In vivo partial cellular reprogramming enhances liver plasticity and regeneration.

Mammals have limited regenerative capacity, whereas some vertebrates, like fish and salamanders, are able to regenerate their organs efficiently. The regeneration in these species depends on cell dedifferentiation followed by proliferation. We generate a mouse model that enables the inducible expression of the four Yamanaka factors (Oct-3/4, Sox2, Klf4, and c-Myc, or 4F) specifically in hepatocytes. Transient in vivo 4F expression induces partial reprogramming of adult hepatocytes to a progenitor state and concomitantly increases cell proliferation. This is indicated by reduced expression of differentiated hepatic-lineage markers, an increase in markers of proliferation and chromatin modifiers, global changes in DNA accessibility, and an acquisition of liver stem and progenitor cell markers. Functionally, short-term expression of 4F enhances liver regenerative capacity through topoisomerase2-mediated partial reprogramming. Our results reveal that liver-specific 4F expression in vivo induces cellular plasticity and counteracts liver failure, suggesting that partial reprogramming may represent an avenue for enhancing tissue regeneration

Dataset for Shojima_BMJ open-Final

Dataset for Shojima_BMJ open-Fina

Data from: Voluntary home and car smoke-free rules in Japan: a cross-sectional study in 2015

Objectives: Recently, the Tokyo Metropolitan Assembly passed an ordinance prohibiting smoking in private homes and cars if children are present. However, no previous study has investigated existing, voluntary home and car smoke-free rules in Japan. Therefore, we examined prevalence and determinants of comprehensive home and car smoke-free rules. Design: A cross-sectional study. Setting: Internet survey data with adjustments using inverse probability weighting for ‘being a respondent in an internet survey’. Participants: 5600 respondents aged 15-69 years in 2015 were analyzed to estimate weighted percentages and prevalence ratios (PRs) with 95% confidence intervals (CIs) of having comprehensive home and car smoke-free rules. Main outcome measures: Respondents who answered ‘smoking is never allowed’ in their home or car were defined as having home and car smoke-free rules. Results: Overall, 47.0% (95% CI = 45.8–48.3) of respondents implemented comprehensive home and car smoke-free rules. People who agreed with ‘smoking relieves stress’ were less likely to have comprehensive smoke-free rules (PR=0.76 [0.71–0.82]), especially among ever-users of electronic nicotine delivery systems (PR=0.49 [0.30–0.81]). Higher education was significantly associated with higher PR for comprehensive smoke-free rules (PR=1.30 [1.19–1.41]). Living with children was significantly associated with higher PR for smoke-free rules among current smokers than not living with children. Among never and former smokers, electronic device ever-users were less likely to have smoke-free rules than non-users (PR=2.91 [1.99–4.27]). Conclusions: In Japan, about 50% of respondents had voluntary smoke-free rules in the home and car. Information on current voluntary smoke-free rules will be useful as baseline information on home and car smoke-free status before enforcement of the 2018 Tokyo home and car smoke-free legislation

Postpartum Methicillin-Resistant Staphylococcus aureus Toxic Shock Syndrome Caused by a Perineal Infection

Although toxic shock syndrome (TSS) is rare, multiorgan failure can occur without early identification and appropriate therapy. In particular, a few cases of postpartum TSS due to methicillin-resistant Staphylococcus aureus (MRSA) have been reported. Here, we describe a rare case in which a 32-year-old Japanese woman had TSS due to MRSA that was caused by a perineal infection after a normal vaginal delivery. Twelve days after giving birth to a healthy child, she was readmitted to our hospital due to a 2-day fever and perineal pain without uterine tenderness. She developed emesis and watery diarrhea on the night of admission. On the second day, a diffuse cutaneous macular rash appeared over her trunk. Laboratory data revealed deteriorated renal function and thrombocytopenia. Her history and clinical results were compatible with a typical course of TSS. Administration of ceftriaxone and clindamycin was started immediately after admission and was effective. The patient recuperated steadily over the next week with desquamation of the skin. MRSA was isolated from her vaginal discharge and was found to produce TSS toxin 1 (TSST-1). Furthermore, since MRSA was not detected in the nasal and vaginal cavity during pregnancy, it suggests that vaginal colonization can also occur postpartum and be the disease source in mothers. Therefore, MRSA infections should be considered when treating for postpartum TSS

Therapeutic strategy for spinal muscular atrophy by combining gene supplementation and genome editing

Abstract Defect in the SMN1 gene causes spinal muscular atrophy (SMA), which shows loss of motor neurons, muscle weakness and atrophy. While current treatment strategies, including small molecules or viral vectors, have shown promise in improving motor function and survival, achieving a definitive and long-term correction of SMA’s endogenous mutations and phenotypes remains highly challenging. We have previously developed a CRISPR-Cas9 based homology-independent targeted integration (HITI) strategy, enabling unidirectional DNA knock-in in both dividing and non-dividing cells in vivo. In this study, we demonstrated its utility by correcting an SMA mutation in mice. When combined with Smn1 cDNA supplementation, it exhibited long-term therapeutic benefits in SMA mice. Our observations may provide new avenues for the long-term and efficient treatment of inherited diseases

In vivo partial cellular reprogramming enhances liver plasticity and regeneration

Mammals have limited regenerative capacity, whereas some vertebrates, like fish and salamanders, are able to regenerate their organs efficiently. The regeneration in these species depends on cell dedifferentiation followed by proliferation. We generate a mouse model that enables the inducible expression of the four Yamanaka factors (Oct-3/4, Sox2, Klf4, and c-Myc, or 4F) specifically in hepatocytes. Transient in vivo 4F expression induces partial reprogramming of adult hepatocytes to a progenitor state and concomitantly increases cell proliferation. This is indicated by reduced expression of differentiated hepatic-lineage markers, an increase in markers of proliferation and chromatin modifiers, global changes in DNA accessibility, and an acquisition of liver stem and progenitor cell markers. Functionally, short-term expression of 4F enhances liver regenerative capacity through topoisomerase2-mediated partial reprogramming. Our results reveal that liver-specific 4F expression in vivo induces cellular plasticity and counteracts liver failure, suggesting that partial reprogramming may represent an avenue for enhancing tissue regeneration