The Program of Gene Transcription for a Single Differentiating Cell Type During Sporulation in \u3cem\u3eBacillus subtilis\u3c/em\u3e

Asymmetric division during sporulation by Bacillus subtilis generates a mother cell that undergoes a 5-h program of differentiation. The program is governed by a hierarchical cascade consisting of the transcription factors: σE, σK, GerE, GerR, and SpoIIID. The program consists of the activation and repression of 383 genes. The σE factor turns on 262 genes, including those for GerR and SpoIIID. These DNA-binding proteins downregulate almost half of the genes in the σE regulon. In addition, SpoIIID turns on ten genes, including genes involved in the appearance of σK. Next, σK activates 75 additional genes, including that for GerE. This DNA-binding protein, in turn, represses half of the genes that had been activated by σK while switching on a final set of 36 genes. Evidence is presented that repression and activation contribute to proper morphogenesis. The program of gene expression is driven forward by its hierarchical organization and by the repressive effects of the DNA-binding proteins. The logic of the program is that of a linked series of feed-forward loops, which generate successive pulses of gene transcription. Similar regulatory circuits could be a common feature of other systems of cellular differentiation

The Program of Gene Transcription for a Single Differentiating Cell Type during Sporulation in Bacillus subtilis

Asymmetric division during sporulation by Bacillus subtilis generates a mother cell that undergoes a 5-h program of differentiation. The program is governed by a hierarchical cascade consisting of the transcription factors: σ(E), σ(K), GerE, GerR, and SpoIIID. The program consists of the activation and repression of 383 genes. The σ(E) factor turns on 262 genes, including those for GerR and SpoIIID. These DNA-binding proteins downregulate almost half of the genes in the σ(E) regulon. In addition, SpoIIID turns on ten genes, including genes involved in the appearance of σ(K) (.) Next, σ(K) activates 75 additional genes, including that for GerE. This DNA-binding protein, in turn, represses half of the genes that had been activated by σ(K) while switching on a final set of 36 genes. Evidence is presented that repression and activation contribute to proper morphogenesis. The program of gene expression is driven forward by its hierarchical organization and by the repressive effects of the DNA-binding proteins. The logic of the program is that of a linked series of feed-forward loops, which generate successive pulses of gene transcription. Similar regulatory circuits could be a common feature of other systems of cellular differentiation

Cellular senescence in white matter microglia is induced during ageing in mice and exacerbates the neuroinflammatory phenotype

Cellular senescence, a state of irreversible cell-cycle arrest caused by a variety of cellular stresses, is critically involved in age-related tissue dysfunction in various organs. However, the features of cells in the central nervous system that undergo senescence and their role in neural impairment are not well understood as yet. Here, through comprehensive investigations utilising single-cell transcriptome analysis and various mouse models, we show that microglia, particularly in the white matter, undergo cellular senescence in the brain and spinal cord during ageing and in disease models involving demyelination. Microglial senescence is predominantly detected in disease-associated microglia, which appear in ageing and neurodegenerative diseases. We also find that commensal bacteria promote the accumulation of senescent microglia and disease-associated microglia during ageing. Furthermore, knockout of p16 INK4a, a key senescence inducer, ameliorates the neuroinflammatory phenotype in damaged spinal cords in mice. These results advance our understanding of the role of cellular senescence in the central nervous system and open up possibilities for the treatment of age-related neural disorders.Matsudaira T., Nakano S., Konishi Y., et al. Cellular senescence in white matter microglia is induced during ageing in mice and exacerbates the neuroinflammatory phenotype. Communications Biology 6, 665 (2023); https://doi.org/10.1038/s42003-023-05027-2

Targeting Ovarian Cancer Cells Overexpressing CD44 with Immunoliposomes Encapsulating Glycosylated Paclitaxel

Paclitaxel (PTX) is one of the front-line drugs approved for the treatment of ovarian cancer. However, the application of PTX is limited due to the significant hydrophobicity and poor pharmacokinetics. We previously reported target-directed liposomes carrying tumor-selective conjugated antibody and encapsulated glycosylated PTX (gPTX-L) which successfully overcome the PTX limitation. The tubulin stabilizing activity of gPTX was equivalent to that of PTX while the cytotoxic activity of gPTX was reduced. In human ovarian cancer cell lines, SK-OV-3 and OVK18, the concentration at which cell growth was inhibited by 50% (IC50) for gPTX range from 15⁻20 nM, which was sensitive enough to address gPTX-L with tumor-selective antibody coupling for ovarian cancer therapy. The cell membrane receptor CD44 is associated with cancer progression and has been recognized as a cancer stem cell marker including ovarian cancer, becoming a suitable candidate to be targeted by gPTX-L therapy. In this study, gPTX-loading liposomes conjugated with anti-CD44 antibody (gPTX-IL) were assessed for the efficacy of targeting CD44-positive ovarian cancer cells. We successfully encapsulated gPTX into liposomes with the loading efficiency (LE) more than 80% in both of gPTX-L and gPTX-IL with a diameter of approximately 100 nm with efficacy of enhanced cytotoxicity in vitro and of convenient treatment in vivo. As the result, gPTX-IL efficiently suppressed tumor growth in vivo. Therefore gPTX-IL could be a promising formulation for effective ovarian cancer therapies

Seismicity controlled by resistivity structure : the 2016 Kumamoto earthquakes, Kyushu Island, Japan

The M JMA 7.3 Kumamoto earthquake that occurred at 1:25 JST on April 16, 2016, not only triggered aftershocks in the vicinity of the epicenter, but also triggered earthquakes that were 50–100 km away from the epicenter of the main shock. The active seismicity can be divided into three regions: (1) the vicinity of the main faults, (2) the northern region of Aso volcano (50 km northeast of the mainshock epicenter), and (3) the regions around three volcanoes, Yufu, Tsurumi, and Garan (100 km northeast of the mainshock epicenter). Notably, the zones between these regions are distinctively seismically inactive. The electric resistivity structure estimated from one-dimensional analysis of the 247 broadband (0.005–3000 s) magnetotelluric and telluric observation sites clearly shows that the earthquakes occurred in resistive regions adjacent to conductive zones or resistive-conductive transition zones. In contrast, seismicity is quite low in electrically conductive zones, which are interpreted as regions of connected fluids. We suggest that the series of the earthquakes was induced by a local accumulated stress and/or fluid supply from conductive zones. Because the relationship between the earthquakes and the resistivity structure is consistent with previous studies, seismic hazard assessment generally can be improved by taking into account the resistivity structure. Following on from the 2016 Kumamoto earthquake series, we suggest that there are two zones that have a relatively high potential of earthquake generation along the western extension of the MTL