Regardless of the presence of cirrhosis, patients with CHB, TB ≥12 mg/dL and INR ≥1.5 should be diagnosed with ACLF. The new criteria diagnosed nearly 20% more patients with an HBV aetiology with ACLF, thus increasing their opportunity to receive timely intensive management.

The homeostatic control of body temperature is essential for survival in mammals and is known to be regulated in part by temperature-sensitive neurons in the hypothalamus. However, the specific neural pathways and corresponding neural populations have not been fully elucidated. To identify these pathways, we used cFos staining to identify neurons that are activated by a thermal challenge and found induced expression in subsets of neurons within the ventral part of the lateral preoptic nucleus (vLPO) and the dorsal part of the dorsomedial hypothalamus (DMD). Activation of GABAergic neurons in the vLPO using optogenetics reduced body temperature, along with a decrease in physical activity. Optogenetic inhibition of these neurons resulted in fever-level hyperthermia. These GABAergic neurons project from the vLPO to the DMD and optogenetic stimulation of the nerve terminals in the DMD also reduced body temperature and activity. Electrophysiological recording revealed that the vLPO GABAergic neurons suppressed neural activity in DMD neurons, and fiber photometry of calcium transients revealed that DMD neurons were activated by cold. Accordingly, activation of DMD neurons using designer receptors exclusively activated by designer drugs (DREADDs) or optogenetics increased body temperature with a strong increase in energy expenditure and activity. Finally, optogenetic inhibition of DMD neurons triggered hypothermia, similar to stimulation of the GABAergic neurons in the vLPO. Thus, vLPO GABAergic neurons suppressed the thermogenic effect of DMD neurons. In aggregate, our data identify vLPO→DMD neural pathways that reduce core temperature in response to a thermal challenge, and we show that outputs from the DMD can induce activity-induced thermogenesis.

The identity and degree of heterogeneity of glial progenitors and their contributions to brain tumor malignancy remain elusive. By applying lineage-targeted single-cell transcriptomics, we uncover an unanticipated diversity of glial progenitor pools with unique molecular identities in developing brain. Our analysis identifies distinct transitional intermediate states and their divergent developmental trajectories in astroglial and oligodendroglial lineages. Moreover, intersectional analysis uncovers analogous intermediate progenitors during brain tumorigenesis, wherein oligodendrocyte-progenitor intermediates are abundant, hyper-proliferative, and progressively reprogrammed toward a stemlike state susceptible to further malignant transformation. Similar actively cycling intermediate progenitors are prominent components in human gliomas with distinct driver mutations. We further unveil lineage-driving networks underlying glial fate specification and identify Zfp36l1 as necessary for oligodendrocyte-astrocyte lineage transition and glioma growth. Together, our results resolve the dynamic repertoire of common and divergent glial progenitors during development and tumorigenesis and highlight Zfp36l1 as a molecular nexus for balancing glial cell-fate decision and controlling gliomagenesis. (A) Immunolabeling for GFAP and GS in the cortex of P5 hGFAP-GFP mice. (B) The percentage of indicated cells among hGFAP-GFP+ cells in P5 mouse cortices (n = 4 for GFAP; n = 3 for GS and PDGFRa). (C) Immunolabeling for GFAP, Olig2, and Slc1a3 from P5 hGFAP-GFP mice. (D) Zoom on boxed area in (C). (E) The percentage of Olig2+ and Olig2À cells among hGFAP-GFP+GFAP+ (left) or hGFAP-GFP+Slc1a3+ (right) cells in P5 mouse cortices (n = 3). (F) Immunolabeling of Blbp in the cortices from hGFAP-GFP mice at P3. (G) Expression of PDGFRa in the cortices of P5 hGFAP-GFP mice. (H) Immunolabeling for Ppp1r14b and Olig2 in the cortices of hGFAP-GFP mice at P3. (I) Immunolabeling for Olig2 and Ki67 from P5 hGFAP-GFP mice. (J) (Left) Enlarged images of (I) show cells co-labeled with Ki67 (arrows) and cells without Ki67 (arrowheads). (Right) Percentage of Olig2+ and Olig2À cells among Ki67+ hGFAP-GFP+ double-positive cells is shown (>300 cell counts from 3 cortices).

Highlights d Hi-C analysis of meiotic chromatin architecture during mouse oocyte development d Late-stage mouse oocytes show unique H3K27me3-marked Polycomb-associating domains d PADs disassemble upon meiotic resumption but briefly reappear in early embryos d PADs are regulated by Polycomb proteins and independent of cohesin

M2-polarized tumor-associated macrophages (TAM) play a critical role in cancer invasion and metastasis. Here, we report that M2 macrophages enhanced metastasis of K7M2 WT osteosarcoma cells to the lungs in mice, thus establishing M2 TAMs as a therapeutic target for blocking osteosarcoma metastasis. We found that retinoic acid (ATRA) inhibited osteosarcoma metastasis via inhibiting the M2 polarization of TAMs. ATRA suppressed IL13- or IL4-induced M2-type macrophages, and then inhibited migration of osteosarcoma cells as promoted by M2-type macrophages ATRA reduced the number of pulmonary metastatic nodes of osteosarcoma and decreased expression of M2-type macrophages in metastatic nodes both in intravenous injection and orthotopic transplantation models. ATRA's effect was independent of conventional STAT3/6 or C/EBPβ signaling, which regulate M2-like polarization of macrophages. Quantitative genomic and functional analyses revealed that MMP12, a macrophage-secreted elastase, was elevated in IL13-skewed TAM polarization, whereas ATRA treatment downregulated IL13-induced secretion of MMP12. This downregulation correlates with the antimetastasis effect of ATRA. Our results show the role of TAM polarization in osteosarcoma metastasis, identify a therapeutic opportunity for antimetastasis treatment, and indicate ATRA treatment as an approach for preventing osteosarcoma metastasis via M2-type polarization intervention. .

Our results delineated an integrated model of the multifaceted interactions between stem cells and recipients, which may open a new avenue to the discovery of single molecule-based therapeutics that simulate stem cell actions.

No abstract

Meiosis initiation is a crucial step for the production of haploid gametes, which occurs from anterior to posterior in fetal ovaries. The asynchrony of the transition from mitosis to meiosis results in heterogeneity in the female germ cell populations, which limits the studies of meiosis initiation and progression at a higher resolution level. To dissect the process of meiosis initiation, we investigated the transcriptional profiles of 19 363 single germ cells collected from E12.5, E14.5, and E16.5 mouse fetal ovaries. Clustering analysis identified seven groups and defined dozens of corresponding transcription factors, providing a global view of cellular differentiation from primordial germ cells toward meiocytes. Furthermore, we explored the dynamics of gene expression within the developmental trajectory with special focus on the critical state of meiosis. We found that meiosis initiation occurs as early as E12.5 and the cluster of oogonia_4 is the critical state between mitosis and meiosis. Our data provide key insights into the transcriptome features of peri‐meiotic female germ cells, which offers new information not only on meiosis initiation and progression but also on screening pathogenic mutations in meiosis‐associated diseases.