Endosomal TLRs (TLR3/7/8/9) are highly analogous innate immunity sensors for various viral or bacterial RNA/DNA molecular patterns. Among them, TLR7, in particular, has been suggested to be a target for various inflammatory disorders and autoimmune diseases including systemic lupus erythematosus (SLE); but few small-molecule inhibitors with elaborated mechanism have been reported in literature. Here, we reported a well-characterized human TLR7-specific small-molecule inhibitor, TH-407b, with promising potency and negligible cytotoxicity through a novel binding mechanism. Notably, TH-407b not only effectively inhibited TLR7-mediated pro-inflammatory signaling in a variety of cultured cell lines but also demonstrated potent inflammation suppressing activities in primary peripheral blood mononuclear cells (PBMCs) derived from SLE patients. Furthermore, TH-407b showed prominent efficacy in vivo, improved survival rate and ameliorated symptoms of SLE model mice. To obtain molecular insights into the TH-407b derivatives' inhibition mechanism, we performed the structural analysis of TLR7/TH-407b complex using cryogenic electron microscopy (cryo-EM) method. As an atomistic resolution cryo-EM structure of the TLR family, it not only of value to facilitate structure-based drug design, but also shed light to methodology development of small proteins using EM. Significantly, TH-407b has unveiled an inhibition strategy for TLR7 via stabilizing its resting/inactivated state. Such a resting state could be generally applicable to all TLRs, rendering a useful method for targeting this group of important immunological receptors.

The cyclic dinucleotide c-di-GMP is known as an important second messenger in bacteria, which controls various important cellular processes, such as cell differentiation, biofilm formation and virulence factors production. It is extremely vital for the development of new antibacterial agents by virtue of blocking c-di-GMP signal conduction. Current research indicates that there are three potential targets for discovering new antibacterial agents based on c-di-GMP regulated signal pathway, which are c-di-GMP synthases, c-di-GMP degrading enzymes and c-di-GMP receptors. Herein, we review small molecules that have been developed to inhibit c-di-GMP related enzymes and indicate perspectives of c-di-GMP inhibitors.

Biofilm is a bacterial lifestyle ubiquitously in natural environments. Bacterial biofilm leads to drug resistance, a main reason why many infectious diseases are difficult to control. Due to the prominent points of biofilms implicated in infectious disease and the spread of multi-drug resistance, it is urgent to discover new antibacterial agents that can regulate biofilm formation and development. This review introduces chemical agents that could modulate bacterial biofilm formation and development.

Objective To obtain the matched parameters between image quality and radiation dose by exploring the influence of the exposure parameters of screening mammography on both the image quality and radiation dose.Methods The correlation between the exposure parameters and average glandular doses to 507 patients undergoing screening mammography were retrospectively analyzed.The influence of breast compression thickness on radiation dose by exposing different thickness of PMMA was obtained.The correlation with image quality was analyzed by combined testing of contrast detail test mode ( CDMAM3.4 )and different thickness of PMMAs.Results The groups aged 30 to 49 years were the main groups in 507examined patients,up to 67.06％ of the total.The mean value of average gland doses ( AGD ) in contrastprior mode was the highest in three kinds of exposure modes,accounting for 137.5％ of standard mode.In standard mode,target material/filtration board combination was Mo/Mo,Mo/Rh and Rh/Rh,accounting for 1/3 respectively.Mo/Rh and Rh/Rh were selected in dose-prior mode,accounting for 50％ respectively.Mo/Mo was mainly selected in contrast-prior,accounting for 52％.Breast compression thickness was positively correlated with average gland doses.Image quality figure inverse (IQFinv) under three kinds of modes (STD,DOSE,CNT) was 98.32,95.41 and 107.02,respectively,and IQFinv of contrast-prior mode was the highest among them.IQFinv was in general agreement in the three kinds of exposure modes when the thickness of PMMA plates plates was greater than or equal to 5 cm.Conclusions In clinical practice,when the breast is of density type and pressed thickness is less than 4 em,the dose-prior mode should be selected.When the pressed thickness is between 4 and 6 cm,the standard exposure mode should be selected.When the pressed thickness is larger than 6 cm,the manual mode should be selected.