Association between reproductive factors with lung cancer incidence and mortality: A pooled analysis of over 308,000 females in the Asia cohort consortium.

Previous studies have investigated the association between reproductive factors and lung cancer risk; however, findings have been inconsistent. In order to assess this association among Asian women, a total of 308,949 female participants from 11 prospective cohorts and four Asian countries (Japan, Korea, China, and Singapore) were included. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CIs). A total of 3,119 primary lung cancer cases and 2247 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). 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 (21-25, ≥26 years) was associated with a lower risk of lung cancer incidence and mortality. Women who ever used hormone replacements had a higher likelihood of developing non-small cell lung cancer (HR = 1.31, 95% CI = 1.02-1.68), compared to those who never used hormone replacements. 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.

Obesity is associated with biliary tract cancer mortality and incidence: A pooled analysis of 21 cohort studies in the Asia Cohort Consortium.

Body fatness is considered a probable risk factor for biliary tract cancer (BTC), whereas cholelithiasis is an established factor. Nevertheless, although obesity is an established risk factor for cholelithiasis, previous studies of the association of body mass index (BMI) and BTC did not take the effect of cholelithiasis fully into account. To better understand the effect of BMI on BTC, we conducted a pooled analysis using population-based cohort studies in Asians. In total, 905 530 subjects from 21 cohort studies participating in the Asia Cohort Consortium were included. BMI was categorized into four groups: underweight (<18.5 kg/m2 ); normal (18.5-22.9 kg/m2 ); overweight (23-24.9 kg/m2 ); and obese (25+ kg/m2 ). The association between BMI and BTC incidence and mortality was assessed using hazard ratios (HR) and 95% confidence intervals (CIs) by Cox regression models with shared frailty. Mediation analysis was used to decompose the association into a direct and an indirect (mediated) effect. Compared to normal BMI, high BMI was associated with BTC mortality (HR 1.19 [CI 1.02-1.38] for males, HR 1.30 [1.14-1.49] for females). Cholelithiasis had significant interaction with BMI on BTC risk. BMI was associated with BTC risk directly and through cholelithiasis in females, whereas the association was unclear in males. When cholelithiasis was present, BMI was not associated with BTC death in either males or females. BMI was associated with BTC death among females without cholelithiasis. This study suggests BMI is associated with BTC mortality in Asians. Cholelithiasis appears to contribute to the association; and moreover, obesity appears to increase BTC risk without cholelithiasis.

Blue-Detuned Magneto-optical Trap of CaF Molecules.

A key method to produce trapped and laser-cooled molecules is the magneto-optical trap (MOT), which is conventionally created using light red detuned from an optical transition. In this work, we report a MOT for CaF molecules created using blue-detuned light. The blue-detuned MOT (BDM) achieves temperatures well below the Doppler limit and provides the highest densities and phase-space densities reported to date in CaF MOTs. Our results suggest that BDMs are likely achievable in many relatively light molecules including polyatomic ones, but our measurements suggest that BDMs will be challenging to realize in substantially heavier molecules due to sub-mK trap depths. In addition to record temperatures and densities, we find that the BDM substantially simplifies and enhances the loading of molecules into optical tweezer arrays, which are a promising platform for quantum simulation and quantum information processing. Notably, the BDM reduces molecular number requirements ninefold compared to a conventional red-detuned MOT, while not requiring additional hardware. Our work therefore substantially simplifies preparing large-scale molecular tweezer arrays, which are a novel platform for simulation of quantum many-body dynamics and quantum information processing with molecular qubits.

Oxymatrine boosts hematopoietic regeneration by modulating MAPK/ERK phosphorylation after irradiation-induced hematopoietic injury.

Hematopoietic toxicity due to ionizing radiation (IR) is a leading cause of death in nuclear incidents, occupational hazards, and cancer therapy. Oxymatrine (OM), an extract originating from the root of Sophora flavescens (Kushen), possesses extensive pharmacological properties. In this study, we demonstrate that OM treatment accelerates hematological recovery and increases the survival rate of mice subjected to irradiation. This outcome is accompanied by an increase in functional hematopoietic stem cells (HSCs), resulting in enhanced hematopoietic reconstitution abilities. Mechanistically, we observed significant activation of the MAPK signaling pathway, accelerated cellular proliferation, and decreased cell apoptosis. Notably, we identified marked increases in the cell cycle transcriptional regulator Cyclin D1 (Ccnd1) and the anti-apoptotic protein BCL2 in HSCs after OM treatment. Further investigation revealed that the expression of Ccnd1 transcript and BCL2 levels were reversed upon specific inhibition of ERK1/2 phosphorylation, effectively negating the rescuing effect of OM. Moreover, we determined that targeted inhibition of ERK1/2 activation significantly counteracted the regenerative effect of OM on human HSCs. Taken together, our results suggest a crucial role for OM in hematopoietic reconstitution following IR via MAPK signaling pathway-mediated mechanisms, providing theoretical support for innovative therapeutic applications of OM in addressing IR-induced injuries in humans.

Bichromatic Imaging of Single Molecules in an Optical Tweezer Array.

We report on a novel bichromatic fluorescent imaging scheme for background-free detection of single CaF molecules trapped in an optical tweezer array. By collecting fluorescence on one optical transition while using another for laser cooling, we achieve an imaging fidelity of 97.7(2)% and a nondestructive detection fidelity of 95.5(6)%. Notably, these fidelities are achieved with a modest photon budget, suggesting that the method could be extended to more complex laser-coolable molecules with less favorable optical cycling properties. We also report on a framework and new methods to characterize various loss mechanisms that occur generally during fluorescent detection of trapped molecules, including two-photon decay and admixtures of higher excited states that are induced by the trapping light. In particular, we develop a novel method to dispersively measure transition matrix elements between electronically excited states. The method could also be used to measure arbitrarily small Franck-Condon factors between electronically excited states, which could significantly aid in ongoing efforts to laser cool complex polyatomic molecules.

Association between dairy intake and risk of incident dementia: the Ohsaki Cohort 2006 Study.

PURPOSE: To investigate the association between dairy intake and risk of incident dementia in older adults. METHODS: A longitudinal analysis of dairy intake with incident dementia was conducted using a cohort study of 11,637 non-disabled Japanese older adults aged ≥ 65 years followed-up for up to 5.7 years (mean: 5.0 years). Data on milk, yogurt, and cheese intake were collected using a validated food frequency questionnaire. Total dairy intake was calculated as the sum of the daily intake of milk, yogurt, and cheese, which was sex-specifically categorized in quintiles. Dementia cases were retrieved from the public long-term care insurance database. Cox proportional hazards model was used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) for incident dementia. RESULTS: During 58,013 person-years of follow-up, 946 persons developed dementia. In the primary analysis, compare to the lowest quintile of total dairy intake, Q2 showed a slightly decreased incident dementia risk (HR for Q2 vs Q1: 0.90, 95% CI: 0.73-1.10) after fully adjusted for demographic, lifestyle, psychological, and nutritional factors, and diseases history. Compared to non-consumers of milk, those consuming for 1-2 times/month showed a lower risk of incident dementia (fully-adjusted HR: 0.76, 95% CI: 0.57-1.02). Daily yogurt consumers also had a reduced risk (fully-adjusted HR: 0.89, 95% CI: 0.74-1.09). But daily cheese consumers showed an increased risk of dementia (fully-adjusted HR: 1.28, 95% CI: 0.91-1.79). In the sensitivity analysis where we excluded dementia cases ascertained in the first 2 years, results were consistent with those from the primary analysis and we further found that yogurt intake might be inversely associated with dementia risk (p for trend = 0.025). CONCLUSION: Low total dairy intake or low milk intake frequency might be associated with lower incident dementia risk, however daily cheese consumers seemed to have an increased risk. Our study also suggested a possible inverse dose-response association between yogurt consumption and dementia risk, but further studies are needed to confirm whether this benefit was from yogurt intake itself or as a part of a healthy dietary pattern.

Dairy consumption and incident risk of thyroid cancer in Japan: a pooled analysis of the Miyagi Cohort Study and the Ohsaki Cohort Study.

PURPOSE: 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. METHODS: 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. RESULTS: 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/m2 (HRs: 0.37, 95% CIs 0.18-0.79, P-trend = 0.010). CONCLUSION: Dairy consumption is inversely associated with the risk of thyroid cancer in women with BMI ≥ 25 kg/m2.

How Long Would You Like to Live? A 25-year Prospective Observation of the Association Between Desired Longevity and Mortality.

BACKGROUND: 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. METHODS: 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. RESULTS: We recruited 39,902 residents 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%. CONCLUSION: 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.

Molecular Laser Cooling in a Dynamically Tunable Repulsive Optical Trap.

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 Letter, 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 Λ-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.

Changes in time spent walking and disability-free life expectancy in Japanese older people: The Ohsaki Cohort 2006 Study.

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.

Association of dairy intake with all-cause, cancer, and cardiovascular disease mortality in Japanese adults: a 25-year population-based cohort.

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.

Dairy intake and incident functional disability among older Japanese adults: the Ohsaki Cohort 2006 Study.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: We found no evidence showing that dairy intake was associated with functional disability among Japanese older adults.

Association Between Long-term Weight Change Since Midlife and Risk of Incident Disabling Dementia Among Elderly Japanese: The Ohsaki Cohort 2006 Study.

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 to +1.4 kg), weight gain (≥+1.5 kg), and weight loss of -2.4 to -1.5 kg, -3.4 to -2.5 kg, -4.4 to -3.5 kg, -5.4 to -4.5 kg, and ≥-5.5 kg. 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 (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 were 0.97 (95% CI, 0.70-1.34) for weight loss of -2.4 to -1.5 kg, 0.98 (95% CI, 0.70-1.38) for -3.4 to -2.5 kg, 1.28 (95% CI, 0.91-1.81) for -4.4 to -3.5 kg, 1.27 (95% CI, 0.92-1.77) for -5.4 to -4.5 kg, and 1.64 (95% CI, 1.29-2.09) for ≥-5.5 kg. CONCLUSION: Our study suggested that a ≥-3.5 kg weight loss over 12 years might be associated with higher risk of incident disabling dementia among elderly Japanese.

Association Between Social Participation and Disability-free Life Expectancy in Japanese Older People: The Ohsaki Cohort 2006 Study.

BACKGROUND: Although social participation has been reported to be associated with significantly lower risks of mortality and disability, to our knowledge, no study has estimated its impact on disability-free life expectancy (DFLE). Therefore, this study aimed to investigate the association between social participation and DFLE in community-dwelling older people. METHODS: We analyzed 11-year follow-up data from a cohort study of 11,982 Japanese older adults (age ≥65 years) in 2006. We collected information on the number of social participations using a questionnaire. Using this information, we categorized the participants into four groups. 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 employed for calculating DFLE. RESULTS: The results revealed that DFLE according to the number of social participations was 17.8 years (95% confidence interval [CI], 17.3-18.2) for no activities, 20.9 (95% CI, 20.4-21.5) for one activity, 21.5 (95% CI, 20.9-22.0) for two activities, and 22.7 (95% CI, 22.1-23.2) for three activities in men, and 21.8 (95% CI, 21.5-22.2), 25.1 (95% CI, 24.6-25.6), 25.3 (95% CI, 24.7-25.9), and 26.7 years (95% CI, 26.1-27.4), respectively, in women. This difference in DFLE did not change after the participants were stratified for smoking, body mass index, physical activity, and depression. CONCLUSION: Social participation is associated with longer DFLE among Japanese older people; therefore, encouraging social participation at the population level could increase life-years lived in good health.

Association between the number of remaining teeth and disability-free life expectancy, and the impact of oral self-care in older Japanese adults: a prospective cohort study.

BACKGROUND: Tooth loss has been reportedly associated with shorter disability-free life expectancy (DFLE). However, no study has explored whether oral self-care offsets reduction in DFLE. The present study aimed to assess the association between oral self-care and DFLE in older individuals with tooth loss. METHODS: Data on the 13-year follow-up from a cohort study of 14,206 older Japanese adults aged ≥ 65 years in 2006 were analyzed. Information on the number of remaining teeth was collected using a questionnaire, and the participants were then categorized into three groups (0-9, 10-19, and ≥ 20 teeth). Additionally, "0-9" and "10-19" groups were divided into two subgroups based on whether they practiced oral self-care. DFLE was defined as the average number of years a person could expect to live without disability, and was calculated by the multistate life table method based on a Markov model. RESULTS: DFLE (95% confidence interval) was 19.0 years (18.7-19.4) for 0-9 teeth, 20.1 (19.7-20.5) for 10-19 teeth, and 21.6 (21.2-21.9) for ≥ 20 teeth for men. For women, DFLE was 22.6 (22.3-22.9), 23.5 (23.1-23.8), and 24.7 (24.3-25.1), respectively. Practicing oral self-care was associated with longer DFLE, by 1.6-1.9 years with brushing ≥ 2 times a day in people with 0-9 and 10-19 teeth, and by 3.0-3.1 years with the use of dentures in those with 0-9 teeth. CONCLUSIONS: Practicing oral self-care is associated with an increase in DFLE in older people with tooth loss.

MicroRNA-21 maintains hematopoietic stem cell homeostasis through sustaining the NF-κB signaling pathway in mice.

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

Inflammasomes and the Maintenance of Hematopoietic Homeostasis: New Perspectives and Opportunities.

Hematopoietic stem cells (HSCs) regularly produce various blood cells throughout life via their self-renewal, proliferation, and differentiation abilities. Most HSCs remain quiescent in the bone marrow (BM) and respond in a timely manner to either physiological or pathological cues, but the underlying mechanisms remain to be further elucidated. In the past few years, accumulating evidence has highlighted an intermediate role of inflammasome activation in hematopoietic maintenance, post-hematopoietic transplantation complications, and senescence. As a cytosolic protein complex, the inflammasome participates in immune responses by generating a caspase cascade and inducing cytokine secretion. This process is generally triggered by signals from purinergic receptors that integrate extracellular stimuli such as the metabolic factor ATP via P2 receptors. Furthermore, targeted modulation/inhibition of specific inflammasomes may help to maintain/restore adequate hematopoietic homeostasis. In this review, we will first summarize the possible relationships between inflammasome activation and homeostasis based on certain interesting phenomena. The cellular and molecular mechanism by which purinergic receptors integrate extracellular cues to activate inflammasomes inside HSCs will then be described. We will also discuss the therapeutic potential of targeting inflammasomes and their components in some diseases through pharmacological or genetic strategies.

MicroRNA 34a promotes ionizing radiation-induced DNA damage repair in murine hematopoietic stem cells.

Hematopoietic stem cells (HSCs) establish the entire hematopoietic system and maintain lifelong hematopoiesis. Previous studies have reported the significance of microRNAs (miRNAs) in the regulation of self-renewal and differentiation of HSCs. In this study, we show that the expression of miRNA 34a (miR-34a) is markedly up-regulated in HSCs from mice subjected to ionizing radiation (IR). Reduced numbers and DNA damage repair, as well as increased apoptosis, are observed in HSCs from miR-34a-deficient mice induced by irradiation, although miR-34a is dispensable for steady-state hematopoiesis. Further investigations show that HSCs deficient in miR-34a exhibit decreased expressions of DNA repair-associated genes involved in homologous recombination and nonhomologous end joining. Competitive transplantation confirms that loss of miR-34a leads to more severe impairment of the long-term hematopoietic function of HSCs after irradiation exposure. Consistently, treating mice with an miR-34a agomir can significantly alleviate irradiation-induced DNA damage in HSCs. Our findings demonstrate that miR-34a contributes to promoting HSCs' survival after irradiation, which provides a promising approach for protecting HSCs from IR.-Zeng, H., Hu, M., Lu, Y., Zhang, Z., Xu, Y., Wang, S., Chen, M., Shen, M., Wang, C., Chen, F., Du, C., Tang, Y., Su,Y., Chen, S., Wang, J. MicroRNA 34a promotes ionizing radiation-induced DNA damage repair in murine hematopoietic stem cells.

Melatonin enhances thrombopoiesis through ERK1/2 and Akt activation orchestrated by dual adaptor for phosphotyrosine and 3-phosphoinositides.

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.

Smoking cessation and incident dementia in elderly Japanese: the Ohsaki Cohort 2006 Study.

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.