the persistence of annual runoff). The sensitivity analyses of runoff variation to precipitation and temperature were also conducted. Our results show that the response of runoff to precipitation is more sensitive than that to temperature. The response of runoff to temperature is only one-third of the response to precipitation. A decrease in temperature may offset the impact of decreasing rainfall on runoff, while an increase in both rainfall and temperature leads to strongest runoff variations in the YRB

Application of BP Neural Network Algorithm in Traditional Hydrological Model for Flood Forecasting

Flooding contributes to tremendous hazards every year; more accurate forecasting may significantly mitigate the damages and loss caused by flood disasters. Current hydrological models are either purely knowledge-based or data-driven. A combination of data-driven method (artificial neural networks in this paper) and knowledge-based method (traditional hydrological model) may booster simulation accuracy. In this study, we proposed a new back-propagation (BP) neural network algorithm and applied it in the semi-distributed Xinanjiang (XAJ) model. The improved hydrological model is capable of updating the flow forecasting error without losing the leading time. The proposed method was tested in a real case study for both single period corrections and real-time corrections. The results reveal that the proposed method could significantly increase the accuracy of flood forecasting and indicate that the global correction effect is superior to the second-order autoregressive correction method in real-time correction

Research on Zero Value Detection Technology of Porcelain Insulator

High-voltage insulators are one of the devices widely used in power systems, and their pros and cons are directly related to the safe and stable operation of the power system. The large-tonnage UHV insulator AC withstand voltage detection method is restricted by conditions at the engineering site, and the detection efficiency is low and difficult to implement. The research on the method of detecting UHV zero-value insulators using high-voltage pulses and the development of portable detection devices are of great significance. This article has completed the portable insulator detection device using a miniaturized high-voltage pulse test power supply. The developed portable UHV zero-value insulator detection device can effectively judge zero-value, low-value and high-value UHV insulators, and adapt to large quantities of UHV insulators. Requirements for efficient testing

Uric acid activates the NF-κB signaling pathway in pancreatic β-cells.

<p>(<b>A</b>) Treatment of Min6 cells with 5 mg/dL uric acid for 24 h upregulated NF-κB transcriptional activity, as detected by a luciferase reporter assay. The uric acid-induced increase in NF-κB transcriptional activity was reversed by benzbromarone. (<b>B</b>) IκBα phosphorylation, detected by Western blotting, increased in a time-dependent manner in Min6 cells stimulated with 5 mg/dL uric acid at 60 mins. (<b>C</b>) Benzbromarone (50 µmol/L) reversed the uric acid-induced increase in IκB phosphorylation. (<b>D</b>) Total p65 protein levels in Min6 cells, detected by Western blotting, were unaffected by treatment with different concentrations of uric acid. **<i>P</i><0.01.</p