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The era of advanced artificial intelligence has arrived with the development of chatbots like ChatGPT (Chat Generative Pre-trained Transformer). As described by Ouyang et al. (2022), ChatGPT demonstrates an impressive ability to generate human-like responses and solve practical problems, surpassing original expectations for its capabilities. The rapid release and adoption of ChatGPT signals a new phase in AI development, powered by large language models that can be fine-tuned through human feedback. However, risks remain regarding how such powerful models may be misused. Further research is needed to ensure safe and ethical deployment of these transformative technologies.

Glucocorticoids are steroid hormones well known for their potent anti-inflammatory effects. However, their immunomodulatory properties are multifaceted. Increasing evidence suggests that glucocorticoid signaling promotes effective immunity and that disruption of glucocorticoid signaling impairs immune function. In this study, we conditionally deleted the glucocorticoid receptor (GR) in the myeloid lineage using the LysM-Cre driver (myGRKO). We examined the impact on macrophage activation and gastric immune responses to Helicobacter pylori, the best-known risk factor of gastric cancer. Our results indicate that, compared with wild type (WT), glucocorticoid receptor knockout (GRKO) macrophages exhibited higher expression of proinflammatory genes in steroid-free conditions. However, when challenged in vivo, GRKO macrophages exhibited aberrant chromatin landscapes and impaired proinflammatory gene expression profiles. Moreover, gastric colonization with H. pylori revealed impaired gastric immune responses and reduced T cell recruitment in myGRKO mice. As a result, myGRKO mice were protected from atrophic gastritis and pyloric metaplasia development. These results demonstrate a dual role for glucocorticoid signaling in preparing macrophages to respond to bacterial infection but limiting their pathogenic activation. In addition, our results support that macrophages are critical for gastric H. pylori immunity. NEW & NOTEWORTHY: Signaling by endogenous glucocorticoids primes macrophages toward more robust responses to pathogens. Disruption of glucocorticoid signaling caused dysregulation of the chromatin landscape, blunted proinflammatory gene activation upon bacterial challenge, and impaired the gastric inflammatory response to Helicobacter pylori infection. [ABSTRACT FROM AUTHOR]

Multiple myeloma is the second most hematological cancer. RUVBL1 and RUVBL2 form a subcomplex of many chromatin remodeling complexes implicated in cancer progression. As an inhibitor specific to the RUVBL1/2 complex, CB-6644 exhibits remarkable anti-tumor activity in xenograft models of Burkitt's lymphoma and multiple myeloma (MM). In this work, we defined transcriptional signatures corresponding to CB-6644 treatment in MM cells and determined underlying epigenetic changes in terms of chromatin accessibility. CB-6644 upregulated biological processes related to interferon response and downregulated those linked to cell proliferation in MM cells. Transcriptional regulator inference identified E2Fs as regulators for downregulated genes and MED1 and MYC as regulators for upregulated genes. CB-6644-induced changes in chromatin accessibility occurred mostly in non-promoter regions. Footprinting analysis identified transcription factors implied in modulating chromatin accessibility in response to CB-6644 treatment, including ATF4/CEBP and IRF4. Lastly, integrative analysis of transcription responses to various chemical compounds of the molecular signature genes from public gene expression data identified CB-5083, a p97 inhibitor, as a synergistic candidate with CB-6644 in MM cells, but experimental validation refuted this hypothesis. [ABSTRACT FROM AUTHOR]

Nucleosome positioning is critical to chromatin accessibility and is associated with gene expression programs in cells.sup.1-3. Previous nucleosome mapping methods assemble profiles from cell populations and reveal a cell-averaged pattern: nucleosomes are positioned and form a phased array that surrounds the transcription start sites of active genes.sup.3-6 and DNase I hypersensitive sites.sup.7. However, even in a homogenous population of cells, cells exhibit heterogeneity in expression in response to active signalling.sup.8,9 that may be related to heterogeneity in chromatin accessibility.sup.10-12. Here we report a technique, termed single-cell micrococcal nuclease sequencing (scMNase-seq), that can be used to simultaneously measure genome-wide nucleosome positioning and chromatin accessibility in single cells. Application of scMNase-seq to NIH3T3 cells, mouse primary naive CD4 T cells and mouse embryonic stem cells reveals two principles of nucleosome organization: first, nucleosomes in heterochromatin regions, or that surround the transcription start sites of silent genes, show large variation in positioning across different cells but are highly uniformly spaced along the nucleosome array; and second, nucleosomes that surround the transcription start sites of active genes and DNase I hypersensitive sites show little variation in positioning across different cells but are relatively heterogeneously spaced along the nucleosome array. We found a bimodal distribution of nucleosome spacing at DNase I hypersensitive sites, which corresponds to inaccessible and accessible states and is associated with nucleosome variation and variation in accessibility across cells. Nucleosome variation is smaller within single cells than across cells, and smaller within the same cell type than across cell types. A large fraction of naive CD4 T cells and mouse embryonic stem cells shows depleted nucleosome occupancy at the de novo enhancers detected in their respective differentiated lineages, revealing the existence of cells primed for differentiation to specific lineages in undifferentiated cell populations.Single-cell micrococcal nuclease sequencing simultaneously measures chromatin accessibility and genome-wide nucleosome positioning in single cells to reveal principles of nucleosome organization., Author(s): Binbin Lai [sup.1] , Weiwu Gao [sup.1] [sup.2] , Kairong Cui [sup.1] , Wanli Xie [sup.1] [sup.3] , Qingsong Tang [sup.1] , Wenfei Jin [sup.4] , Gangqing Hu [sup.1] [...]

Simple Summary: Multiple myeloma cells mainly proliferate in the bone marrow (BM). Mesenchymal stem cells (MSCs) in the BM of MM patients are tumor supportive and exhibit an inflammatory transcription signature and contribute to drug resistance. Due to their rarity in the BM, downstream functional characterization of the cells requires in vitro expansion. We conducted a systemic analysis of public expression data and reported the loss of the inflammatory signature during in vitro expansion. However, further analysis on additional publicly available expression data revealed that cytokine stimulations and coculture with immune cells or cancer cells were able to reactivate the transcription signature. Our findings established a crucial foundation for future research into the contribution of the inflammatory status to the tumor-supportive functions of BM MSCs in disease progression and resistance to therapy. Bone marrow mesenchymal stem cells (BM MSCs) play a tumor-supportive role in promoting drug resistance and disease relapse in multiple myeloma (MM). Recent studies have discovered a sub-population of MSCs, known as inflammatory MSCs (iMSCs), exclusive to the MM BM microenvironment and implicated in drug resistance. Through a sophisticated analysis of public expression data from unexpanded BM MSCs, we uncovered a positive association between iMSC signature expression and minimal residual disease. While in vitro expansion generally results in the loss of the iMSC signature, our meta-analysis of additional public expression data demonstrated that cytokine stimulation, including IL1-β and TNF-α, as well as immune cells such as neutrophils, macrophages, and MM cells, can reactivate the signature expression of iMSCs to varying extents. These findings underscore the importance and potential utility of cytokine stimulation in mimicking the gene expression signature of early passage of iMSCs for functional characterizations of their tumor-supportive roles in MM. [ABSTRACT FROM AUTHOR]