Some secondary metabolites from plants show to have potent inhibitory activities against microbial pathogens, such as human immunodeficiency virus (HIV), herpes simplex virus (HSV), Treponema pallidum, Neisseria gonorrhoeae, etc. Here we report that lignosulfonic acid (LSA), a polymeric lignin derivative, exhibits potent and broad activity against HIV-1 isolates of diverse subtypes including two North America strains and a number of Chinese clinical isolates values ranging from 21.4 to 633 nM. Distinct from other polyanions, LSA functions as an entry inhibitor with multiple targets on viral gp120 as well as on host receptor CD4 and co-receptors CCR5/CXCR4. LSA blocks viral entry as determined by time-of-drug addiction and cell-cell fusion assays. Moreover, LSA inhibits CD4-gp120 interaction by blocking the binding of antibodies specific for CD4-binding sites (CD4bs) and for the V3 loop of gp120. Similarly, LSA interacts with CCR5 and CXCR4 via its inhibition of specific anti-CCR5 and anti-CXCR4 antibodies, respectively. Interestingly, the combination of LSA with AZT and Nevirapine exhibits synergism in viral inhibition. For the purpose of microbicide development, LSA displays low in vitro cytotoxicity to human genital tract epithelial cells, does not stimulate NF-κB activation and has no significant up-regulation of IL-1α/β and IL-8 as compared with N-9. Lastly, LSA shows no adverse effect on the epithelial integrity and the junctional protein expression. Taken together, our findings suggest that LSA can be a potential candidate for tropical microbicide.

Small interfering RNAs (siRNAs) have been used extensively in reverse genetic research, and many have made their way into clinical trials. The most widely used siRNA structure consists of double-stranded RNA with 19 base pairs and 2-nucleotide overhangs at the 3'-end of both strands (19 + 2). Although widely used, this symmetric structure bears inherent disadvantages in both research and clinical applications. One of the most common caveats is the off-target effect leading to adverse effects in clinical application. In the current study, using C-C chemokine receptor (CCR5) as a target, we have shown that 19 + 2 siRNA could still cause considerable global off-target effects regardless of rational design based on its thermodynamic asymmetry. However, we demonstrated that structurally asymmetric siRNA targeting CCR5 could be adopted to improve the strand specificity and greatly reduce the off-target effects without significantly compromising its on-target effects. Data from microarray analysis suggest that an unidentified mechanism resulting in global gene down-regulation might be avoided through strand shortening. Taken together, our work suggested a promising and simple way to improve strand specificity and overcome the off-target gene-expression effects without introducing more complications while retaining the efficacy of siRNA.

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Genetic algorithm is widely used in multi-objective mechanical structure optimization. In this paper, a genetic algorithm-based optimization method for ladle refractory lining structure is proposed. First, the parametric finite element model of the new ladle refractory lining is established by using ANSYS Workbench software. The refractory lining is mainly composed of insulating layer, permanent layer and working layer. Secondly, a mathematical model for multi-objective optimization is established to reveal the functional relationship between the maximum equivalent force on the ladle lining, the maximum temperature on the ladle shell, the total mass of the ladle and the structural parameters of the ladle refractory lining. Genetic algorithm translates the optimization process of ladle refractory lining into natural evolution and selection. The optimization results show that, compared with the unoptimized ladle refractory lining structure (insulation layer thickness of 0 mm, permanent layer thickness of 81 mm, and working layer thickness of 152 mm), the refractory lining with insulation layer thickness of 8.02 mm, permanent layer thickness of 76.20 mm, and working layer thickness of 148.61 mm has the best thermal insulation performance and longer service life within the variation of ladle refractory lining structure parameters. Finally, the results of the optimization are verified and analyzed in this paper. The study found that by optimizing the design of the ladle refractory lining, the maximum equivalent force on the ladle lining, the maximum temperature on the ladle shell and the ladle mass were reduced. The thermal insulation performance and the lightweight performance of the ladle are improved, which is very important for improving the service life of the ladle.