Arachidonic acid released by PIK3CA mutant tumor cells triggers malignant transformation of colonic epithelium by inducing chromatin remodeling.

Key gene mutations are essential for colorectal cancer (CRC) development; however, how the mutated tumor cells impact the surrounding normal cells to promote tumor progression has not been well defined. Here, we report that PIK3CA mutant tumor cells transmit oncogenic signals and result in malignant transformation of intestinal epithelial cells (IECs) via paracrine exosomal arachidonic acid (AA)-induced H3K4 trimethylation. Mechanistically, PIK3CA mutations sustain SGK3-FBW7-mediated stability of the cPLA2 protein, leading to the synthetic increase in AA, which is transported through exosome and accumulated in IECs. Transferred AA directly binds Menin and strengthens the interactions of Menin and MLL1/2 methyltransferase. Finally, the combination of VTP50469, an inhibitor of the Menin-MLL interaction, and alpelisib synergistically represses PDX tumors harboring PIK3CA mutations. Together, these findings unveil the metabolic link between PIK3CA mutant tumor cells and the IECs, highlighting AA as the potential target for the treatment of patients with CRC harboring PIK3CA mutations.

Macaque Brainnetome Atlas: A multifaceted brain map with parcellation, connection, and histology.

The rhesus macaque (Macaca mulatta) is a crucial experimental animal that shares many genetic, brain organizational, and behavioral characteristics with humans. A macaque brain atlas is fundamental to biomedical and evolutionary research. However, even though connectivity is vital for understanding brain functions, a connectivity-based whole-brain atlas of the macaque has not previously been made. In this study, we created a new whole-brain map, the Macaque Brainnetome Atlas (MacBNA), based on the anatomical connectivity profiles provided by high angular and spatial resolution ex vivo diffusion MRI data. The new atlas consists of 248 cortical and 56 subcortical regions as well as their structural and functional connections. The parcellation and the diffusion-based tractography were evaluated with invasive neuronal-tracing and Nissl-stained images. As a demonstrative application, the structural connectivity divergence between macaque and human brains was mapped using the Brainnetome atlases of those two species to uncover the genetic underpinnings of the evolutionary changes in brain structure. The resulting resource includes: (1) the thoroughly delineated Macaque Brainnetome Atlas (MacBNA), (2) regional connectivity profiles, (3) the postmortem high-resolution macaque diffusion and T2-weighted MRI dataset (Brainnetome-8), and (4) multi-contrast MRI, neuronal-tracing, and histological images collected from a single macaque. MacBNA can serve as a common reference frame for mapping multifaceted features across modalities and spatial scales and for integrative investigation and characterization of brain organization and function. Therefore, it will enrich the collaborative resource platform for nonhuman primates and facilitate translational and comparative neuroscience research.

Betulinic acid arrests cell cycle at G2/M phase by up-regulating metallothionein 1G inhibiting proliferation of colon cancer cells.

Betulinic acid (BA) is a pentacyclic triterpene found in many plant species and has a broad-spectrum anti-tumor effect in various cancers, including colon cancer (CRC). However, its anticancer mechanism in CRC is no clear. RNA sequencing and bioinformatics analysis showed BA up-regulated 378 genes and down-regulated 137 genes in HT29 cells, while 2303 up-regulated and 1041 down-regulated genes were found in SW480 cells. KEGG enrichment analysis showed BA significantly stimulated the expression of metallothionein 1 (MT1) family genes in both HT29 and SW480 cells. Metallothionein 1G (MT1G) was the gene with the highest upregulation of MT1 family genes induced by BA dose-dependently. High MT1G expression enhanced the sensitivity of CRC cells to BA, whereas, MT1G knockdown had the opposite effect in vitro and in vivo. GSEA and GSCA showed genes affected by BA treatment were involved in cell cycle and G2/M checkpoint in CRC. Flow cytometry further exhibited BA reduced the percentage of G0/G1 cells and increased the percentage of G2/M cells in a dose-dependent manner, which could be rescued by MT1G knockdown. Moreover, MT1G also counteracted the BA-induced changes in cell cycle-related proteins (CDK2 and CDK4) and p-Rb. In summary, we have revealed a new anti-tumor mechanism that BA altered the cell cycle progression of CRC cells by upregulating MT1G gene, thereby inhibiting the proliferation of CRC cells.

Variations in culturable bacterial communities and biochemical properties in the foreland of the retreating Tianshan No. 1 glacier

Abstract As a glacier retreats, barren areas are exposed, and these barren areas are ideal sites to study microbial succession. In this study, we characterized the soil culturable bacterial communities and biochemical parameters of early successional soils from a receding glacier in the Tianshan Mountains. The total number of culturable bacteria ranged from 2.19 × 105 to 1.30 × 106 CFU g-1 dw and from 9.33 × 105 to 2.53 × 106 CFU g-1 dw at 4 °C and 25 °C, respectively. The number of culturable bacteria in the soil increased at 25 °C but decreased at 4 °C along the chronosequence. The total organic carbon, total nitrogen content, and enzymatic activity were relatively low in the glacier foreland. The number of culturable bacteria isolated at 25 °C was significantly positively correlated with the TOC and TN as well as the soil urease, protease, polyphenoloxidase, sucrase, catalase, and dehydrogenase activities. We obtained 358 isolates from the glacier foreland soils that clustered into 35 groups using amplified ribosomal DNA restriction analysis. These groups are affiliated with 20 genera that belong to six taxa, namely, Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, Actinobacteria, Bacteroides, and Deinococcus-Thermus, with a predominance of members of Actinobacteria and Proteobacteria in all of the samples. A redundancy analysis showed that the bacterial succession was divided into three periods, an early stage (10a), a middle stage (25-74a), and a late stage (100-130a), with the total number of culturable bacteria mainly being affected by the soil enzymatic activity, suggesting that the microbial succession correlated with the soil age along the foreland.