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Hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) have robust self-renewal potential, which is responsible for sustaining normal and malignant hematopoiesis, respectively. Although considerable efforts have been made to explore the regulation of HSC and LSC maintenance, the underlying molecular mechanism remains obscure. Here, we observe that the expression of thymocyte-expressed, positive selection-associated 1 (Tespa1) is markedly increased in HSCs after stresses exposure. Of note, deletion of Tespa1 results in short-term expansion but long-term exhaustion of HSCs in mice under stress conditions due to impaired quiescence. Mechanistically, Tespa1 can interact with CSN subunit 6 (CSN6), a subunit of COP9 signalosome, to prevent ubiquitination-mediated degradation of c-Myc protein in HSCs. As a consequence, forcing c-Myc expression improves the functional defect of Tespa1-null HSCs. On the other hand, Tespa1 is identified to be highly enriched in human acute myeloid leukemia (AML) cells and is essential for AML cell growth. Furthermore, using MLL-AF9-induced AML model, we find that Tespa1 deficiency suppresses leukemogenesis and LSC maintenance. In summary, our findings reveal the important role of Tespa1 in promoting HSC and LSC maintenance and therefore provide new insights on the feasibility of hematopoietic regeneration and AML treatment.

Hematopoietic stem cells (HSCs) possess the great self-renewal and multidirectional differentiation ability, which contributes to the continuous generation of various blood cells. Although many intrinsic and extrinsic factors have been found to maintain HSC homeostasis, how to precisely regulate hematopoiesis under stress conditions is poorly understood. In this study, we show that melanocortin receptor 5 (MC5R) is abundantly expressed in hematopoietic stem progenitor cells (HSPCs). Using a MC5R knockout (MC5R-/-) mouse model, we observe that it is not essential for steady-state hematopoiesis. Interestingly, the levels of α-melanocyte stimulating hormone (α-MSH), an important sub-type of melanocortin, are elevated in serum and bone marrow, and the expression of MC5R is upregulated in HSPCs from mice after irradiation. MC5R deficiency aggravates irradiation-induced myelosuppression due to the impairment in the proliferation and reconstitution function of HSCs. Further investigations exhibit that melanocortin/MC5R axis regulates the proliferation of HSCs through activating the PI3K/AKT and MAPK pathways. More importantly, α-MSH treatment can significantly accelerate the hematopoietic recovery in irradiated mice. In conclusion, our data demonstrate that melanocortin/MC5R axis plays a crucial role in regulating HSC proliferation under stress, thus providing a promising strategy to promote hematopoietic regeneration when suffering from injury.

Previous studies have investigated the association between dairy intake and functional disability, but their results were inconsistent. Our study aimed to investigate whether dairy intake may protect against incident functional disability among Japanese older adults.We conducted a longitudinal analysis of dairy intake with incident functional disability in a prospective cohort study of 11,911 Japanese individuals aged ≥ 65 years who were followed up for 8.2 years on average. Data on milk, yogurt, and cheese intake were collected using a validated food frequency questionnaire. Total dairy intake was the sum of the daily intake of milk, yogurt, and cheese, which was sex-specifically categorized in quintiles. Data on functional disability were retrieved from the public Long-term Care Insurance database. The Cox proportional hazards model was used to estimate the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (95%CIs) for incident functional disability.During 97,234 person-years of follow-up, 4874 persons (40.9%) were ascertained as having functional disability. Our study suggested a null association between total dairy intake and incident risk of functional disability; compared to Q1 (the lowest quintile) group, the multivariable-adjusted HRs (95%CIs) were 0.96 (0.88-1.05) for Q2, 0.93 (0.85-1.02) for Q3, 0.93 (0.85-1.02) for Q4, and 1.01 (0.92-1.10) for Q5 (p-trend = 0.840). We did not find any associations between milk, yogurt, or cheese intake and incident risk of functional disability.We found no evidence showing that dairy intake was associated with functional disability among Japanese older adults.

Mitochondria are fundamental but complex determinants for hematopoietic stem cell (HSC) maintenance. However, the factors involved in the regulation of mitochondrial metabolism in HSCs and the underlying mechanisms have not been fully elucidated. Here, we identify sterol regulatory element binding factor-1c (Srebf1c) as a key factor in maintaining HSC biology under both steady-state and stress conditions. Srebf1c knockout (Srebf1c

AIM Maintaining ≥20 teeth is a public health goal worldwide. Healthy aging, which includes psychological and social well-being, as well as physical indicators, has attracted a great deal of attention with the progression of aging societies. However, no studies have examined the association between the number of remaining teeth and healthy aging. This study aimed to investigate the association between the number of remaining teeth and healthy aging. METHODS This community-based longitudinal cohort study included 8300 Japanese people aged ≥65 years who were free of disability and depression in the baseline survey in 2006. The participants were categorized into four groups according to the number of remaining teeth at baseline: 0-9, 10-19, 20-24 and ≥25. The primary outcome was healthy aging (defined as meeting all four of the following criteria: free of disability, free of depression, high health-related quality of life and high life satisfaction), as assessed by a questionnaire survey carried out in 2017. Multiple logistic regression was used to calculate the corresponding odds ratios and 95% confidence intervals. RESULTS During about 11 years of follow-up, 621 (7.5%) participants attained healthy aging. Participants with ≥20 remaining teeth showed a higher healthy aging rate. Compared with participants with 0-9 teeth, the multivariate-adjusted odds ratios (95% confidence intervals) for 10-19, 20-24 and ≥25 teeth were 0.98 (0.77-1.26), 1.28 (1.01-1.63) and 1.59 (1.24-2.03), respectively. CONCLUSIONS These findings suggest that maintaining ≥20 teeth was associated with healthy aging. Geriatr Gerontol Int 2021; ••: ••-••.

Ionizing radiation (IR)-induced excessive reactive oxygen species (ROS) is an important contributor of the injury of hematopoietic system. Grape seed proanthocyanidin extract (GSPE) is a new type of antioxidant, whereas whether it could ameliorate IR-induced hematopoietic injury remains unclear. Here, we show that GSPE treatment improves the survival of irradiated mice and alleviates IR-induced myelosuppression. Meanwhile, the hematopoietic reconstituting ability of hematopoietic stem cells (HSCs) in mice following irradiation exposure is significantly increased after GSPE treatment. Furthermore, GSPE treatment can reduce IR-induced ROS production and relieve DNA damage and apoptosis in hematopoietic stem progenitor cells (HSPCs). Interestingly, we find that a critical antioxidant-associated gene fokhead box transcription factor O1 (Foxo1) is significantly decreased in HSPCs after irradiation. Consistently, hematopoietic specific deletion of Foxo1 increases the radiosensitivity of mice. Further investigations reveal that GSPE treatment specifically upregulates the expression of Foxo1, as well as its target genes superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2) and catalase (CAT). Importantly, Foxo1 deficiency largely abolishes the radioprotection of GSPE on HSPCs. Collectively, our data demonstrate that GSPE plays an important role in ameliorating IR-induced HSPC injury via the Foxo1-mediated pathway. Therefore, GSPE may be used as a promising radioprotective agent.

Hematopoietic stem cell (HSC) fate is tightly controlled by various regulators, whereas the underlying mechanism has not been fully uncovered due to the high heterogeneity of these populations. In this study, we identify tetraspanin CD63 as a novel functional marker of HSCs in mice. We show that CD63 is unevenly expressed on the cell surface in HSC populations. Importantly, HSCs with high CD63 expression (CD63(hi)) are more quiescent and have more robust self-renewal and myeloid differentiation abilities than those with negative/low CD63 expression (CD63(-/lo)). On the other hand, using CD63 knockout mice, we find that loss of CD63 leads to reduced HSC numbers in the bone marrow. In addition, CD63-deficient HSCs exhibit impaired quiescence and long-term repopulating capacity, accompanied by increased sensitivity to irradiation and 5-fluorouracil treatment. Further investigations demonstrate that CD63 is required to sustain TGFβ signaling activity through its interaction with TGFβ receptors I and II, thereby playing an important role in regulating the quiescence of HSCs. Collectively, our data not only reveal a previously unrecognized role of CD63 but also provide us with new insights into HSC heterogeneity.

Background Healthy aging has attracted a great deal of attention worldwide with the progression of aging societies. However, few studies have investigated the association between social support and healthy aging. Thus, our study aimed to examine the association of emotional and instrumental social support with healthy aging among older Japanese adults. Methods This community-based prospective cohort study was conducted in Ohsaki City, Japan, and included 8,232 people aged ≥ 65 years at the baseline survey in 2006. Based on information obtained from this survey, participants were categorized according to two types of social support: having / lacking emotional social support and having / lacking instrumental social support. The primary outcome was healthy aging (defined as meeting all four of the following criteria: free of disability, free of depression, high health-related quality of life and high life satisfaction), as assessed by a questionnaire survey carried out in 2017. Multiple logistic regression was used to calculate the corresponding odds ratios (ORs) and 95% confidence intervals (95%CIs). Results During approximately 11 years of follow-up, 620 (7.5%) participants attained healthy aging. Compared with participants lacking emotional social support, the multivariable-adjusted OR (95%CI) was 1.60 (1.12–2.29) for those having emotional social support. Compared with participants lacking instrumental social support, the multivariable-adjusted OR (95%CI) was 1.71 (1.32–2.23) for those having instrumental social support. Furthermore, we found that the likelihood of healthy aging was significantly higher in the group that had both types of social support, but not in those with only one compared with those having neither type of social support. Conclusions These findings suggest that both emotional and instrumental social support are associated with healthy aging of older people in Japan.

Background Our study examined the association between social participation and healthy aging using a community-based cohort study among Japanese older adults. Methods This prospective study was conducted in Ohsaki City, Japan, and included 7226 participants aged ≥65 years at the baseline survey in 2006. We obtained information on frequency of participation in 3 types of community activities (ie, neighborhood activities, hobbies, and volunteer activities) at baseline. Exposure was measured by the number of types of community activities participated in and participants were categorized into 4 groups (ie, none, 1 type, 2 types, and 3 types). The primary outcome was healthy aging as assessed by a questionnaire survey conducted in 2017, and was defined as meeting the following 4 criteria: free of disability, free of depression, high health-related quality of life, and high life satisfaction. We used multiple logistic regression models to calculate the corresponding odds ratios and 95% confidence intervals. Results During 11 years of follow-up, 574 (7.9%) participants attained healthy aging. Compared with participants not participating in any activity, the multivariable-adjusted odds ratios (95% confidence intervals) were 1.90 (1.40, 2.59) for those participating in 1 type, 2.49 (1.84, 3.38) for 2 types, and 3.06 (2.30, 4.07) for 3 types (p for trend < .0001). Furthermore, for each type of community activity, a higher frequency of participation was related to higher probability of healthy aging. Conclusions Our study suggests that social participation is associated with the promotion of healthy aging, and that the benefits were observed across different types of community activities.

Background: Previous studies have investigated the association between reproductive factors and lung cancer risk; however, findings have been inconsistent. This study aims to assess the association between reproductive factors with lung cancer incidence and mortality among Asian women. Methods: A total of 308,949 female participants with a mean age of 55.13 from 11 prospective cohorts and four Asian countries (Japan, Korea, China, and Singapore) in the Asia Cohort Consortium (ACC) were included. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CIs). Results: A total of 3,119 primary lung cancer cases and 2,247 lung cancer deaths were identified with a mean follow-up of 16.4 years. Parous women had a lower risk of lung cancer incidence and mortality as compared with nulliparous women, with HRs of 0.82 (95% CI = 0.70 - 0.96) and 0.78 (95% CI = 0.65 - 0.94). Corresponding HRs were lowest among women with 1-2 children, with HRs of 0.78 (95% CI = 0.66 - 0.93) and 0.72 (95% CI = 0.59 - 0.87) for lung cancer incidence and mortality. The protective association of parity and lung cancer incidence was greater among ever-smokers (HR=0.66, 95% CI = 0.49 - 0.87) than in never-smokers (HR=0.90, 95% CI = 0.74 - 1.09) (P-interaction = 0.029). Compared with age at first delivery ≤20 years, older age at first delivery (≥26 years) was associated with a lower risk of lung cancer incidence and mortality. Compared with age at menopause Conclusions: Distinct from Western women, Asian parous women, especially those who have 1-2 children had a lower risk of lung cancer incidence and mortality compared with nulliparous women. Future studies are needed to assess the underlying mechanisms, the relationships within these female reproductive factors, and the potential changes in smoking habits over time. Citation Format: Xin Yin, Rie Kishida, Sarah Krull Abe, Md. Rashedul Islam, Md. Shafiur Rahman, Eiko Saito, Qing Lan, Batel Bletcher, Melissa Merritt, Ji-Yeob Choi, Aesun Shin, Ryoko Katagiri, Xiao-Ou Shu, Norie Sawada, Akiko Tamakoshi, Woon-Puay Koh, Ichiro Tsuji, Chisato Nagata, Sue K. Park, Sun-Seog Kweon, Yu-Tang Gao, Shoichiro Tsugane, Takashi Kimura, Jian-Min Yuan, Yukai Lu, Seiki Kanemura, Yumi Sugawara, Keiko Wada, Min-Ho Shin, Habibul Ahsan, Paolo Boffetta, Kee Seng Chia, Keitaro Matsuo, You-Lin Qiao, Nathaniel Rothman, Wei Zheng, Manami Inoue, Daehee Kang, Wei Jie Seow. Association between reproductive factors with lung cancer incidence and mortality: A pooled analysis of over 308,000 females in the Asia Cohort Consortium. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4200.

Hematopoietic system is one of the main target organs of irradiation injury. Exposure to radiation can cause acute myelosuppression and long-term hematopoietic injury due to the direct and indirect damage of hematopoietic stem cells (HSCs) that can self-renew and differentiate into all types of blood cells. So far, many factors in the modulation of HSC biology at steady status have been revealed, while how to orchestrate HSCs in the context of radiation has not been well established. Recently, an increasing number of studies focus on the underlying mechanisms involved in regulating HSC fate after radiation exposure by affecting DNA damage response (DDR), including DNA-damage repair, cell-cycle arrest, apoptosis and senescence, or bone marrow (BM) microenvironment. In this review, we summarize recent findings on intrinsic and extrinsic factors in the regulation of HSC fate after radiation exposure, which may further deepen our understanding of the radioprotection of HSCs.

To investigate the association of smoking status and years since smoking cessation with the risk of incident dementia among elderly Japanese. We conducted a longitudinal analysis of smoking status and smoking cessation with dementia in prospective cohort study of 12,489 Japanese individuals aged ≥ 65 years who were followed up for 5.7 years. Information on smoking status and other lifestyle factors was collected via a questionnaire in 2006. Data on incident dementia were retrieved from the public Long-term Care Insurance Database. The Cox proportional hazards model was used to estimate the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for incident dementia. During 61,613 person-years of follow-up, 1110 cases (8.9%) of incident dementia were documented. Compared with individuals who had never smoked, current smokers showed a higher risk of dementia (HR 1.46, 95% CI 1.17, 1.80). Among ex-smokers, the risk for those who had stopped smoking for ≤ 2 years was still high (HR 1.39, 95% CI 0.96, 2.01), however, quitting smoking for 3 years or longer mitigated the increased risk incurred by smokers; the multivariable HRs (95% CIs) were 1.03 (0.70, 1.53) for those who had stopped smoking for 3–5 years, 1.04 (0.74, 1.45) for 6–10 years, 1.19 (0.84, 1.69) for 11–15 years, and 0.92 (0.73, 1.15) for > 15 years. Our study suggests that the risk of incident dementia among ex-smokers becomes the same level as that of never smokers if they maintain abstinence from smoking for at least 3 years. Electronic supplementary material The online version of this article (10.1007/s10654-020-00612-9) contains supplementary material, which is available to authorized users.

As a promising microwave absorber filler, molybdenum disulfide (MoS2), because of the unique structure, high electrical conductivity, and polarization effect, is receiving more and more interest. Developing MoS2-based composites with specific structure and morphology is a hot top in the field of microwave absorbers, because of its strong multiple scattering and reflecting for microwaves as well as its unique interfacial characteristics. Now, with a facile solvothermal method, a novel core–shell CoFe2O4@1T/2H-MoS2 composite is synthesized, where the CoFe2O4 nanospheres are entirely embedded in a special three-dimensional (3D) nest-like 1T/2H phase MoS2. Notably, in comparison with superparamagnetic CoFe2O4 nanospheres, the coercivities of as-synthesized CoFe2O4@1T/2H-MoS2 composites greatly increase. Here, 1T/2H-MoS2 exhibits ferromagnetism superimposed onto large diamagnetism. It is noted that, by adjusting the content of 1T/2H-phase MoS2, the microwave absorption performance of as-synthesized composites ...

With population aging, an increasing attention has been paid to quality of life rather than mere longevity. Now, it is urgently needed to clarify predictors of well-being in later life, i.e., "successful aging (SA)." The aim of this study is to investigate whether the number of remaining teeth impacts on maintenance of SA among Japanese older people. The present study was conducted in Tsurugaya district, a suburban area of Sendai, in northern Japan, and included older people aged ≥ 70 years who had met the criteria for SA at a 2003 baseline survey. At the baseline survey, dentists obtained data for the number of remaining teeth. We obtained information about Long-term Care Insurance certification, including the dates of incident functional disability and death between 2003 and 2012. Data pertaining to health-related quality of life (HRQOL) were collected at the 2003 baseline survey and the 2012 follow-up survey. Maintenance of SA was defined in terms of survival, disability-free status and high HRQOL in both 2003 and 2012. Among 450 participants, 108 (24.0%) were considered to have maintained a state of SA. When participants were classified into three groups according to previous studies, in comparison with participants who retained 0-9 teeth, the multivariate prevalence ratios (95% confidence intervals) were 1.39 (0.81-2.36) for those who retained 10-19 teeth and 1.58 (1.002-2.50) for those who retained ≥ 20 teeth (p trend = 0.046). The present results suggest that retaining ≥ 20 teeth is associated with maintenance of SA among Japanese older people.

Rationale: The hematopoietic system and skeletal system have a close relationship, and megakaryocytes (MKs) may be involved in maintaining bone homeostasis. However, the exact role and underlying mechanism of MKs in bone formation during steady-state and stress conditions are still unclear. Methods: We first evaluated the bone phenotype with MKs deficiency in bone marrow by using c-Mpl-deficient mice and MKs-conditionally deleted mice. Then, osteoblasts (OBs) proliferation and differentiation and CD31hiEmcnhi tube formation were assessed. The expression of growth factors related to bone formation in MKs was detected by RNA-sequencing and enzyme-linked immunosorbent assays (ELISAs). Mice with specific depletion of TGF-β1 in MKs were used to further verify the effect of MKs on osteogenesis and angiogenesis. Finally, MKs treatment of irradiation-induced bone injury was tested in a mouse model. Results: We found that MKs deficiency significantly impaired bone formation. Further investigations revealed that MKs could promote OBs proliferation and differentiation, as well as CD31hiEmcnhi vessels formation, by secreting high levels of TGF-β1. Consistent with these findings, mice with specific depletion of TGF-β1 in MKs displayed significantly decreased bone mass and strength. Importantly, treatment with MKs or thrombopoietin (TPO) substantially attenuated radioactive bone injury in mice by directly or indirectly increasing the level of TGF-β1 in bone marrow. MKs-derived TGF-β1 was also involved in suppressing apoptosis and promoting DNA damage repair in OBs after irradiation exposure. Conclusions: Our findings demonstrate that MKs contribute to bone formation through coupling osteogenesis with angiogenesis by secreting TGF-β1, which may offer a potential therapeutic strategy for the treatment of irradiation-induced osteoporosis.

The impact of dairy consumption on thyroid cancer is unclear. The purpose of this study was to elucidate the association between dairy consumption and the risk of thyroid cancer in Japanese people.The association between dairy consumption and the risk of thyroid cancer in Japanese people was examined by conducting a pooled analysis of two prospective studies of residents in Miyagi Prefecture, Japan. Data from 64,340 men and women aged 40-79 years registered in the Miyagi Cohort Study in 1990 and in the Ohsaki Cohort Study in 1994 were analyzed. Dairy consumption was assessed at baseline using a self-administered food frequency questionnaire and was divided into quartiles based on the weight (in grams) of total dairy consumption per day.During 1,075,018 person-years of follow-up, there were 190 incident cases of thyroid cancer (29 men and 161 women). The hazard ratios (HRs) and 95% confidence intervals (CIs) for thyroid cancer incidence in the highest quartile of dairy consumption compared with the lowest quartile were 0.83 (95% CIs 0.28-2.43, P-trend = 0.823) for men and 0.67 (95% CIs 0.42-1.06, P-trend = 0.056) for women. After stratification for BMI, a decreased risk was observed in women with BMI ≥ 25 kg/mDairy consumption is inversely associated with the risk of thyroid cancer in women with BMI ≥ 25 kg/m

Desired longevity represents how strongly people esteem possible extensions of their own lifetime. The association between desired longevity and mortality risk has been reported in only one prospective study, which examined a small sample of older participants. We aimed to examine the hypothesis that desired longevity at middle-age predicted long-term survival.In the prospective cohort study, residents aged 40-64 years were asked how long they would like to live and asked to choose one from three options: longer than, as long as, or shorter than the life expectancy. We used Cox proportional hazards model to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality according to the three groups for desired longevity, treating the "longer than" group as the reference. We conducted mediation analysis to investigate the mechanism for the association between desired longevity and mortality.39,902 residents were recruited to the study. Risk of all-cause mortality was significantly higher in the "shorter than" group (HR 1.12; 95% CI, 1.04-1.21). The association was independent of sex, age, marital status, education, medical history and health status. Regarding cause of death, mortality risk of cancer (HR 1.14; 95% CI, 1.00-1.29) and suicide (HR 2.15; 95% CI, 1.37-3.38) were also higher in the "shorter than" group. The unhealthy lifestyle mediated this association with all-cause mortality by 30.4%.Shorter desired longevity was significantly associated with an increased risk of all-cause mortality, and mortality from cancer and suicide. Lifestyle behaviors particularly mediated this association.

Recent work with laser-cooled molecules in attractive optical traps has shown that the differential AC Stark shifts arising from the trap light itself can become problematic, limiting collisional shielding efficiencies, rotational coherence times, and laser-cooling temperatures. In this work, we explore trapping and laser-cooling of CaF molecules in a ring-shaped repulsive optical trap. The observed dependences of loss rates on temperature and barrier height show characteristic behavior of repulsive traps and indicate strongly suppressed average AC Stark shifts. Within the trap, we find that $\Lambda$-enhanced gray molasses cooling is effective, producing similar minimum temperatures as those obtained in free space. By combining in-trap laser cooling with dynamical reshaping of the trap, we also present a method that allows highly efficient and rapid transfer from molecular magneto-optical traps into conventional attractive optical traps, which has been an outstanding challenge for experiments to date. Notably, our method could allow nearly lossless transfer over millisecond timescales., Comment: 14 pages, 12 figures

An increase in time spent walking is significantly associated with lower risks of mortality and disability. This study aimed to investigate the association between changes in time spent walking and disability-free life expectancy (DFLE) in community-dwelling older people. Thirteen-year follow-up data from a cohort study of 7105 Japanese older adults (age ≥ 65 years) in 2006 were analyzed. Information on time spent walking was collected using questionnaires at two time points (1994 and 2006). Based on this information, the participants were categorized into four groups according to changes in time spent walking: remained inactive, became inactive, became active, and remained active. DFLE was defined as the average number of years a person could expect to live without disability. The multistate life table method using a Markov model was used to calculate DFLE. Of those who were inactive in 1994, DFLE of those who became active in 2006 (20.30 years in men; 24.06 years in women) was longer by about 2 years than of those who remained inactive (17.96 years in men; 21.87 years in women), and it was as long as those who remained active (20.34 years in men; 24.16 years in women). The 2-year difference in DFLE did not change after the participants were stratified by body mass index, motor function, cognitive function, and history of diseases. Increase in time spent walking is associated with longer DFLE in Japanese older people. Encouraging simple physical activity such as walking at the population level could increase life-years lived in good health.

The cell cycle progression of hematopoietic stem cells (HSCs) and acute myeloid leukemia (AML) cells is precisely controlled by multiple regulatory factors. However, the underlying mechanisms are not fully understood. Here, we find that cyclin-dependent kinase 19 (CDK19), not its paralogue CDK8, is relatively enriched in mouse HSCs, and its expression is more significantly increased than CDK8 after proliferative stresses. Furthermore, SenexinB (a CDK8/19 inhibitor) treatment impairs the proliferation and self-renewal ability of HSCs. Moreover, overexpression of CDK19 promotes HSC function better than CDK8 overexpression. Using CDK19 knockout mice, we observe that CDK19

Purpose The association between dairy intake and mortality remains uncertain, and evidence for the Japanese population is scarce. We aimed to investigate the association between dairy intake and all-cause, cancer, and cardiovascular disease (CVD) mortality in Japanese adults. Methods A total of 34,161 participants (16,565 men and 17,596 women) aged 40–64 years without a history of cancer, myocardial infarction, or stroke at baseline were included in the analysis, using data from the Miyagi Cohort Study initiated in 1990. Milk, yogurt, and cheese intake were obtained using a validated food frequency questionnaire. Total dairy intake was calculated as the sum of milk, yogurt, and cheese intake and then categorized by quartile. The outcomes were all-cause, cancer, and CVD mortality. Cox proportional hazards regression models were used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality risks. Results During 750,016 person-years of follow-up, the total number of deaths was 6498, including 2552 deaths due to cancer and 1693 deaths due to CVD. There was no association between total dairy intake and all-cause, cancer, and CVD mortality for both men and women. We also examined the associations between subgroup dairy products and mortality. For milk and yogurt intake, our results suggest null associations. However, cheese intake was modestly associated with lower all-cause mortality in women; compared with non-consumers, the multivariable HRs (95%CIs) were 0.89 (0.81–0.98) for 1–2 times/month, 0.88 (0.78–1.00) for 1–2 times/week, and 0.89 (0.74–1.07) for 3 times/week or almost daily (p trend = 0.016). Conclusion Dairy intake was not associated with mortality in Japanese adults, except for limited evidence showing a modest association between cheese intake and a lower all-cause mortality risk in women.

Background Both weight loss and cognitive impairment are common in late-life, but it remains unknown whether weight change is associated with risk of incident dementia among elderly Japanese. Our study aimed to investigate the association between long-term weight change since midlife and risk of incident disabling dementia using a community-based cohort study of elderly Japanese. Methods In 2006, we conducted a cohort study of 6,672 disability-free Japanese adults aged ≥65 years. In both 1994 and 2006, the participants reported their weight using a self-reported questionnaire. Based on weight obtained at these two time points, participants were classified into: stable weight (-1.4 - +1.4kg), weight gain (≥ +1.5kg), and weight loss of -2.4 - -1.5kg, -3.4 - -2.5 kg, -4.4 - -3.5kg, -5.4 - -4.5kg, and ≤-5.5kg. Incident disabling dementia was retrieved from the public Long-term Care Insurance database. Participants were followed-up for 5.7 years (between April 2007 and November 2012). Cox proportional hazards model was used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for incident disabling dementia. Results During 32,865 person-years of follow-up, 564 participants were ascertained as having incident disabling dementia. Compared with stable weight, the multivariable-adjusted HRs (95%CIs) were 0.97 (0.70, 1.34) for weight loss of -2.4 - -1.5kg, 0.98 (0.70, 1.38) for -3.4 - -2.5kg, 1.28 (0.91, 1.81) for -4.4 - -3.5kg,1.27 (0.92, 1.77) for -5.4 - -4.5kg, and 1.64 (1.29, 2.09) for ≤-5.5kg. Conclusion Our study suggested that a ≤-3.5kg weight loss over 12 years might be associated with higher risk of incident disabling dementia among elderly Japanese.

The Japanese dietary pattern has long been discussed as one of the factors behind the longevity of Japanese people. However, the health benefits of the Japanese dietary pattern have not been fully elucidated. We published the first report in the world regarding the relation between the Japanese dietary pattern and cardiovascular disease mortality in 2007 using cohort studies including Japanese residents of Ohsaki City, Miyagi Prefecture, Japan. Since then, we have developed the Japanese Diet Index (JDI) that was based on previous findings to assess the degree of the Japanese dietary pattern and to advance the evidence on the health effects of the Japanese dietary pattern. So far, we have explored the associations between the JDI score (in quartiles) and various outcomes. For all-cause mortality, in comparison to Q1 (the lowest), the multivariable hazard ratios (HRs) and 95% confidence intervals (95%CIs) were 0.92 (0.85–1.00) for Q2, 0.91 (0.83–0.99) for Q3, and 0.91 (0.83–0.99) for Q4 (the highest). For functional disability, the multivariable HRs (95%CIs) were 0.94 (0.81–1.09) for Q2, 0.90 (0.77–1.05) for Q3, and 0.79 (0.68–0.92) for Q4. For dementia, the multivariable HRs (95%CIs) were 0.88 (0.74–1.05) for Q2, 0.87 (0.73–1.04) for Q3, 0.79 (0.66–0.95) for Q4. In addition, people with higher adherence to the Japanese dietary pattern also showed decreases in disability and dementia risks. The purpose of this article was to review all six papers, summarize the health effects of the Japanese dietary pattern, and discuss implications for future research.

Summary Background & aims Previous studies have reported that the Japanese diet is associated with a lower risk of dementia; however, whether changes in adherence to the Japanese diet affects incident dementia remains unknown. We aimed to evaluate the association between long-term changes in adherence to the Japanese diet and risk of incident dementia among older Japanese individuals. Methods We collected dietary information from community-dwelling older individuals living in Ohsaki city, Japan using a validated 39-item food frequency questionnaire in 1994 and 2006. Adherence to the Japanese diet was assessed using the 8-item Japanese Diet Index (JDI8) score (range: 0 to 8 points). Changes in adherence to the Japanese diet were defined as changes in the JDI8 score from 1994 to 2006. Next, the participants were classified into five groups: great decrease, moderate decrease, no changes [ref.], moderate increase, or great increase. Then, 3146 Japanese adults aged ≥65 years in 2006 were followed-up for 5.7 years. Incident dementia was retrieved from the long-term care insurance database. The Cox proportional hazards model was used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for incident dementia. Results During 14,336 person-years of follow up, 231 cases of dementia were ascertained. Compared with no changes in the JDI8 score, the multivariable-adjusted HRs (95%CIs) were 1.72 (1.13, 2.62) for great decrease, 1.10 (0.73, 1.66) for moderate decrease, 0.82 (0.54, 1.25) for moderate increase, and 0.62 (0.38, 1.02) for great increase (p-trend Conclusions An increase in adherence to the Japanese diet was associated with a reduced risk of incident dementia, whereas a decrease in adherence was associated with an elevated risk among older Japanese individuals.

Natural killer (NK)–cell development and maturation is a well-organized process. The steroid receptor coactivator 3 (SRC-3) is a regulator of the hematopoietic and immune systems; however, its role in NK cells is poorly understood. Here, SRC-3 displayed increased nuclear translocation in NK cells during terminal differentiation and upon inflammatory cytokine stimulation. Targeted deletion of SRC-3 altered normal NK-cell distribution and compromised NK-cell maturation. SRC-3 deficiency led to significantly impaired NK-cell functions, especially their antitumor activity. The expression of several critical T-bet target genes, including Zeb2, Prdm1, and S1pr5, but not T-bet itself, was markedly decreased in NK cells in the absence of SRC-3. There was a physiologic interaction between SRC-3 and T-bet proteins, where SRC-3 was recruited by T-bet to regulate the transcription of the aforementioned genes. Collectively, our findings unmask a previously unrecognized role of SRC-3 as a coactivator of T-bet in NK-cell biology and indicate that targeting SRC-3 may be a promising strategy to increase the tumor surveillance function of NK cells.

As a promising microwave absorber filler, molybdenum disulfide (MoS

Melatonin (MT), endogenously secreted by the pineal gland, is closely related to multiple biological processes; however, its effect on thrombopoiesis is still not well illustrated. Here, we demonstrate that MT administration can elevate peripheral platelet levels. Analysis of different stages in thrombopoiesis reveals that MT has the capacity to promote the expansion of CD34+ and CD41+ cells, and accelerate proplatelet formation (PPF) and platelet production. Furthermore, in vivo experiments show that MT has a potential therapeutic effect on radiation-induced thrombocytopenia. The underlying mechanism suggests that both extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt signaling are involved in the processes of thrombopoiesis facilitated by MT. Interestingly, in addition to the direct regulation of Akt signaling by its upstream phosphoinositide 3-kinase (PI3K), ERK1/2 signaling is also regulated by PI3K via its effector, dual adaptor for phosphotyrosine and 3-phosphoinositides (DAPP1), in megakaryocytes after MT treatment. Moreover, the expression level of DAPP1 during megakaryocyte differentiation is closely related to the activation of ERK1/2 and Akt at different stages of thrombopoiesis. In conclusion, our data suggest that MT treatment can promote thrombopoiesis, which is modulated by the DAPP1-orchestrated activation of ERK1/2 and Akt signaling.

Long-term hematopoietic output is dependent on hematopoietic stem cell (HSC) homeostasis which is maintained by a complex molecular network in which microRNA play crucial roles, although the underlying molecular basis has not been fully elucidated. Here we show that microRNA-21 (miR-21) is enriched in murine HSC, and that mice with conditional knockout of miR-21 exhibit an obvious perturbation in hematopoiesis. Moreover, significant loss of HSC quiescence and long-term reconstituting ability are observed in the absence of miR-21. Further studies revealed that miR-21 deficiency markedly decreases the nuclear factor kappa B (NF-B) pathway, accompanied by increased expression of PDCD4, a direct target of miR-21, in HSC. Interestingly, overexpression of PDCD4 in wild-type HSC generates similar phenotypes as those of miR-21-deficient HSC. More importantly, knockdown of PDCD4 can significantly rescue the attenuation of NF-B activity, thereby improving the defects in miR-21-null HSC. On the other hand, we found that miR-21 is capable of preventing HSC from ionizing radiation- induced DNA damage via activation of the NF-B pathway. Collectively, our data demonstrate that miR-21 is involved in maintaining HSC homeostasis and function, at least in part, by regulating the PDCD4-mediated NF-B pathway and provide a new insight into radioprotection of HSC.