Rapid growth of genome data provides opportunities for updating microbial evolutionary relationships, but this is challenged by the discordant evolution of individual genes. Here we build a reference phylogeny of 10,575 evenly-sampled bacterial and archaeal genomes, based on a comprehensive set of 381 markers, using multiple strategies. Our trees indicate remarkably closer evolutionary proximity between Archaea and Bacteria than previous estimates that were limited to fewer “core” genes, such as the ribosomal proteins. The robustness of the results was tested with respect to several variables, including taxon and site sampling, amino acid substitution heterogeneity and saturation, non-vertical evolution, and the impact of exclusion of candidate phyla radiation (CPR) taxa. Our results provide an updated view of domain-level relationships.

Background: Using a toxin-induced nonhuman primate model of acute liver failure (ALF), we previously reported that peripheral infusion of human umbilical cord mesenchymal stem cells (hUC-MSCs) strongly suppresses the activation of circulating monocytes and interleukin-6 (IL-6) production, thereby disrupting the development of a cytokine storm and improving the prognosis of monkeys. MSCs are considered to play a therapeutic role under different stresses by adaptively producing specific factors, prompting us to investigate the factors that hUC-MSCs produce in response to high serum levels of IL-6, which plays a critical role in initiating and accelerating ALF. Methods: We stimulated hUC-MSCs with IL-6, and the hUC-MSC-derived exosomes were deeply sequenced. The miRNAs in the exosomes that have potential to suppress IL-6-associated signaling pathway were screened, and the role of one of the most possible miRNAs was tested in the mouse model of inflammatory liver injury. Result: We determined that miR-455-3p, which is secreted through exosomes and potentially targets PI3K signaling, was highly produced by hUC-MSCs with IL-6 stimulation. The miR-455-3p-enriched exosomes could inhibit the activation and cytokine production of macrophages challenged with lipopolysaccharide (LPS) both in vivo and in vitro. In a chemical liver injury mouse model, enforced expression of miR-455-3p could attenuate macrophage infiltration and local liver damage and reduce the serum levels of inflammatory factors, thereby improving liver histology and systemic disorder. Conclusions: miR-455-3p-enriched exosomes derived from hUC-MSCs are a promising therapy for acute inflammatory liver injury.

Blockade antibodies of the immunoinhibitory receptor PD-1 can stimulate the anti-tumor activity of T cells, but clinical benefit is limited to a fraction of patients. Evidence suggests that BTLA, a receptor structurally related to PD-1, may contribute to resistance to PD-1 targeted therapy, but how BTLA and PD-1 differ in their mechanisms is debated. Here, we compared the abilities of BTLA and PD-1 to recruit effector molecules and to regulate T cell signaling. While PD-1 selectively recruited SHP2 over the stronger phosphatase SHP1, BTLA preferentially recruited SHP1 to more efficiently suppress T cell signaling. Contrary to the dominant view that PD-1 and BTLA signal exclusively through SHP1/2, we found that in SHP1/2 double-deficient primary T cells, PD-1 and BTLA still potently inhibited cell proliferation and cytokine production, albeit more transiently than in wild type T cells. Thus, PD-1 and BTLA can suppress T cell signaling through a mechanism independent of both SHP1 and SHP2.

Accumulating evidence suggests that microRNAs and DNA methylation can cause tumor suppressor gene inactivation and promote tumor malignancy. However, the functional mechanisms of miR-29c-3p and DNA methylation in hepatocellular carcinoma (HCC) are unclear. Here, we reported that miR-29c-3p expression was significantly downregulated in HCC tissues and cell lines. Low miR-29c-3p expression correlated with tumor size, multiplicity pathologic features, and shorter overall survival. Overexpression of miR-29c-3p significantly inhibited HCC cell proliferation, apoptosis, migration, and tumor growth in vivo. Moreover, DNA methyltransferases 3B (DNMT3B) was upregulated in HCC tissues, and was negatively correlated with miR-29c-3p expression. Luciferase reporter and western blotting assays revealed that DNMT3B is a target gene directly regulated by miR-29c-3p. Furthermore, miR-29c-3p regulates the methylation of large tumor suppressor gene 1 (LATS1) by DNMT3B, and abnormal methylation of LATS1 inactivates Hippo signaling pathway. We subsequently identified that high DNMT3B expression and low LATS1 expression were frequently identified in HCC tissues and were associated with poor prognosis. In conclusion, our results indicate that miR-29c-3p acts as a tumor suppressor in HCC by targeting DNMT3B and the LATS1-associated Hippo signaling pathway, which might represent a novel potential therapeutic target for HCC.

The current decolonizing global health movement is calling us to take a post-colonial perspective at the research and practice of global health, an area that has been re-defined by contemporary scholars and advocates with the purpose of promoting equity and justice. In this article, we summarize the main points of discussion from the Symposium organized by the editorial board of Global Health Research and Policy, convened in July 2021 in Wuhan, China. Experts participating in the symposium discussed what decolonizing global health means, how to decolonize it, and what criteria to apply in measuring its completion. Through the meeting, a consensus was reached that the current status quo of global health is still replete with various forms of colonial vestiges–ideologies and practices–, and to fully decolonize global health, systemic reforms must be taken that target the fundamental assumptions of global health: does investment in global health bring socioeconomic development, or is it the other way around? Three levels of colonial vestiges in global health were raised and one guiding principle was proposed when thinking of solutions for them. More theoretical discussion needs to be explored to guide practices to decolonize global health.