In Vivo Generation of Engraftable Murine Hematopoietic Stem Cells by Gfi1b, c-Fos, and Gata2 Overexpression within Teratoma.

Generation of hematopoietic stem cells (HSCs) from pluripotent stem cells (PSCs) could potentially provide unlimited HSCs for clinical transplantation, a curative treatment for numerous blood diseases. However, to date, bona fide HSC generation has been largely unsuccessful in vitro. We have previously described proof of concept for in vivo HSC generation from PSCs via teratoma formation. However, our first-generation system was complex and the output low. Here, we further optimize this technology and demonstrate the following: (1) simplified HSC generation using transcription factor overexpression; (2) improved HSC output using c-Kit-deficient host mice, and (3) that teratomas can be transplanted and cryopreserved. We demonstrate that overexpression of Gfi1b, c-Fos, and Gata2, previously reported to transdifferentiate fibroblasts into hematopoietic progenitors in vitro, can induce long-term HSC formation in vivo. Our in vivo system provides a useful platform to investigate new strategies and re-evaluate existing strategies to generate HSCs and study HSC development

Balance Measures Derived from Insole Sensor Differentiate Prodromal Dementia with Lewy Bodies

Dementia with Lewy bodies is the second most common type of neurodegenerative dementia, and identification at the prodromal stage$-$i.e., mild cognitive impairment due to Lewy bodies (MCI-LB)$-$is important for providing appropriate care. However, MCI-LB is often underrecognized because of its diversity in clinical manifestations and similarities with other conditions such as mild cognitive impairment due to Alzheimer's disease (MCI-AD). In this study, we propose a machine learning-based automatic pipeline that helps identify MCI-LB by exploiting balance measures acquired with an insole sensor during a 30-s standing task. An experiment with 98 participants (14 MCI-LB, 38 MCI-AD, 46 cognitively normal) showed that the resultant models could discriminate MCI-LB from the other groups with up to 78.0% accuracy (AUC: 0.681), which was 6.8% better than the accuracy of a reference model based on demographic and clinical neuropsychological measures. Our findings may open up a new approach for timely identification of MCI-LB, enabling better care for patients

A Novel Immunoglobulin-Immunoglobulin Interaction in Autoimmunity

Well over six decades since its first description, the Rheumatoid Factor (RF)—autoantibodies recognizing Fc (constant) portion of IgG through their own Fab (antigen binding variable segments)—is believed to have come of age. Autoimmune pancreatitis is a unique form of pancreatitis, biologically characterized by an elevated serum IgG4 concentration. Given the fact that IgG4 myeloma proteins can act as RF, we initially hypothesized that IgG4 in autoimmune pancreatitis might do likewise, hence potentially contributing to disease pathogenesis. Indeed Western blotting clearly showed that IgG4 binds to IgG1 κ, IgG2 κ, IgG3 κ myeloma proteins, as well as to IgG Fc, in line with a typical RF activity. Further experiments however unraveled the unexpected fact that unlike hitherto known RF, IgG4 does not engage IgG Fc through its Fab, but its very own Fc. These data therefore collectively describe a Novel RF (NRF) in autoimmune pancreatitis. In the future, the relevance of NRF, beyond autoimmune pancreatitis, in both diagnosis/prognosis as well as pathophysiology of autoimmune and other systemic diseases where IgG4's role seems paramount, needs to be systematically assessed

Natural Variation in the Flag Leaf Morphology of Rice Due to a Mutation of the NARROW LEAF 1 Gene in Oryza sativa L.

We investigated the natural variations in the flag leaf morphology of rice. We conducted a principal component analysis based on nine flag leaf morphology traits using 103 accessions from the National Institute of Agrobiological Sciences Core Collection. The first component explained 39% of total variance, and the variable with highest loading was the width of the flag leaf (WFL). A genome-wide association analysis of 102 diverse Japanese accessions revealed that marker RM6992 on chromosome 4 was highly associated with WFL. In analyses of progenies derived from a cross between Takanari and Akenohoshi, the most significant quantitative trait locus (QTL) for WFL was in a 10.3-kb region containing the NARROW LEAF 1 (NAL1) gene, located 0.4 Mb downstream of RM6992. Analyses of chromosomal segment substitution lines indicated that a mutation (G1509A single-nucleotide mutation, causing an R233H amino acid substitution in NAL1) was present at the QTL. This explained 13 and 20% of total variability in WFL and the distance between small vascular bundles, respectively. The mutation apparently occurred during rice domestication and spread into japonica, tropical japonica, and indica subgroups. Notably, one accession, Phulba, had a NAL1 allele encoding only the N-terminal, or one-fourth, of the wild-type peptide. Given that the Phulba allele and the histidine-type allele showed essentially the same phenotype, the histidine-type allele was regarded as malfunctional. The phenotypes of transgenic plants varied depending on the ratio of histidine-type alleles to arginine-type alleles, raising the possibility that H(233)-type products function differently from and compete with R(233)-type products

Nutritional factors, parasite infection and allergy in rural and suburban Vietnamese school children

Urban areas often have more allergy than rural areas. Dietary patterns and parasite infection have been suggested as possible related factors. This study evaluated the prevalence of allergy in school children in one rural and suburban area of Vietnam where parasite infection is common. A total of 195 children aged 9 to 13 years old completed a self-administered allergy questionnaire and provided blood and stool samples for analysis. Nutritional status, dietary intake and parasite infection were determined in all participants. Allergy was more common in girls (10.7% vs. 7.6%), suburban children (11.8% vs. 6.9%), children with weight-for-age (16.7% vs. 6.0%) and height-for-age (14.8% vs. 4.9%) in the10th to75th percentile compared to lt3rd percentile, and in children without trichuriasis compared to light trichuriasis (12.5%vs. 9.3%), although none of these comparisons were statistically significant. Logistic regression adjusted for sex, age and area of residence revealed no association between allergy and nutritional status, food intake or parasite infection. Intake of riboflavin, however, was negatively associated with allergy (OR=0.00,95% CI:0.00-0.65, p=0.038). In conclusion, we were unable to detect any association between allergy and nutritional status, diet, or parasite infection. However, in a population with high undernutrition and parasite infection, the prevalence of allergy was low and the extremely low intake of riboflavin was associated with a higher risk of allergy

A safeguard system for induced pluripotent stem cell-derived rejuvenated T cell therapy

The discovery of induced pluripotent stem cells (iPSCs) has created promising new avenues for therapies in regenerative medicine. However, the tumorigenic potential of undifferentiated iPSCs is a major safety concern for clinical translation. To address this issue, we demonstrated the efficacy of suicide gene therapy by introducing inducible caspase-9 (iC9) into iPSCs. Activation of iC9 with a specific chemical inducer of dimerization (CID) initiates a caspase cascade that eliminates iPSCs and tumors originated from iPSCs. We introduced this iC9/CID safeguard system into a previously reported iPSC-derived, rejuvenated cytotoxic T lymphocyte (rejCTL) therapy model and confirmed that we can generate rejCTLs from iPSCs expressing high levels of iC9 without disturbing antigen-specific killing activity. iC9-expressing rejCTLs exert antitumor effects in vivo. The system efficiently and safely induces apoptosis in these rejCTLs. These results unite to suggest that the iC9/CID safeguard system is a promising tool for future iPSC-mediated approaches to clinical therapy