Although the stem cells of various tissues remain in the quiescent state to maintain their undifferentiated state, they also undergo cell divisions as required, and if necessary, even a single stem ...cell is able to provide for lifelong tissue homeostasis. Stem cell populations are precisely controlled by the balance between their symmetric and asymmetric divisions, with their division patterns determined by whether the daughter cells involved retain their self-renewal capacities. Recent studies have reported that metabolic pathways and the distribution of mitochondria are regulators of the division balance of stem cells and that metabolic defects can shift division balance toward symmetric commitment, which leads to stem cell exhaustion. It has also been observed that in asymmetric division, old mitochondria, which are central metabolic organelles, are segregated to the daughter cell fated to cell differentiation, whereas in symmetric division, young and old mitochondria are equally distributed between both daughter cells. Thus, metabolism and mitochondrial biology play important roles in stem cell fate decisions. As these decisions directly affect tissue homeostasis, understanding their regulatory mechanisms in the context of cellular metabolism is critical.
Summary
In Arabidopsis thaliana, heterodimers comprising two bHLH family proteins, LONESOME HIGHWAY (LHW) and TARGET OF MONOPTEROS5 (TMO5) or its homolog TMO5‐LIKE 1 (T5L1) control vascular ...development in the root apical meristem (RAM). The LHW‐TMO5/T5L1 complex regulates vascular cell proliferation, vascular pattern organization, and xylem vessel differentiation; however, the mechanism of preparation for xylem vessel differentiation in the RAM remains elusive.
We examined the relationship between LHW‐T5L1 and VASCULAR‐RELATED NAC‐DOMAIN (VND) genes, which are key regulators of vessel differentiation, using reverse genetics approaches.
LHW‐T5L1 upregulated the expression of VND1, VND2, VND3, VND6, and VND7 but not that of other VNDs. The expression of VND1–VND3 in the RAM was decreased in lhw. In vnd1 vnd2 vnd3 triple loss‐of‐function mutant roots, metaxylem differentiation was delayed, and VND6 and VND7 expression was reduced. Furthermore, transcriptome analysis of VND1‐overexpressing cells revealed that VND1 upregulates genes involved in the synthesis of secondary cell wall components.
These results suggest that LHW‐T5L1 upregulates VND1–VND3 at the early stages of vascular development in the RAM, and VNDs promote a predifferentiation state for xylem vessels by triggering low levels of VND6 and VND7 as well as genes for the synthesis of secondary cell wall materials.
Leukemia stem cells (LSCs, also known as leukemia-initiating cells) not only drive leukemia initiation and progression, but also contribute to drug resistance and/or disease relapse. Therefore, ...eradication of every last LSC is critical for a patient’s long-term cure. Chronic myeloid leukemia (CML) is a myeloproliferative disorder that arises from multipotent hematopoietic stem and progenitor cells. Tyrosine kinase inhibitors (TKIs) have dramatically improved long-term outcomes and quality of life for patients with CML in the chronic phase. Point mutations of the kinase domain of BCR-ABL1 lead to TKI resistance through a reduction in drug binding, and as a result, several new generations of TKIs have been introduced to the clinic. Some patients develop TKI resistance without known mutations, however, and the presence of LSCs is believed to be at least partially associated with resistance development and CML relapse. We previously proposed targeting quiescent LSCs as a therapeutic approach to CML, and a number of potential strategies for targeting insensitive LSCs have been presented over the last decade. The identification of specific markers distinguishing CML-LSCs from healthy HSCs, and the potential contributions of the bone marrow microenvironment to CML pathogenesis, have also been explored. Nonetheless, 25% of CML patients are still expected to switch TKIs at least once, and various TKI discontinuation studies have shown a wide range in the incidence of molecular relapse (from 30% to 60%). In this review, we revisit the current knowledge regarding the role(s) of LSCs in CML leukemogenesis and response to pharmacological treatment and explore how durable treatment-free remission may be achieved and maintained after discontinuing TKI treatment.
The success or failure of food technologies in society depends to a large extent on the public interest, concerns, images, and expectations surrounding them. This paper delves into the landscape of ...public attitudes towards gene-edited foods in Japan, exploring the reasons behind the acceptance or rejection of these products. A literature review and preliminary findings from a survey conducted in Japan in 2022, aim to identify key issues crucial for evaluating societal acceptance of gene-edited foods. The study showed that the public view gene-edited foods as somewhat unnatural, but upon closer examination, significant variation in attitudes was observed among respondents. Some respondents expressed a favorable perception towards gene-edited foods, particularly those that benefit consumers, while others expressed concerns about its perceived artificiality. Moreover, a significant number of respondents displayed indifference or lack of clear perspective regarding gene-edited foods. These findings reflect the complex relationship between public attitudes, naturalness, and social acceptance of gene-edited foods. Furthermore, the study indicates the importance of paying close attention to those who refrain from expressing their viewpoints in the survey. This nuanced landscape warrants further exploration.
Lean body mass is essential for health, yet consensus regarding the effectiveness of protein interventions in increasing lean body mass is lacking.
The aim of this systematic review was to evaluate ...the dose-response relationship of the effects of protein intake on lean body mass.
The PubMed and Ichushi-Web databases were searched electronically, and reference lists of the literature included here and in other meta-analyses were searched manually.
Randomized controlled trials evaluating the effects of protein intake on lean body mass were included.
Two authors independently screened the abstracts; 5 reviewed the full texts.
A total of 5402 study participants from 105 articles were included. In the multivariate spline model, the mean increase in lean body mass associated with an increase in protein intake of 0.1 g/kg of body weight per day was 0.39 kg (95%CI, 0.36-0.41) and 0.12 kg (95%CI, 0.11-0.14) below and above the total protein intake of 1.3 g/kg/d, respectively.
These findings suggest that slightly increasing current protein intake for several months by 0.1 g/kg/d in a dose-dependent manner over a range of doses from 0.5 to 3.5 g/kg/d may increase or maintain lean body mass.
UMIN registration number UMIN000039285.
The role of mitochondria in the fate determination of hematopoietic stem and progenitor cells (HSPCs) is not solely limited to the switch from glycolysis to oxidative phosphorylation, but also ...involves alterations in mitochondrial features and properties, including mitochondrial membrane potential (ΔΨmt). HSPCs have a high ΔΨmt even when the rates of respiration and phosphorylation are low, and we have previously shown that the minimum proton flow through ATP synthesis (or complex V) enables high ΔΨmt in HSPCs. Here we show that HSPCs sustain a unique equilibrium between electron transport chain (ETC) complexes and ATP production. HSPCs exhibit high expression of ETC complex II, which sustains complex III in proton pumping, although the expression levels of complex I or V are relatively low. Complex II inhibition by TTFA caused a substantial decrease of ΔΨmt, particularly in HSPCs, while the inhibition of complex I by Rotenone mainly affected mature populations. Functionally, pharmacological inhibition of complex II reduced in vitro colony-replating capacity but this was not observed when complex I was inhibited, which supports the distinct roles of complex I and II in HSPCs. Taken together, these data highlight complex II as a key regulator of ΔΨmt in HSPCs and open new and interesting questions regarding the precise mechanisms that regulate mitochondrial control to maintain hematopoietic stem cell self-renewal.
•TMRM staining showed a downward trend of ΔΨmt along with hematopoietic differentiation•Unlike complex I and complex V, complex II expression is similar in HSCs and mature populations•Higher complex II: complex V ratio gives rise to high ΔΨmt in HSPCs due to the limited coupling of electron transport chain•Complex II mainly contributes to sustaining ΔΨmt in HSCs•TTFA, inhibitor of complex II, causes a reduction in in vitro colony-forming capacity of HSPCs
The Ten-eleven translocation (TET) enzymes regulate gene expression by promoting DNA demethylation and partnering with chromatin modifiers. TET2, a member of this family, is frequently mutated in ...hematological disorders. The contributions of TET2 in hematopoiesis have been attributed to its DNA demethylase activity, and the significance of its nonenzymatic functions has remained undefined. To dissect the catalytic and non-catalytic requirements of Tet2, we engineered catalytically inactive Tet2 mutant mice and conducted comparative analyses of Tet2 mutant and Tet2 knockout animals. Tet2 knockout mice exhibited expansion of hematopoietic stem and progenitor cells (HSPCs) and developed myeloid and lymphoid disorders, while Tet2 mutant mice predominantly developed myeloid malignancies reminiscent of human myelodysplastic syndromes. HSPCs from Tet2 knockout mice exhibited distinct gene expression profiles, including downregulation of Gata2. Overexpression of Gata2 in Tet2 knockout bone marrow cells ameliorated disease phenotypes. Our results reveal the non-catalytic roles of TET2 in HSPC homeostasis.
Display omitted
•Loss of Tet2 enhances colony replating more than loss of its catalytic activity•Tet2 catalytic mutant mice predominantly develop myeloid malignancies•Tet2 knockout mice develop both myeloid and lymphoid disorders•Tet2 catalytic mutant versus knockout HSPCs exhibit distinct gene expression profiles
The DNA demethylase TET2 is commonly mutated in hematological disorders, but the significance of its enzymatic versus nonenzymatic roles in hematopoiesis remains undefined. Using Tet2 catalytic-mutant and knockout mice, Ito et al. find that Tet2 enzymatic activity is critical for myelopoiesis, while aberrant lymphopoiesis is mainly associated with complete loss of Tet2.
The ASTRIO study was a randomised, multicentre, 24-week study that compared the effects of ferric citrate hydrate (FC) and non-iron-based phosphate binders (control) on anaemia management in ...haemodialysis (HD) patients receiving erythropoiesis-stimulating agents (ESAs). In that study, FC reduced the doses of ESAs and intravenous iron without affecting haemoglobin (Hb); however, the cost-effectiveness of FC was unclear. We retrospectively implemented a cost-effectiveness analysis comparing the incremental cost-effectiveness ratios (ICERs) in FC (n = 42) and control (n = 40) groups in patients with serum phosphate and Hb controlled within the ranges of 3.5-6.0 mg/dL and 10-12 g/dL, respectively. Costs included drug costs of phosphate binders, ESAs, and intravenous iron. Elevated red cell distribution width (RDW) has been reported to be associated with mortality in HD patients and was therefore used as an effectiveness index. The mean (95% confidence interval) differences in drug costs and RDW between the FC and control groups were US$ - 421.36 (- 778.94 to - 63.78, p = 0.02) and - 0.83% (- 1.61 to - 0.05, p = 0.04), respectively. ICER indicated a decrease of US$ 507.66 per 1% decrease in RDW. FC was more cost-effective than non-iron-based phosphate binders. Iron absorbed via FC could promote erythropoiesis and contribute to renal anaemia treatment.
We present safety and efficacy data from Japanese clinical studies on monotherapy with tocilizumab (TCZ), a humanized anti-interleukin 6 receptor monoclonal antibody, in which 601 patients with ...moderate to severe rheumatoid arthritis, with a total of 2188 patient-years (pt-yr) exposure, were enrolled. The median treatment duration was 3.8 years. The incidence of adverse events (AEs), including abnormal laboratory test results, was calculated as 465.1 per 100 pt-yr. The most common serious adverse events (SAEs) were infections (6.22 per 100 pt-yr). There was no increase in the frequency of AEs or SAEs with long-term treatment. Abnormalities in the laboratory test results, such as increases in lipid parameters or abnormal liver function parameters, were common, but most were mild and there were no SAEs related to them. At baseline, 546 patients (90.8%) were taking corticosteroids; of these, 77.8% were able to decrease their corticosteroid dose during the study period, while 35.2% discontinued corticosteroids altogether. In the patients treated longer than 5 years, 91.3, 73.0, and 51.3% met the ACR20, ACR50, and ACR70 response criteria, respectively, and 59.7% met the DAS remission criterion (DAS28 <2.6) at 5 years. In conclusion, based on these results, TCZ has shown good tolerability and high efficacy during long-term treatment.
Patients with iron deficiency anemia are treated with iron preparations, but gastrointestinal symptoms such as nausea and vomiting occur frequently. These symptoms may negatively affect the quality ...of life and work productivity in patients with iron deficiency anemia. This study assessed the impact of nausea and vomiting on the quality of life and work productivity of patients taking iron preparations for heavy menstrual bleeding or anemia.
An online survey was conducted among patients taking iron preparations for heavy menstrual bleeding or anemia. Demographic data and information about medication use and the health condition were collected. The patients were asked to answer the 5-level EQ-5D version, and work productivity and activity impairment questionnaires. The outcomes were reported by patients in the presences of nausea, vomiting, and nausea or vomiting. The association with the 5-level EQ-5D version utility score for the severity and frequency of the symptoms were also assessed.
A total of 385 patients were enrolled, and 96 were patients with nausea or vomiting, of which 94 were with nausea and 27 were with vomiting. The 5-level EQ-5D version utility scores for the patients with nausea, vomiting, and nausea or vomiting were significantly lower than those of the patients without these symptoms (p < 0.001 for each). The 5-level EQ-5D version utility score was correlated with the severity of nausea and the frequency of vomiting per day (p < 0.001 for each). As for the work productivity and activity impairment, the presenteeism, the overall work impairment, and the activity impairment of the patients with nausea, vomiting, and nausea or vomiting were significantly higher than those without these symptoms (p < 0.001 for each). The absenteeism was slightly higher trend was observed, but not significant.
Patients taking iron preparations who have nausea or vomiting experience a significant burden in terms of poorer quality of life and higher work productivity impairment.
UMIN000045700 ( http://www.umin.ac.jp/ctr/ ). Registered on October 11, 2021.
PDF
