CCN2 is required for recruitment of Sox2-expressing cells during cutaneous tissue repair

Connective tissue growth factor (CTGF/CCN2), a member of the CCN family of matricellular proteins is upregulated in both fibrosis as well as tissue repair. Recently, we showed that, in mice, CCN2 expression by fibroblasts was required for dermal fibrogenesis, but not for cutaneous tissue repair. Lineage tracing analysis linked the ability of CCN2 to promote fibrosis to the requirement for CCN2 to recruit cells expressing the progenitor cell marker Sox2 to fibrotic connective tissue and for differentiating these cells into myofibroblasts. Herein, we show that although loss of CCN2 expression by Sox2-expressing cells does not impair cutaneous tissue repair, CCN2 was required for recruitment of cells derived from Sox2-expressing cells to the wound area. Collectively, these results are consistent with the notion that neither CCN2 nor Sox2-expressing progenitor cells are essential for cutaneous tissue repair and that CCN2 represents a specific anti-fibrotic target.     

Targeting papain-like protease for broad-spectrum coronavirus inhibition

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13238-022-00909-3.     

Increasing synchrony opposes stabilizing effects of species richness on terrestrial communities

Aim

Ecological theory has predicted that species richness should stabilize communities, with mechanisms including species synchrony and population variability determining the net impacts. While these theories have been supported empirically, results can be sensitive to taxonomic bias as studies are often focussed on plants. Trophic differences between consumers and primary producers can lead to varying stabilizing effects of species richness. Here, we compared the impact of species richness on community variability in four taxonomic groups: terrestrial birds, mammals, invertebrates and plants.

Location

Global.

Method

Using data from 6763 time series globally (BioTIME) for four terrestrial taxa, we quantified community and population variability and species synchrony based on abundance fluctuations over time.

Results

Species richness destabilized communities through increasing synchrony and stabilized communities through reducing population variability in all taxa. Such opposing effects weakened the net impacts of species richness on communities. Population variability had higher importance relative to synchrony in plant communities. By contrast, synchrony had more comparable (or even higher) importance compared with population variability in animal communities. When synchrony and population variability were not controlled, stabilizing impacts of species richness were detected in plant communities only.

Main Conclusions

Our results highlight how species richness drives stabilizing and destabilizing mechanisms simultaneously across all taxa, with strong taxonomic variation in the relative importance of these mechanisms in regulating community variability. This questions the generality of previous findings on stabilizing impacts of species richness based on limited taxonomic coverage. Additionally, our results indicate the need to understand how the importance of stabilizing and destabilizing mechanisms differs in determining community variability across organisms and environments.     

Structure-activity relationship of a neurite outgrowth-promoting substance purified from the brown alga,Sargassum macrocarpum, and its analogues on PC12D cells

The structure-activity relationship of a neurite outgrowth-promotingsubstance (designated as MC14) from the brown alga, Sargassummacrocarpum, was analysed. Eight synthetic carotenoids and1,4-benzoquinone were used to determine the moiety of the MC14molecule structurally responsible for the nerve growth factor(NGF)-mediated neurite outgrowth-promoting activity on PC12D cells.The bioassays showed that none of these carotenoids exhibitedNGF-potentiating activity. In contrast, 1,4-benzoquinone enhancedsignificantly NGF-mediated neurite outgrowth from PC12D cells, therebeing a 260% increase over the activity of negative control (10 ngmL^-1 NGF). The effect of quinone structure on NGF-potentiatingactivity, when examined using 12 naturally occurring quinones,demonstrated that lawsone, alizarin and lapachol significantly enhancedNGF-mediated neurite outgrowth by 329%, 325% and 265%,respectively, of that in the negative control. These results show thatquinone is the structural moiety of MC14 molecule responsible for theneurite outgrowth-promoting activity. In addition, the hydroxyl groupbonded to quinone had a significant effect on neuritogenic activity. Thebearing of a hydroxyl group at the 1'-position of benzoquinone, and thebearing of two hydroxyl groups at the 1' and 2'-positions of anthraquinone,played a crucial role in enhancing the neurite outgrowth-promoting actionof NGF.