We synthesized a series of poly(disulfide)s by ring-opening polymerization and demonstrated that the copolymerization of monomer 1 containing diethylenetriamine moieties and monomer 2 containing guanidyl ligands could generate an efficient delivery platform for different forms of CRISPR-Cas9-based genome editors, including plasmid, mRNA, and protein. The excellent delivery performance of designed poly(disulfide)s stems from their delicate molecular structures to interact with genome-editing biomacromolecules, unique delivery pathways to mediate the cellular uptake of CRISPR-Cas9 cargoes, and strong ability to escape the endosome. The degradation of poly(disulfide)s by intracellular glutathione not only promotes the timely release of CRISPR-Cas9 machineries into the cytosol but also minimizes the cytotoxicity that nondegradable polymeric carriers often encounter. These merits collectively account for the excellent ability of poly(disulfide)s to mediate different forms of CRISPR-Cas9 for their efficient genome-editing activities in vitro and in vivo.

Anthropogenic climate change threatens ecosystem functioning. Soil biodiversity is essentialfor maintaining the health of terrestrial systems, but how climate change affects the richness and abundance of soil microbial communities remains unresolved. We examined the effects of warming, altered precipitation and annual biomass removal on grassland soil bacterial, fungal and protistan communities over 7 years to determine how these representative climate changes impact microbial biodiversity and ecosystem functioning. We show that experimental warming and the concomitant reductions in soil moisture played the predominant role in shaping microbial biodiversity by decreasing the richness of bacteria (9.6%), fungi (14.5%), and protists (7.5%). Our results also show positive associations between microbial biodiversity and ecosystem functional processes such as gross primary productivity and microbial biomass. We conclude that the detrimental effects of biodiversity loss might be more severe in a warmer world. MAINBiodiversity, the variety of genes, species, and ecosystems which constitute life on our planet 1 , is dramatically affected by human alterations of global environment 2 . Biodiversity underscores healthy ecosystem functions and assures the production of essential goods, services, and benefits to society, such as climate regulation, landscape stability, fibers, and food production 1 . However, such benefits are threatened by the unprecedented biodiversity loss 3,4 caused by anthropogenic global environmental changes like climate warming, altered precipitation patterns, and land use changes 5 . Studies demonstrate that biodiversity loss impairs the functioning of natural ecosystems * *

Based on the high frequency of concurrent adenomatous polyposis coli (APC) and KRAS mutations and their strong cooperative interaction in human colorectal cancer (CRC) promotion, we herein develop a CRISPR-Cas9-based genome-editing nanomedicine to target both APC and KRAS mutations for the treatment of CRC. To this end, a hyaluronic acid (HA)-decorated phenylboronic dendrimer (HAPD) was designed for the targeted delivery of Cas9 ribonucleoprotein (RNP), by which both APC and KRAS genetic mutations harboring in CRC cells can be synergistically disrupted. Systemic administration of Cas9 RNP targeting APC and KRAS enabled by HAPD significantly inhibits tumor growth on xenografted and orthotopic CRC mouse models and also greatly prevents CRC-induced liver metastasis and lung metastasis. Thus, this duplex genome-editing system provides a promising gene therapy strategy for the treatment of human CRC and can be extended to other types of cancers with activated Wnt/β-catenin and RAS/extracellular signal-regulated kinase (ERK) pathways.

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Ganoderma lucidum polysaccharide (GLP) extracted from Ganoderma lucidum (Leyss. ex Fr.) Karst, a traditional Chinese medicine, is a biologically active substance reported to possess anti-oxidative, anti-apoptotic, and neurological protection. However, it is unknown whether GLP have any protective effect against high-fat constituents-induced epithelial cell injury. The aim of this study was to investigate the protection and molecular mechanism of GLP on injury induced by palmitic acid (PA) in the intestinal porcine epithelial cell line (IPEC-J2). First, we tested whether the treatment of GLP attenuate PA-induced IPEC-J2 cell death. GLP markedly blocked PA-caused cytotoxicity and apoptosis in IPEC-J2 cells. Moreover, GLP recovered the decreased mitochondrial function and inhibited activation of caspase-dependent apoptotic pathway. Interestingly, PA promoted cell apoptosis and autophagy through stimulation of phosphorylation of mitogen-activated protein kinases (MAPKs), AMP-activated protein kinase (AMPK), and inhibition of phosphorylation of Akt and mammalian target of rapamycin (mTOR), which was reversed by GLP. Taken together, this study revealed a protective effect of GLP against PA-evoked IPEC-J2 cell death through anti-apoptotic and anti-autophagic properties.

Listeria monocytogenes, which causes serious foodborne infections and public health problems worldwide, is one of the most important foodborne pathogens. Linalool has been identified as an antimicrobial agent against some microorganism, but its mechanism of action is currently unclear. Here, we investigated the efficacy of linalool against L. monocytogenes while planktonic and as a biofilm and explored potential mechanisms of action. Linalool exhibited strong anti-listeria activity in the planktonic stage. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) observations revealed seven stages were classified of cells at microscopic level. Mesosome-like structures were observed for the first time in L. monocytogenes after linalool treatment. Linalool also showed significant anti-biofilm activity through both dispersal and killing of cells in the biofilm based on confocal scanning laser microscopy (CLSM) and SEM imaging, crystal violet staining, XTT and COMSTAT assays. Moreover, comparative transcriptome analysis demonstrated many potential mechanisms of action for linalool and some important pathways were screened out through the analysis of GO enrichment and KEGG. Our study provides evidence that linalool exhibits a strong antimicrobial activity against both the planktonic and biofilm forms of L. monocytogenes and gives insight into its mechanism of action.

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