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A central issue in stem cell biology is to understand the mechanisms that regulate the self-renewal of haematopoietic stem cells (HSCs), which are required for haematopoiesis to persist for the lifetime of the animal. We found that adult and fetal mouse and adult human HSCs express the proto-oncogene Bmi-1. The number of HSCs in the fetal liver of Bmi-1-/- mice was normal. In postnatal Bmi-1-/- mice, the number of HSCs was markedly reduced. Transplanted fetal liver and bone marrow cells obtained from Bmi-1-/- mice were able to contribute only transiently to haematopoiesis. There was no detectable self-renewal of adult HSCs, indicating a cell autonomous defect in Bmi-1-/- mice. A gene expression analysis revealed that the expression of stem cell associated genes, cell survival genes, transcription factors, and genes modulating proliferation including p16Ink4a and p19Arf was altered in bone marrow cells of the Bmi-1-/- mice. Expression of p16Ink4a and p19Arf in normal HSCs resulted in proliferative arrest and p53-dependent cell death, respectively. Our results indicate that Bmi-1 is essential for the generation of self-renewing adult HSCs.

Stem cells persist throughout life by self-renewing in numerous tissues including the central and peripheral nervous systems. This raises the issue of whether there is a conserved mechanism to effect self-renewing divisions. Deficiency in the polycomb family transcriptional repressor Bmi-1 leads to progressive postnatal growth retardation and neurological defects. Here we show that Bmi-1 is required for the self-renewal of stem cells in the peripheral and central nervous systems but not for their survival or differentiation. The reduced self-renewal of Bmi-1-deficient neural stem cells leads to their postnatal depletion. In the absence of Bmi-1, the cyclin-dependent kinase inhibitor gene p16Ink4a is upregulated in neural stem cells, reducing the rate of proliferation. p16Ink4a deficiency partially reverses the self-renewal defect in Bmi-1-/- neural stem cells. This conserved requirement for Bmi-1 to promote self-renewal and to repress p16Ink4a expression suggests that a common mechanism regulates the self-renewal and postnatal persistence of diverse types of stem cell. Restricted neural progenitors from the gut and forebrain proliferate normally in the absence of Bmi-1. Thus, Bmi-1 dependence distinguishes stem cell self-renewal from restricted progenitor proliferation in these tissues.

Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: hematopoietic stem cell (HSC); senescence-associated heterochromatic foci (SAHF); retinoblastoma protein (pRB); acute myeloid leukemia (AML); mouse embryonic fibroblast (MEF); cyclin-dependent kinase (Cdk); mouse double minute 2 (MDM2); mammary epithelial cell (MEC). Stem cells generate the differentiated cell types within many organs throughout the lifespan of an organism and are thus ultimately responsible for the longevity of multicellular organisms. Therefore, senescence of stem cells must be prevented. Bmi1 is required for the maintenance of adult stem cells in some tissues partly because it represses genes that induce cellular senescence and cell death. PERSPECTIVE SERIES

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Ca2؉ /calmodulin-dependent protein kinase IV (CaMkinase IV), a member of the CaM-kinase family involved in transcriptional regulation, is stimulated by Ca 2؉ /CaM but also requires phosphorylation by a CaM-kinase kinase for full activation. In this study we investigated the physiological role of a CaM-kinase cascade in Jurkat T human lymphocytes through antigen receptor (CD3) signaling. Total and Ca 2؉ -independent CaM-kinase IV activities were increased 8 -14-fold by anti-CD3 antibody. This CD3-mediated activation involved phosphorylation since the immunoprecipitated CaM-kinase IV from stimulated Jurkat cells could be subsequently inactivated in vitro by protein phosphatase 2A. CaM-kinase IV immunoprecipitated from unstimulated Jurkat cells or CD3-negative mutant Jurkat cells could be activated in vitro 10 -40-fold by CaM-kinase kinase purified from rat brain or thymus, whereas CaM-kinase IV from CD3-stimulated wild-type Jurkat cells was only activated to 2-3-fold by exogenous CaM-kinase kinase. CaM-kinase IV activation was triggered by Ca 2؉ acting through calmodulin since activation could also be elicited by ionomycin treatment, and CD3-mediated activation was blocked by the calmodulin antagonist calmidazolium. These data are consistent with a CaM-kinase cascade in which CaMkinase IV is activated by a CaM-kinase kinase cascade triggered by elevated intracellular calcium in Jurkat cells.

Nosocomial transmission of COVID-19 among immunocompromised hosts can have a serious impact on COVID-19 severity, underlying disease progression and SARS-CoV-2 transmission to other patients and healthcare workers within hospitals. We experienced a nosocomial outbreak of COVID-19 in the setting of a daycare unit for paediatric and young adult cancer patients. Between 9 and 18 November 2020, 473 individuals (181 patients, 247 caregivers/siblings and 45 staff members) were exposed to the index case, who was a nursing staff. Among them, three patients and four caregivers were infected. Two 5-year-old cancer patients with COVID-19 were not severely ill, but a 25-year-old cancer patient showed prolonged shedding of SARS-CoV-2 RNA for at least 12 weeks, which probably infected his mother at home approximately 7-8 weeks after the initial diagnosis. Except for this case, no secondary transmission was observed from the confirmed cases in either the hospital or the community. To conclude, in the day care setting of immunocompromised children and young adults, the rate of in-hospital transmission of SARS-CoV-2 was 1.6% when applying the stringent policy of infection prevention and control, including universal mask application and rapid and extensive contact investigation. Severely immunocompromised children/young adults with COVID-19 would have to be carefully managed after the mandatory isolation period while keeping the possibility of prolonged shedding of live virus in mind.

Lignin-based polycaprolactone (LigPCL) copolymer was synthesized by both the ring opening reaction of εcaprolactone with the hydroxyl groups in the lignin and the concomitant polymerization of ε-caprolactone. FTIR spectra showed C=O (1755 cm-1) and CO (1202 cm-1) peaks confirming that the esterification reaction took place successfully between lignin and ε-caprolactone. T 2 , at which the weight loss of 2% occurs, of pristine lignin and LigPCL were measured as 63 and 211 o C, respectively, and so the synthesized LigPCL had superior thermal stability to the lignin. PP/Lig-PCL blends were prepared at various contents of LigPCL up to 30 wt% by a melt extrusion process. In proportion to the content of the LigPCL, tensile strengths, flexural strengths, and tensile modulus of PP/LigPCL blends greatly decreased, but elongations at break of those greatly increased. To improve the compatibility between PP and LigPCL, maleic anhydride-grafted polypropylene (PP-g-MA) was added. SEM images for the fracture surfaces of the blends showed that the PP-g-MA was effective in reducing the domain size of dispersed phase. Thus, T 2 , tensile strength, tensile modulus, and elongation at break of a 70/30 blend of PP/LigPCL were enhanced by 6 o C, 17%, 31%, and 79%, respectively, by the addition of PP-g-MA. This work clearly demonstrates that thermoplastic LigPCL could be desirably synthesized and applied for value added and eco-friendly products through common melt processes used for polymer blend or composites manufacturing.