Isoform-specific potentiation of stem and progenitor cell engraftment by AML1/RUNX1

Background: AML1/RUNX1 is the most frequently mutated gene in leukaemia and is central to the normal biology of hematopoietic stem and progenitor cells. However, the role of different AML1 isoforms within these primitive compartments is unclear. Here we investigate whether altering relative expression of AML1 isoforms impacts the balance between cell self-renewal and differentiation in vitro and in vivo. Methods and Findings: The human AML1a isoform encodes a truncated molecule with DNA-binding but no transactivation capacity. We used a retrovirus-based approach to transduce AML1a into primitive haematopoietic cells isolated from the mouse. We observed that enforced AML1a expression increased the competitive engraftment potential of murine long-term reconstituting stem cells with the proportion of AML1a-expressing cells increasing over time in both primary and secondary recipients. Furthermore, AML1a expression dramatically increased primitive and committed progenitor activity in engrafted animals as assessed by long-term culture, cobblestone formation, and colony assays. In contrast, expression of the full-length isoform AML1b abrogated engraftment potential. In vitro, AML1b promoted differentiation while AML1a promoted proliferation of progenitors capable of short-term lymphomyeloid engraftment. Consistent with these findings, the relative abundance of AML1a was highest in the primitive stem/progenitor compartment of human cord blood, and forced expression of AML1a in these cells enhanced maintenance of primitive potential both in vitro and in vivo. Conclusions: These data demonstrate that the "a" isoform of AML1 has the capacity to potentiate stem and progenitor cell engraftment, both of which are required for successful clinical transplantation. This activity is consistent with its expression pattern in both normal and leukaemic cells. Manipulating the balance of AML1 isoform expression may offer novel therapeutic strategies, exploitable in the contexts of leukaemia and also in cord blood transplantation in adults, in whom stem and progenitor cell numbers are often limiting. © 2007 Tsuzuki et al

Establishment of Rat Embryonic Stem Cells and Making of Chimera Rats

The rat is a reference animal model for physiological studies and for the analysis of multigenic human diseases such as hypertension, diabetes, neurological disorders, and cancer. The rats have long been used in extensive chemical carcinogenesis studies. Thus, the rat embryonic stem (rES) cell is an important resource for the study of disease models. Attempts to derive ES cells from various mammals, including the rat, have not succeeded. Here we have established two independent rES cells from Wister rat blastocysts that have undifferentiated characters such as Nanog and Oct3/4 genes expression and they have stage-specific embryonic antigen (SSEA) -1, -3, -4, and TRA-1-81 expression. The cells were successfully cultured in an undifferentiated state and can be possible over 18 passages with maintaining more than 40% of normal karyotype. Their pluripotent potential was confirmed by the differentiation into derivatives of the endoderm, mesoderm, and ectoderm. Most importantly, the rES cells are capable of producing chimera rats. Therefore, we established pluripotent rES cell lines that are widely used to produce genetically modified experimental rats for study of human diseases

Effects of pyrolysis temperature and feedstock type on particulate matter emission characteristics during biochar combustion

Aiming to reduce the emission of particulate matter (PM) during biomass combustion, we investigated the effects of pyrolysis temperature and feedstock type on the chemical properties of biochar and PM emission characteristics during subsequent combustion. Wood- and manure-based char samples were prepared at pyrolysis temperatures ranging from 200 to 500 °C and combusted in a laboratory-scale tube furnace at 850 °C. Due to the removal of volatile matter (VM), the total PM emission factor (EF) of the wood char decreased with increasing pyrolysis temperature, becoming negligible with pyrolysis at temperatures over 400 °C. For manure char, although pyrolysis removed VM and reduced the total PM EF from 12.5 ± 2.7 to 5.8 ± 2.9 mg/g-fuel, the high ash content precluded any effect on the emission of ash-derived PM. The occurrence of ash-derived PM resulted from release of Na, Mg, K, and Ca and was enhanced at higher combustion temperatures. We demonstrated that the pyrolysis of low-ash biomass effectively reduces the risk of PM emission. However, the efficacy of thermal treatment of high-ash biomass is limited but might be improved with further treatment, such as ash removal

Crystalline functionalized endohedral C60 metallofullerides

Endohedral metallofullerenes have been extensively studied since the first experimental observation of La@C₆₀ in a laser-vaporized supersonic beam in 1985. However, most of these studies have focused on metallofullerenes larger than C₆₀ such as (metal)@C₈₂, and there are no reported purified C₆₀-based monomeric metallofullerenes, except for [Li@C₆₀]⁺(SbCl₆)⁻salt. Pure (metal)@C₆₀ compounds have not been obtained because of their extremely high chemical reactivity. One route to their stabilization is through chemical functionalization. Here we report the isolation, structural determination and electromagnetic properties of functionalized crystalline C₆₀-based metallofullerenes Gd@C₆₀(CF₃)₅ and La@C₆₀(CF₃)₅. Synchrotron X-ray single-crystal diffraction reveals that La and Gd atoms are indeed encapsulated in the Ih-C₆₀ fullerene. The HOMO-LUMO gaps of Gd@C₆₀ and La@C₆₀ are significantly widened by an order of magnitude with addition of CF₃ groups. Magnetic measurements show the presence of a weak antiferromagnetic coupling in Gd@C₆₀(CF₃)₅ crystals at low temperatures

Risk Factors for Therapeutic Intervention of Remdesivir in Mild to Moderate COVID-19—A Single-Center Retrospective Study of the COVID-19 Fourth Pandemic Period in Wakayama, Japan

Background and Objectives: The incidence of coronavirus disease 2019 (COVID-19) has increased in Wakayama, Japan, due to the spread of the highly infectious B.1.1.7 variant. Before this event, the medical systems were almost unaffected. We aimed to assess the clinical characteristics of patients hospitalized with COVID-19 and the risk factors for therapeutic intervention of remdesivir during the fourth pandemic period in Wakayama, Japan. Materials and Methods: This single-center retrospective study enrolled 185 patients with mild to moderate COVID-19 hospitalized in our hospital without intensive care between 14 March and 31 May 2021. Results: In this period, 125 (67.6%) of the 185 patients had the B.1.1.7 variant. Sixty-three patients (34.1%) required remdesivir treatment. Age upon admission and length of hospitalization were significantly different between remdesivir treatment and careful observation groups (mean (standard deviation); 59.6 (14.7) versus 45.3 (20.6) years; p p p p = 0.002), B.1.1.7 variant (OR 5.30; p = 0.005), lower respiratory symptoms (OR 3.13, p = 0.011), headache (OR 3.82, p = 0.011), and fever ≥37.5 °C (OR 4.55, p = 0.001) were independent risk factors to require remdesivir treatment during the admission. Conclusions: Many patients with mild to moderate COVID-19 required the therapeutic intervention of remdesivir during the fourth pandemic period in Wakayama, Japan. From the clinical data obtained at admission, these risk factors could contribute to a prediction regarding the requirement of remdesivir treatment in cases of mild to moderate COVID-19

Lymphotoxin-alpha polymorphisms and presence of cancer in 1,536 consecutive autopsy cases

<p>Abstract</p> <p>Background</p> <p>Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine with anti-tumor activity. The objective of this study was to determine whether <it>LTA </it>polymorphisms influence the presence of cancer.</p> <p>Methods</p> <p><it>LTA </it>polymorphisms C804A (rs1041981, T60N) and T495C (rs2229094, C13R) were determined in 1,536 consecutive autopsy cases and were registered in the Japanese single-nucleotide polymorphisms (SNPs) for geriatric research (JG-SNP) Internet database. Tumors were systematically reviewed, pathologically confirmed, and assessed in relation to <it>LTA </it>genotype.</p> <p>Results</p> <p>The study population consisted of 827 males and 709 females, with a mean age of 80 years. Altogether, we studied 606 subjects without cancer and 930 subjects with cancer of the stomach (n = 183), lung (n = 164), colon or rectum (n = 143), or other sites. The presence of cancer was higher in males than in females. The C804A and T495C polymorphisms were associated with cancer in males (CA + AA: CC, adjusted OR = 0.72, 95% CI = 0.53 – 0.99; TC + CC: TT, adjusted OR = 1.45, 95% CI = 1.04 – 2.02; respectively) but not in females. In males, the C804A polymorphism was associated with lung cancer (CA + AA: CC, adjusted OR = 0.60, 95% CI = 0.37 – 0.97), whereas the T495C polymorphism was associated with gastric cancer (TC + CC: TT, adjusted OR = 1.68, 95% CI = 1.06 – 2.65).</p> <p>Conclusion</p> <p>We found some evidence of an association between <it>LTA </it>polymorphisms and cancer risk in elderly Japanese men. Further studies in larger populations should examine this hypothesis.</p