Chronic cough relief by allosteric modulation of P2X3 without taste disturbance.

P2X receptors are cation channels that sense extracellular ATP. Many therapeutic candidates targeting P2X receptors have begun clinical trials or acquired approval for the treatment of refractory chronic cough (RCC) and other disorders. However, the present negative allosteric modulation of P2X receptors is primarily limited to the central pocket or the site below the left flipper domain. Here, we uncover a mechanism of allosteric regulation of P2X3 in the inner pocket of the head domain (IP-HD), and show that the antitussive effects of quercetin and PSFL2915 (our nM-affinity P2X3 inhibitor optimized based on quercetin) on male mice and guinea pigs were achieved by preventing allosteric changes of IP-HD in P2X3. While being therapeutically comparable to the newly licensed P2X3 RCC drug gefapixant, quercetin and PSFL2915 do not have an adverse effect on taste as gefapixant does. Thus, allosteric modulation of P2X3 via IP-HD may be a druggable strategy to alleviate RCC.

Solidification Mechanism of Pb and Cd in S2--Enriched Alkali-Activated Municipal Solid Waste Incineration Fly Ash.

S2--enriched alkali-activator (SEAA) was prepared by modifying the alkali activator through Na2S. The effects of S2--enriched alkali-activated slag (SEAAS) on the solidification performance of Pb and Cd in MSWI fly ash were investigated using SEAAS as the solidification material for MSWI fly ash. Combined with microscopic analysis through scanning electron microscopy (SEM), X-ray fluorescence spectroscopy (XRF), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FT-IR), the effects of SEAAS on the micro-morphology and molecular composition of MSWI fly ash were studied. The solidification mechanism of Pb and Cd in S2--enriched alkali-activated MSWI fly ash was discussed in detail. The results showed that the solidification performance for Pb and Cd in MSWI fly ash induced by SEAAS was significantly enhanced first and then improved gradually with the increase in dosage of ground granulated blast-furnace slag (GGBS). Under a low GGBS dosage of 25%, SEAAS could eliminate the problem of severely exceeding permitted Pb and Cd in MSWI fly ash, which compensated for the deficiency of alkali-activated slag (AAS) in terms of solidifying Cd in MSWI fly ash. The highly alkaline environment provided by SEAA promoted the massive dissolution of S2- in the solvent, which endowed the SEAAS with a stronger ability to capture Cd. Pb and Cd in MSWI fly ash were efficiently solidified by SEAAS under the synergistic effects of sulfide precipitation and chemical bonding of polymerization products.

Experimental Research on Improving Activity of Calcinated Coal Gangue via Increasing Calcium Content.

In this investigation, non-spontaneous combustion coal gangue was activated by two methods: (1) low-temperature calcination and (2) calcium addition. Differences in the activity of the activated coal gangue were studied at various calcination temperatures and amounts of calcium addition. Meanwhile, the cementation activity of the activated coal gangue was evaluated according to the activity effect analysis. Furthermore, the influences of the activated coal gangue on the cementation activity of cement were investigated. The results indicated that the activities of the activated coal gangue increased at a temperature between 500 °C and 700 °C. The calcium addition method can also increase the activity of coal gangue, with the effect being better when the gangue is mixed with slag. The addition of calcium and the calcination of coal gangue can promote the production of active minerals such as metakaolin, which is the main reason for the increased cementation activity.

Strengthening Mechanism for the Mechanical Properties of Cement-Based Materials after Internal Nano-SiO2 Production.

This study focuses on overcoming the agglomeration issue of nano-SiO2 powder in cement, facilitating the strengthening mechanism of cement-based materials. A nano-SiO2 precursor solution (NSPS) was added to cement-based materials to replace nano-SiO2 powder. The influencing laws of the alkalinity and dosage of the NSPS on the mechanical properties of cement were investigated. Further, the strengthening mechanism of the mechanical properties of cement-based materials after internal nano-SiO2 production was analysed. The results show that (1) when the alkalinity of the precursor solution is a weak acid (pH = 6), the compressive strength of cement-based materials after internal nano-SiO2 production is 25%~36% higher than that of pure cement-based materials and 16%~22% higher than that of cement-based materials with silica fume; (2) when the solid content of SiO2 in the current displacement solution is about 0.16% of the cement mass, the compressive strength of the prepared cement-based material is the highest. With the continuous increase in the solid content of SiO2 in the precursor solution, the compressive strength of cement-based materials after internal nano-SiO2 production decreases but is always greater than the compressive strength of the cement-based material mixed with nano-SiO2 micro powder. According to a microstructural analysis, nano-SiO2 particles that precipitate from the precursor solution can facilitate the hydration process of cement and enrich the gel products formed on the cement particle surface. In addition, new network structures among cement particles are formed, and precipitated nano-SiO2 particles fill in the spaces among these cement particles as crystal nuclei to connect the cement particles more tightly and compact the cement-based materials. This reinforces the mechanical properties of cement-based materials.

The Stabilization Mechanism of Nano-SiO2 Precursor Solution.

The issues associated with the fabrication of nano-silica (NS) mineral powder, such as high cost and agglomeration, can be effectively mitigated by using a precursor solution of NS as the external mixture of cement-based materials. Based on the liquid-phase preparation of NS mineral powder, its preparation technology was thoroughly investigated herein. The precursor solution of NS was synthesized using acid media (HCL, HNO3, HBO3, HCOOH, CH3COOH)-the acetic acid concentration was 1~15%-and siliceous materials. (The concentration of sodium silicate was 20~38%). In addition, the pH value (pH4~pH8) of the precursor solution was measured using a pH detector. The indexes of NS, such as precipitation time, morphology, and distribution, were observed to formulate a preparation technique for the precursor solution of NS that possessed the best results for the precipitation of nanoparticles. From the acquired results, it was demonstrated that acetic acid solution (concentration ≤ 3%) and sodium silicate solution (concentration ≤ 25%) were mixed into a solution with pH = 6, which was the optimum mixing ratio for the precursor solution of NS. The prepared precursor solution of NS was also added to the Ca(OH)2 saturated solution, and the precursor solution became active from a stable state. Then, NS particles were precipitated in an alkaline solution and reacted with Ca(OH)2 to form calcium silicate gel, which made the solution increasingly turbid and generated many visible and uniformed flocculating substances. With time, gels were continuously produced, which then turn white. Similarly, NS particles can be precipitated when the precursor solution is added to cement paste, which reacts with the Ca(OH)2 to generate CSH gel and improve the compactness of the cement paste.

LCTX-F2, a Novel Potentiator of Coagulation Factors From the Spider Venom of Lycosa singoriensis.

Spider venoms contain many functional proteins/peptides such as proteinases, serine/cysteine proteinase inhibitors, insecticidal toxins, and ion channel toxins. However, to date, no peptide toxin with procoagulant activities has been identified from spider venom. In this study, a novel toxin LCTX-F2 with coagulation-promoting activity was identified and characterized in the venom of the spider Lycosa singoriensis (L. singoriensis). LCTX-F2 significantly shortened activated partial thromboplastin time (APTT), clotting time, and plasma recalcification time. This toxin directly interacted with several coagulation factors such as FXIIa, kallikrein, thrombin, and FXa and increased their protease activities. In liver bleeding and tail bleeding mouse models, LCTX-F2 significantly decreased the number of blood cells and bleeding time in a dose-dependent manner. At the same dosage, LCTX-F2 exhibited a more significant procoagulant effect than epsilon aminocaproic acid (EACA). Moreover, LCTX-F2 showed no cytotoxic or hemolytic activity against either normal cells or red blood cells. Our results suggested that LCTX-F2 is a potentiator of coagulation factors with the potential for use in the development of procoagulant drugs.

Eriodictyol attenuates cisplatin-induced kidney injury by inhibiting oxidative stress and inflammation.

Eriodictyol, a flavonoid present in citrus fruits, has been reported to have antioxidant and anti-inflammatory effects. In this study, the protective effects of eriodictyol on cisplatin (CP)-induced kidney injury were detected. CP-induced kidney injury model was established by administration of CP (20mg/kg). The results showed that treatment of eriodictyol inhibited the production of blood urea nitrogen (BUN), creatinine, MDA, TBARS, reactive oxygen species (ROS), as well as the production of TNF-α, and IL-1ß in kidney tissues induced by CP. Eriodictyol also up-regulated the activities of SOD, CAT, and GSH-PX decreased by CP. Furthermore, eriodictyol was found to up-regulate the expression of Nrf2/HO-1 and inhibited CP-induced NF-κB activation in kidney tissues. In conclusion, eriodictyol protected against CP-induced kidney injury through activating Nrf2 and inhibiting NF-κB activation.

Planktonic and sedimentary bacterial diversity of Lake Sayram in summer.

Lake Sayram is an ancient cold water lake locating at a mountain basin in Xinjiang, China. The lake water is brackish, alkaline, unpolluted, and abundant in SO4(2-) and Mg(2+). The lacustrine ecosystem of Lake Sayram has been intensely investigated. However, profiles of the microbial communities in the lake remain largely unknown. In this study, taxonomic compositions of the planktonic and sedimentary bacterial communities in Lake Sayram were investigated using 16S rRNA metagenomics. The lacustrine bacterial communities were generally structured by environmental conditions, including the hydrological and physicochemical parameters. Proteobacteria was the dominating phylum. In the lake water, the genera Acinetobacter and Ilumatobacter held an absolute predominance, implying their metabolic significance. In the bottom sediment, biogeochemically significant bacteria and thermophilic or acidothermophilic extremophiles were recovered. In contrast to the planktonic bacteria, an appreciable portion of the sedimentary bacteria could not be classified into any known taxonomic unit, indicating the largely unknown bacteriosphere hiding in the bottom sediment of Lake Sayram.