Search

This study aims to investigate the dosage pattern, efficacy, and safety of sacubitril/valsartan (Sac/Val) in Chinese heart failure with reduced ejection fraction (HFrEF) patients regarding real-world settings. Patients from 27 centers with a confirmed diagnosis of HFrEF and initiated Sac/Val treatment were enrolled. The primary objective was to evaluate the dosage pattern and change of heart failure status. In a final cohort of 983 patients, outpatient Sac/Val treatment demonstrated a similar beneficial effect in NT-proBNP and cardiac function. After initiating the treatment, overall and sub-population showed similar safety and efficacy. Patients who received a higher dose of Sac/Val (> 200 mg/d) demonstrated better improvement in LV function and reduction of NT-proBNP regardless of adjustment. Among Chinese HFrEF patients, Sac/Val showed a comparable reduction in NT-proBNP and improvement in cardiac function. Data further support guideline recommendations of Sac/Val in Chinese population. Optimal up-titration might provide further benefits. Further long-term and prognostic studies are needed. Graphical abstract

Chronic stress impairs radial neural stem cell (rNSC) differentiation and adult hippocampal neurogenesis (AHN), whereas promoting AHN can increase stress resilience against depression. Therefore, investigating the mechanism of neural differentiation and AHN is of great importance for developing antidepressant drugs. The nonpsychoactive phytocannabinoid cannabidiol (CBD) has been shown to be effective against depression. However, whether CBD can modulate rNSC differentiation and hippocampal neurogenesis is unknown. Here, by using the chronic restraint stress (CRS) mouse model, we showed that hippocampal rNSCs mostly differentiated into astrocytes under stress conditions. Moreover, transcriptome analysis revealed that the FoxO signaling pathway was involved in the regulation of this process. The administration of CBD rescued depressive-like symptoms in CRS mice and prevented rNSCs overactivation and differentiation into astrocyte, which was partly mediated by the modulation of the FoxO signaling pathway. These results revealed a previously unknown neural mechanism for neural differentiation and AHN in depression and provided mechanistic insights into the antidepressive effects of CBD.

Recent reports indicated that mitophagy protects against alcohol-induced liver injury, which helps remove damaged mitochondria to reduce the accumulation of reactive oxygen species (ROS). AMP-activated protein kinase (AMPK) has been recently used in ALD (alcoholic liver disease) and mitochondrial dysfunction research. However, the inner mechanism, whether AMPK can regulate mitophagy in ALD, remains unknown. Here we found that AMPK can significantly reduce alcohol-induced liver injury and enhances hepatocytes��� mitophagy level. Next, we identified that AMPK rescued alcohol-induced low expression of UQCRC2 (ubiquinol-cytochrome c reductase core protein 2). Interestingly, UQCRC2 knockdown (KD) treatment causes impaired mitophagy, whereas UQCRC2 overexpression (OE) can significantly increase mitophagy to attenuate liver injury. Also, we identified that AMPK indirectly upregulates UQCRC2 protein level, and RNA-seq, chromatin immunoprecipitation (ChIP) assay, bioinformatics, and luciferase assays helped us understand that AMPK enhanced UQCRC2 gene transcription through activating NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2). Our results demonstrate that AMPK regulating UQCRC2 is a significant mitochondrial event in mitophagy. It identifies a new signaling axis, AMPK-NFE2L2-UQCRC2, in the regulation of mitophagy levels in the liver, suggesting a possible therapeutic strategy to treat ALD. Abbreviations: AAV: AENO-associated virus; ALD: alcoholic liver disease; AMPK: AMP-activated protein kinase; BUN: blood urea nitrogen; H&E: hematoxylin and eosin; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ChIP: chromatin immunoprecipitation assay; CO-IP: co-immunoprecipitation; COPD: chronic obstructive pulmonary disease; EM: electron microscope; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic���pyruvic transaminase; IF: immunofluorescence; IHC: immunohistochemistry; KD: knockdown; MAP1LC3/LC3: microtubule associated protein 1 light chain protein 3; MTDR: MitoTracker Deep Red; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; mtDNA: mitochondrial DNA; MTRC: MitoTracker Red CMXRos; OCR: Oxygen consumption rate; OE: overexpress; PINK1: PTEN induced kinase 1; qRT-PCR: quantitative real-time PCR; ROS: reactive oxygen species; SD: standard deviation; SOD2: superoxide dismutase 2; UQCRC2: ubiquinol-cytochrome c reductase core protein 2; WB: western blot; ����: mitochondrial membrane potential

Background: Online health communities (OHCs) are one of the developments related to online health. Patient compliance plays a vital role in improving health treatment outcomes. Patient activation is associated with patient activities in OHCs, such as physician-patient communication and health information seeking. In other words, OHCs influence patient compliance. Therefore, identifying the relationship between patient activation in OHCs and patient compliance is important for improved health outcomes. Methods: This study established a research model consisting of one independent variable (patient activation), four mediators (physician-patient communication, health information seeking, perceived information asymmetry, and e-health literacy), one dependent variable (patient compliance) and four control variables (gender, age, education level, and status). Data were obtained through a web-based survey, involving a total of 387 valid participants in China. These data were analyzed and tested through structural equation modeling and partial least squares. Results: Patient activation positively affects patient compliance through the mediation of physician-patient communication, health information seeking, perceived information asymmetry, and e-health literacy. Perceived information asymmetry has no direct effect on patient compliance. However, perceived information asymmetry affects patient compliance through the mediation of e-health literacy. Conclusions: Patient compliance is significantly affected by patient activation. Thus, physicians can achieve higher patient compliance by improving patient activation. Guaranteeing and improving the information quality in OHCs is essential for physicians and OHCs operators. Physicians should pay extra attention in cultivating patients' e-health literacy through communications and health information-seeking behaviors to further improve patient compliance.

BackgroundThe rise of the popular e-cigarette, JUUL, has been partly attributed to various teen-friendly e-liquid flavours offered. However, the possible health risks associated with each e-liquid flavour still remain unclear. This research focuses on the possible associations between JUUL flavours and health symptoms using social media data from Reddit.MethodsKeyword filtering was used to obtain 5,746 JUUL flavour-related posts and 7927 health symptom-related posts from June 2015 to April 2019 from Reddit. Posts from September 2016 to April 2019 were used to conduct temporal analysis for nine health symptom categories and the 8 JUUL flavours. Finally, associations between the JUUL flavours and health symptom categories were examined on the user level using generalised estimating equation models.ResultsAccording to our temporal analysis, Mango and Mint were the most discussed JUUL flavours on Reddit. Respiratory and throat symptoms were the most discussed health issues together with JUUL on Reddit over time. Respiratory symptoms had potential associations with the Mango, Mint and Fruit JUUL flavours. Digestive symptoms had a potential association with the Crème flavour, psychological symptoms had a potential association with the Cucumber flavour, and cardiovascular symptoms had a potential association with the tobacco flavours.ConclusionsMango and Mint were the two most mentioned JUUL flavours on Reddit. Certain JUUL flavours were more likely to be mentioned together with certain categories of health symptoms by the same Reddit users. Our findings could prompt further medical research into the health symptoms associated with different e-liquid flavours.

Background: Personal trust tendency is an individual characteristic that can affect one's evaluation of others, behavior and its related outcomes. It may significantly affect one's health information seeking behavior and compliance. Therefore, this article aims at figuring out how personal trust tendency influences patient compliance through the internet health information seeking and patient satisfaction with it. Methods: Data were collected from 336 valid participants through an online survey in China. There are two independent variables: (1) cognition-based trust tendency and (2) affect-based trust tendency, three intervening variables (emerging internet health information seeking, conservative internet health information seeking, and satisfaction with internet health information), one dependent variable (patient compliance), and control variables. We performed confirmative factor analysis and structural equation modeling to test the hypotheses. Results: The cognition- and affect-based trust tendency positively affects patient compliance through the mediation of emerging and conservative internet health information seeking and satisfaction with internet health information. Surprisingly, strong positive relationships between affect-based trust tendency and emerging and conservative internet health information seeking were found, which are contrary to our initial hypothesis. Conclusions: Health information is considerably important when regarding health-related issues for individuals with cognition- and affect-based trust tendency. Physicians should encourage patients to seek health information on the internet and guide them to use internet health information that suits them. Information exchange and correlations should be involved in doctor-patient interactions. By following the suggestions just cited, better patient compliance can likely be obtained.

Objective: To further explore the relationship between the blood urea nitrogen to creatinine (BUN/Cr) ratio and the prognosis of patients with acute heart failure (AHF), a two-part study consisting of a prospective cohort study and meta-analysis were conducted. Methods: A total of 509 hospitalized patients with AHF were enrolled and followed up. Cox proportional hazards regression was used to analyze the relationship between the BUN/Cr ratio and the long-term prognosis of patients with AHF. Meta-analysis was also conducted regarding the topic by searching PubMed and Embase for relevant studies published up to October 2019. Results: During a median follow-up of 2.8 years, 197 (42.6%) deaths occurred. The cumulative survival rate of patients with a BUN/Cr ratio in the bottom quartile was significantly lower than in the other 3 groups (log-rank test: p = 0.003). In multivariate Cox regression models, the mortality rate of AHF patients with a BUN/Cr ratio in the bottom quartile was significantly higher than in the top quartile (adjusted HR 1.52; 95% CI 1.03–2.24). For the meta-analysis, we included 8 studies with 4,700 patients, consisting of 7 studies from the database and our cohort study. The pooled analysis showed that the highest BUN/Cr ratio category was associated with an 77% higher all-cause mortality than the lowest category (pooled HR 1.77; 95% CI 1.52–2.07). Conclusions: Elevated BUN/Cr ratio is associated with poor prognosis in patients with AFH and is an independent predictor of all-cause mortality.

Background: Through mass media, some patients tend to seek mature treatment-related health information whereas some prefer information related to emerging treatments, which may influence patient compliance, specifically, following the medical diagnoses and treatment regimens. Given that traditional mass media (TMM) and the internet (INT) may promote the publication of different treatment-related information, this study aims to identify the difference between TMM and the INT in influencing patient compliance with mature treatments (PCMTs). Materials and Methods: Our subjects were Chinese who had received therapies within a month and had experience of seeking health information through mass media. An online survey involving 384 valid responses was conducted to collect data. The confirmatory factor analysis and structural equation modeling were adopted to test hypotheses. Results: Both TMM and the INT significantly affect PCMTs, through the mediation of mature treatment-related health information. Conclusions: A provision of mature treatment-related information via TMM can effectively help patients gain awareness and knowledge about treatments. In addition, physicians can update patients' knowledge by making cutting-edge treatments continuously available to patients through the mass media and analyzing patient's access patterns for different treatment-related information.

Background eHealth literacy is significantly associated with patients’ online information behavior, physician-patient relationship, patient adherence, and health outcomes. As an important product of the internet, online health communities (OHCs) can help redistribute idle medical resources, increase medical resource utilization, and improve patient adherence. However, studies on eHealth literacy in OHCs are limited. Therefore, this study examined patients’ eHealth literacy regarding health information–seeking behavior and physician-patient communication in OHCs. Objective This study aimed to investigate the association between eHealth literacy in OHCs and patient adherence by employing social cognitive theory. Methods This was an empirical study, in which a research model consisting of 1 independent variable (patients’ eHealth literacy), 3 mediators (physician-patient communication in OHCs, patient health information–seeking behavior in OHCs, and patients’ perceived quality of health information in OHCs), 1 dependent variable (patient adherence), and 4 control variables (age, gender, living area, and education level) was established to examine the associations. Multi-item scales were used to measure variables. An anonymous online survey involving 560 participants was conducted through Chinese OHCs in July 2018 to collect data. Partial least squares and structural equation modeling were adopted to analyze data and test hypotheses. Results The survey response rate was 79.6% (446/560). The reliability, convergent validity, and discriminant validity were acceptable. Age, gender, living area, and education level were positively associated with patient adherence, and gender was positively associated with physician-patient communication and patients’ perceived quality of internet health information in OHCs. Patients’ eHealth literacy was positively associated with patient adherence through the mediations of physician-patient communication, internet health information–seeking behavior, and perceived quality of internet health information in OHCs. Conclusions Results indicate that physician-patient communication, internet health information–seeking behavior, and the perceived quality of internet health information are significantly associated with improving patient adherence via a guiding of eHealth literacy in OHCs. These findings suggest that physicians can understand and guide their patients’ eHealth literacy to improve treatment efficiency; OHCs’ operators should this strengthen the management of information quality, develop user-friendly features, and minimize the gap between the actual and perceived information quality.

Background: A growing number of patients have increasingly used health websites to search and gather health information. Nevertheless, few studies have focused on the driving factors of in...

Using data from the National Health and Nutrition Examination Survey (NHANES), this study aimed to explore the relationship between ethylene oxide (EO) exposure and serum lipid profiles as well as the mediation effect of systemic inflammation among the general adult population.This cross-sectional study analyzed NHANES data from 2013 to 2016, examining a total of 2721 participants. The EO biomarker (hemoglobin adduct of EO [HbEO]) was quantified in blood using a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. The association among HbEO levels, inflammatory biomarkers, and four serum lipids was evaluated using a multivariable linear regression model. Mediating analysis was performed to examine the effect of inflammatory biomarkers on the relationship between HbEO levels and serum lipid profiles.As the quartiles of HbEO increased, high-density lipoprotein cholesterol (HDL-C) monotonically decreased (p for trend0.001). Using the lowest quartile of HbEO as a reference, the percent change for HDL-C was 6.30% (95% CI: 3.89%, 8.71%) in the highest quartile of HbEO. HbEO levels were dose-dependently associated with triglycerides (TG) (p for trend = 0.001). The percent change in TG in the fourth quartile of HbEO was 17.24% (95% CI: 2.01%, 32.48%) compared to the first quartile. Overall, inflammatory biomarkers (hs-CRP, alkaline phosphatase, white blood cell count, neutrophil count, and lymphocyte count) increased monotonically in correlation with increasing HbEO levels (all p for trend0.01); were positively correlated with total cholesterol (TC), TG, and low-density lipoprotein cholesterol (LDL-C); and were negatively associated with HDL-C. Additionally, inflammatory biomarkers strongly mediated the relationships between HbEO and HDL-C and TG with maximum mediated proportions of 21.40% and 33.40%, respectively.These findings suggest that HbEO is closely linked to serum lipid profiles and that systemic inflammation may be a key mediator of this association.

Human embryonic stem cells (hESCs) are self-renewing and pluripotent cells that originate from the inner cell mass of the blastocyst. Mitosis is fundamental to organism survival and reproduction and is responsible for the equal distribution of duplicated chromosomes into daughter cells. Mitotic dysfunction is associated with a wide variety of human diseases, not least cancer. hESCs have a unique cell cycle distribution, but it is unclear exactly how the mitotic activity of hESCs is related to their proliferation and differentiation. Here, we established a cell line of hESCs stably expressing GFP-α-tubulin and mCherry-H2B by lentiviral infection to analyze and visualize mitosis in detail. During metaphase, the mitotic spindle was smaller and wider and contained a greater proportion of astral microtubules than normal cells. In addition, spindle microtubules were more stable, and chromosome alignment was faster in hESCs than in somatic cells. We also found that the spindle assembly checkpoint was functional in hESCs. These findings thus reveal a specialized mitotic behavior of hESCs.

Cobalt exposure has adverse health effects on the cardiovascular system in occupational and laboratory studies, but these effects have not been assessed in the general population. We aimed to determine whether serum cobalt levels had relationship with the prevalence of cardiovascular disease (CVD) in the general population. Using data from the National Health and Nutrition Examination Survey (NHANES) (2015–2016), we performed the cross-sectional study. We analyzed the baseline chrematistics of 3,389 participants (1623 men and 1766 women). Generalized linear models and restricted cubic spline plots curve were undertaken to elucidate the relationship. Stratified subgroup analysis was tested to exclude interaction between different variates and cobalt. Our results showed that the adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for CVD prevalence across the quartiles of cobalt were 0.94 (0.68, 1.30), 1.58 (1.17, 2.13), and 1.84 (1.37, 2.48) compared with lowest quartile. The restricted cubic spline curve also suggested nonlinear and positive association between cobalt and CVD (P for nonlinearity = 0.005). In summary, our cross-sectional results verify that higher cobalt levels are associated with a higher prevalence of cardiovascular disease.

Notch signaling and epigenetic factors are known to play critical roles in regulating tissue homeostasis in most multicellular organisms, but how Notch signaling coordinates with epigenetic modulators to control differentiation remains poorly understood. Here, we identify heterochromatin protein 1c (HP1c) as an essential epigenetic regulator of gut homeostasis in Drosophila. Specifically, we observe that HP1c loss-of-function phenotypes resemble those observed after Notch signaling perturbation and that HP1c interacts genetically with components of the Notch pathway. HP1c represses the transcription of Notch target genes by directly interacting with Suppressor of Hairless (Su(H)), the key transcription factor of Notch signaling. Moreover, phenotypes caused by depletion of HP1c in Drosophila can be rescued by expressing human HP1γ, suggesting that HP1γ functions similar to HP1c in Drosophila. Taken together, our findings reveal an essential role of HP1c in normal development and gut homeostasis by suppressing Notch signaling.

Background Liver and renal function evaluated by the model for end-stage liver disease (MELD) score, the MELD excluding the international normalized ratio (MELD_XI) score and the MELD including sodium (MELD_sodium) score have been considered predictors of adverse events for patients with acute heart failure (AHF). However, the prognostic value of the MELD including albumin (MELD_albumin) score in patients with AHF has not been assessed. Methods A total of 466 patients with AHF were prospectively evaluated. We compared the accuracy of the 4 MELD score formulas using the time-dependent receiver operating characteristic (ROC) curve and corresponding areas under the curve (AUC). Results During a median follow-up period of 34 months, 196 deaths occurred. In the fully adjusted Cox regression model, standardized hazard ratios with 95% confidence interval expressing the risk of all-cause mortality were 1.22 (1.06–1.40), 1.20 (1.04–1.39), 1.23 (1.06–1.42) and 1.21 (1.05–1.41) for MELD, MELD_XI, MELD_sodium and MELD_albumin scores, respectively. The MELD_albumin score showed the best prognostic accuracy (AUC = 0.658) for the prediction of long-term all-cause mortality, followed by the MELD_sodium score (AUC = 0.590), the MELD score (AUC = 0.580), and the MELD_XI score (AUC = 0.544); the MELD_albumin score performs significantly more accurate than MELD and MELD_XI score for predicting the risk of all-cause mortality. Considering reclassification, MELD_albumin score increased the net reclassification improvement over and beyond MELD (13.1%, P = 0.003), MELD_XI (14.8%, P = 0.002), and MELD_sodium (11.9%, P = 0.006) scores for all-cause mortality. Conclusions The MELD_albumin score increases risk stratification of all-cause mortality over and beyond the MELD score and the other modified MELD scores in patients with acute heart failure.

Supplemental Digital Content is available in the text, An increasing number of studies outline renal function as an important risk marker for mortality in acute heart failure (AHF). However, routine estimation of glomerular filtration rate (eGFR) based on serum creatinine is imprecise. This study aims to compare the prognostic impact of CKD-EPI creatinine based equation (eGFRcr), cystatin C based equation (eGFRcyst), and creatinine–cystatin C equation (eGFRcrcyst) for the mortality stratification in AHF. A total of 354 Patients with AHF were prospectively included between January 2012 and June 2016. Creatinine and cystatin C were measured using the same blood sample tube on admission. We quantified eGFR by the eGFRcr, eGFRcyst, and eGFRcrcyst equations. The continuous net reclassification improvement (cNRI) and integrated discrimination improvement (IDI) were calculated to compare the discriminative prognostic value of different CKD-EPI formula. After a median follow-up of 35 months, 161 patients (45.5%) died. Reduced eGFRcyst and eGFRcrcyst remained significant association with death after adjustment. eGFRcyst showed the best area under the curve value (0.706) for the prediction of all-cause mortality. Considering mortality reclassification, both eGFRcyst (IDI = 7.3%, P

Background Flavored electronic cigarettes (e-cigarettes) have become popular in recent years, especially among youth and young adults. To address the epidemic of e-cigarettes, New York State approved a ban on sales of most flavored vaping products other than tobacco and menthol flavors on September 17, 2019. Objective This study aims to examine the attitude of Twitter users to the policy on flavored e-cigarettes in New York State and the impact of this policy on public perceptions of e-cigarettes. This study also compares the attitudes and topics between New York Twitter users and Twitter users from other states who were not directly affected by this policy. Methods Tweets related to e-cigarettes and the New York State policy on flavored e-cigarettes were collected using the Twitter streaming application programming interface from June 2019 to December 2019. Tweets from New York State and those from other states that did not have a flavored e-cigarette policy were extracted. Sentiment analysis was applied to analyze the proportion of negative and positive tweets about e-cigarettes or the flavor policy. Topic modeling was applied to e-cigarette–related data sets and New York flavor policy–related data sets to identify the most frequent topics before and after the announcement of the New York State policy. Results We found that the average number of tweets related to e-cigarettes and the New York State policy on flavored e-cigarettes increased in both New York State and other states after the flavor policy announcement. Sentiment analysis revealed that after the announcement of the New York State flavor policy, in both New York State and other states, the proportion of negative tweets on e-cigarettes increased from 34.07% (4531/13,299) to 44.58% (18,451/41,390) and from 32.48% (14,320/44,090) to 44.40% (64,262/144,734), respectively, while positive tweets decreased significantly from 39.03% (5191/13,299) to 32.86% (13,601/41,390) and from 42.78% (18,863/44,090) to 33.93% (49,105/144,734), respectively. The majority of tweets related to the New York State flavor policy were negative both before and after the announcement of this policy in both New York (87/98, 89% and 3810/4565, 83.46%, respectively) and other states (200/255, 78.4% and 12,695/15,569, 81.54%, respectively), while New York State had a higher proportion of negative tweets than other states. Topic modeling results demonstrated that teenage vaping and health problems were the most discussed topics associated with e-cigarettes. Conclusions Public attitudes toward e-cigarettes became more negative on Twitter after New York State announced the policy on flavored e-cigarettes. Twitter users in other states that did not have such a policy on flavored e-cigarettes paid close attention to the New York State flavor policy. This study provides some valuable information about the potential impact of the flavored e-cigarettes policy in New York State on public attitudes toward flavored e-cigarettes.

Background: Patients are increasingly using technology to seek health information, particularly on treatments. Treatment-related internet health information-seeking behavior may have impact on patients' trust in their physicians and the patient-physician relationship. Therefore, understanding the impacts of treatment-related internet health information-seeking behavior on patient-physician relationship, especially patient compliance, from the perspective of trust is important. Methods: The established research model has two independent variables (emerging and mature treatment-related internet health information seeking), two mediators (cognition- and affect-based trust), and one dependent variable (patient compliance). All variables were measured using previously validated multiple-item scales. We collected data through a web-based questionnaire survey in China and obtained 336 valid responses. The questionnaire validity rate was 89.6% (336/375), and reliability and validity were acceptable. Finally, we used confirmatory factor analysis and structural equation modeling to test the hypotheses and develop the research model. Results: Cognition- and affect-based trust had a direct positive impact on patient compliance. Cognition-based trust had a direct positive impact on affect-based trust. Mature treatment-related internet health information seeking had a significant positive impact on patient compliance through patients' cognition- and affect-based trust in their physicians. However, the emerging treatment-related internet health information seeking indicated a nonsignificant impact on patients' cognition- and affect-based trust in their physicians. Conclusions: Providing patients with access to treatment-related internet health information will not have a negative impact on the patient-physician relationship. Instead, encouraging patients to seek treatment-related health information online can improve patient compliance. Physicians can also learn much about health information related to emerging treatments to enhance their professionalism and reliability.

During learning, interleaving exemplars from different categories (e.g., ABCBCACAB) rather than blocking by category (e.g., AAABBBCCC) often enhances inductive learning, especially when the categories are highly similar. However, when allowed to select their own study schedules, learners overwhelmingly tend to block rather than interleave. Category similarity has been shown to moderate the relative benefit of interleaved versus blocked study. We investigated whether learners were sensitive to category similarity when choosing exemplars for study, and whether these choices predicted their learning outcomes. In Experiment 1, learners interleaved more often when the categories were highly similar (difficult to discriminate from each other), compared with when similarity was low. In Experiment 2, learners were presented with two sets of categories to learn; categories within each set were similar to each other, but categories were dissimilar across sets. When learners chose to interleave, they tended to switch to a similar rather than dissimilar category. Importantly, learners' study choices predicted their subsequent categorization performance. Our findings suggest that learners are strategic in their search for commonalities within versus differences among categories and can regulate their study behaviors based on category similarity.

The effect of aldehyde exposure on the cardiovascular system remains unclear. The objective of this study was to determine whether aldehyde exposure is associated with the prevalence of cardiovascular disease (CVD). We analyzed associations between aldehydes and CVD using data from 1962 adult participants in the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2014. Multivariable logistic regression and restricted cubic spline models were used to examine the association between aldehydes and CVD. The prevalence of CVD was 10.3%. After adjusting for confounding factors, including age, sex, education level, race, diabetes mellitus, smoking, alcohol use, hypertension, body mass index, the poverty-income ratio, physical activity, energy intake, high-density cholesterol (HDL) and low-density cholesterol (LDL), compared with the lowest quartiles, the odds ratios (ORs) with 95% confidence intervals (CIs) for CVD across the quartiles were 0.52 (0.31, 0.87), 0.73 (0.43, 1.22), and 1.13 (0.68, 1.86) for benzaldehyde and 1.48 (0.87, 2.52), 1.70 (1.01, 2.92), and 2.13 (1.19, 3.86) for isopentanaldehyde. There was no significant association between other aldehydes and CVD. The restricted cubic spline plot showed a J-curve relationship between benzaldehyde and CVD. The inflection point for the curve was found at a benzaldehyde level of 0.98 ng/ml. The ORs (95% CIs) for CVD were 0.51 (0.31, 0.86) and 1.58 (1.15, 2.17) on the left and right sides of the inflection point, respectively. Our results demonstrate a J-curve relationship between benzaldehyde and CVD. Isopentanaldehyde is positively associated with CVD. Further study is warranted to verify this association and to elucidate its underlying mechanisms.

Background In recent years, flavored electronic cigarettes (e-cigarettes) have become popular among teenagers and young adults. Discussions about e-cigarettes and e-cigarette use (vaping) experiences are prevalent online, making social media an ideal resource for understanding the health risks associated with e-cigarette flavors from the users’ perspective. Objective This study aimed to investigate the potential associations between electronic cigarette liquid (e-liquid) flavors and the reporting of health symptoms using social media data. Methods A dataset consisting of 2.8 million e-cigarette–related posts was collected using keyword filtering from Reddit, a social media platform, from January 2013 to April 2019. Temporal analysis for nine major health symptom categories was used to understand the trend of public concerns related to e-cigarettes. Sentiment analysis was conducted to obtain the proportions of positive and negative sentiment scores for all reported health symptom categories. Topic modeling was applied to reveal the topics related to e-cigarettes and health symptoms. Furthermore, generalized estimating equation (GEE) models were used to quantitatively measure potential associations between e-liquid flavors and the reporting of health symptoms. Results Temporal analysis showed that the Respiratory category was consistently the most discussed health symptom category among all categories related to e-cigarettes on Reddit, followed by the Throat category. Sentiment analysis showed higher proportions of positive sentiment scores for all reported health symptom categories, except for the Cancer category. Topic modeling conducted on all health-related posts showed that 17 of the top 100 topics were flavor related. GEE models showed different associations between the reporting of health symptoms and e-liquid flavor categories, for example, lower association of the Beverage flavors with Respiratory compared with other flavors and higher association of the Fruit flavors with Cardiovascular than other flavors. Conclusions This study identified different potential associations between e-liquid flavors and the reporting of health symptoms using social media data. The results of this study provide valuable information for further investigation of the health effects associated with different e-liquid flavors.

Objective Patient health information seeking and physician-patient communication in OHCs proved to have impacts on patient compliance, but related studies from psychological perspectives are limited. This study aims to investigate the impact of patient health information seeking and physician-patient communication in OHCs on patient compliance. Methods This study established a research model and proposed six hypotheses. An anonymous investigation was conducted using Chinese OHCs. Confirmatory factor analysis, partial least squares, and structural equation modelling were used to test the hypotheses. Results We received 371 responses, and 316 of them were valid. Patient health information seeking and physician-patient communication frequency in OHCs had positive impacts on patients’ perceived affective and cognitive empathies, which positively impacted patient compliance. Conclusions Patient compliance can be improved by patient health information seeking and physician-patient communication in OHCs and affective and cognitive empathies. Patients’ perceived affective empathy is the preferred perspective to improve patient compliance. Practice implications Physicians should encourage patients to seek health information and communicate with them through OHCs, be concerned about patients’ experiences, feelings, and attitudes, understand patients’ demands and mental states, and show their patients that they can feel patients’ pain. Increasing physician-patient communication frequency in OHCs can help improve patient compliance.

BackgroundOn January 2, 2020, the US Food and Drug Administration (FDA) released the electronic cigarette (e-cigarette) flavor enforcement policy to prohibit the sale of all flavored cartridge–based e-cigarettes, except for menthol and tobacco flavors.ObjectiveThis research aimed to examine the public perception of this FDA flavor enforcement policy and its impact on the public perception of e-cigarettes on Twitter.MethodsA total of 2,341,660 e-cigarette–related tweets and 190,490 FDA flavor enforcement policy–related tweets in the United States were collected from Twitter before (between June 13 and August 22, 2019) and after (between January 2 and March 30, 2020) the announcement of the FDA flavor enforcement policy. Sentiment analysis was conducted to detect the changes in the public perceptions of the policy and e-cigarettes on Twitter. Topic modeling was used for finding frequently discussed topics about e-cigarettes.ResultsThe proportion of negative sentiment tweets about e-cigarettes significantly increased after the announcement of the FDA flavor enforcement policy compared with before the announcement of the policy. In contrast, the overall sentiment toward the FDA flavor enforcement policy became less negative. The FDA flavor enforcement policy was the most popular topic associated with e-cigarettes after the announcement of the FDA flavor enforcement policy. Twitter users who discussed about e-cigarettes started to talk about other alternative ways of getting e-cigarettes after the FDA flavor enforcement policy.ConclusionsTwitter users’ perceptions of e-cigarettes became more negative after the announcement of the FDA flavor enforcement policy.

The nonlinear associations of serum perfluoroalkyl acids (PFAAs) with hypertension and blood pressure have not been addressed. Cross-sectional data from 6967 adults (age ≥ 20 years) from the 2003–2012 National Health and Nutrition Examination Survey (NHANES) were analyzed. Hypertension was defined as an average systolic blood pressure above 140 mmHg, an average diastolic blood pressure above 90 mmHg or self-reported use of prescribed medicine for diagnosed hypertension. After multivariable adjustment, compared with the lowest tertile, the odds ratios (ORs) with 95% confidence intervals (CIs) of hypertension for the highest tertile of perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS) and perfluorononanoic acid (PFNA) were 1.32 (1.13, 1.54), 1.14 (0.97, 1.34), 1.16 (0.99, 1.36) and 1.18 (1.01, 1.37), respectively. PFOA and PFNA displayed a J-shaped relationship with the prevalence of hypertension. Furthermore, threshold effect analysis showed that the inflection point of PFOA was 1.80 ng/ml. Each 10-fold change in PFOA exhibited a 44% decrease (OR 0.56, 95%CI (0.32, 0.99)) in the odds of hypertension on the left side of the inflection point, and an 85% increase (OR 1.85, 95%CI (1.34, 2.54)) on the right side of the inflection point. Threshold effect analysis also indicated that the inflection point of PFNA was 0.53 ng/ml. Each 10-fold change in PFNA exhibited a 60% decrease (OR 0.40, 95%CI (0.18, 0.85)) in the odds of hypertension on the left side of the inflection point, and an 85% increase (OR 1.64, 95%CI (1.25, 2.14)) on the right side of the inflection point. These cross-sectional data showed a J-shaped association between perfluoroalkyl acids and hypertension.

In China, the utilization of medical resources is contentious, and a large of hospitals are seriously congested because of the huge population and uneven distribution of medical resources. Online health communities (OHCs) provide patients with platforms to interact with physicians and to get professional suggestions and emotional support. This study adopted the unified theory of acceptance and use of technology to identify factors influencing patients&rsquo, behavioral intention and usage behavior when interacting with physicians in OHCs. An investigation involving 378 valid responses was conducted through several Chinese OHCs to collect data. Confirmatory factor analysis and structural equation modelling were utilized to test hypotheses. Both the reliability and validity of the scales were acceptable. All five hypotheses were supported, and behavioral intention played a significant mediating role between independent variables and dependent variables. This study clarified the mechanism by which performance expectancy, effort expectancy, social influence and attitude toward using technology affect usage behavior through the mediation of behavioral intention in OHCs. These findings suggest that OHCs can change the actions of websites such as adopting some incentives to promote patients&rsquo, intention of interaction. Physicians should understand patients&rsquo, actual attitudes toward OHCs and try to guide patients in their interactions, improving the quality of physician&ndash, patient interaction.

Background Triggering receptor expressed on myeloid cells-1 (TREM-1) is inducible on monocyte/macrophages and neutrophils and amplifies the inflammatory response. The aim of this study was to determine whether rheumatoid arthritis synovial fibroblasts (RASF) promote the expression of TREM-1 in monocytes and its potential regulatory mechanism. Methods Synovial fluid and paired peripheral blood from rheumatoid arthritis (RA) patients were analyzed using flow cytometry. Expression of TREM-1 in monocytes was detected after co-culture with RASF, with or without pre-treatment with toll-like receptor (TLR) ligands. Whether RASF-regulated TREM-1 level in monocytes require direct cell contact or soluble factors was evaluated by transwell experiment. COX-2 expression and PGE2 secretion in RASF were determined by quantitative PCR (qPCR) and ELISA. RASF, with and without TLR ligand stimulation, were treated with COX-2 inhibitors, COX-2 siRNA (siCOX-2) or EP1–4 antagonists, and the resulting TREM-1 level in CD14+ monocytes was measured using flow cytometry. Results TREM-1 was highly expressed in CD14+ cells from peripheral blood and especially synovial fluid from RA patients. The expression of TREM-1 in monocytes was increased by co-culture with RASF. TLR-ligand-activated RASF further elevated TREM-1 level. Transwell assay indicated that soluble factors played a key role in RASF-promoted expression of TREM-1 in monocytes. RASF, with or without stimulation by TLR ligands, increased secretion of PGE2 in a cyclooxygenase (COX)-2-dependent manner. PGE2 enhanced the increase in TREM-1 level in monocytes. Finally, studies using COX-2 inhibitors, COX-2 siRNA (siCOX-2) and EP1–4 antagonists, showed that RASF promotion of TREM-1 expression in monocytes was mediated by COX-2/PGE2/EP2,4 signaling. Conclusions Our data is the first report to reveal the critical role of RASF in upregulating TREM-1 expression in monocytes, which indicates that TREM-1 might be a novel target for RA therapy. Electronic supplementary material The online version of this article (10.1186/s13075-019-1954-3) contains supplementary material, which is available to authorized users.

Background: In China, the utilization of medical resources is tense, and most hospitals are highly congested because of the large population and uneven distribution of medical resources. Online health communities (OHCs) play an important role in alleviating hospital congestions, thereby improving the utilization of medical resources and relieving medical resource shortages. OHCs have positive effects on physician-patient relationships and health outcomes. Moreover, as one of the main ways for patients to seek health-related information in OHCs, physician-patient communication may affect patient compliance in various ways. In consideration of the inevitable development of OHCs, although they have several shortcomings, identifying how physician-patient communication can impact patient compliance is important to improve patients’ health outcomes through OHCs. Objective: This study aimed to investigate the impact of physician-patient communication on patient compliance in OHCs through the mediation of the perceived quality of internet health information, decision-making preference, and physician-patient concordance, using an empirical study based on the self-determination theory. Methods: A research model was established, including 1 independent variable (physician-patient communication), 3 mediators (perceived quality of internet health information, decision-making preference, and physician-patient concordance), 1 dependent variable (patient compliance), and 4 control variables (age, gender, living area, and education level). Furthermore, a Web-based survey involving 423 valid responses was conducted in China to collect data, and structural equation modeling and partial least squares were adopted to analyze data and test the hypotheses. Results: The questionnaire response rate was 79.2% (487/615) and the validity rate was 86.9% (423/487); reliability and validity are acceptable. The communication between physicians and patients in OHCs positively affects patient compliance through the mediation of the perceived quality of internet health information, decision-making preference, and physician-patient concordance. Moreover, physician-patient communication exhibits similar impacts on the perceived quality of internet health information, decision-making preference, and physician-patient concordance. Patients’ decision-making preference shows the weakest impact on patient compliance compared with the other 2 mediators. Ultimately, all 3 mediators play a partially mediating role between physician-patient communication and patient compliance. Conclusions: We conclude that physician-patient communication in OHCs exhibits a positive impact on patient compliance; thus, patient compliance can be improved by guiding physician-patient communication in OHCs. Furthermore, our findings suggest that physicians can share high-quality health information with patients, discuss benefits, risks, and costs of treatment options with patients, encourage patients to express their attitudes and participate in health-related decision making, and strengthen the emotional connection with patients in OHCs, thereby decreasing patients’ misunderstanding of information and increasing concordance between physicians and patients. OHCs are required to not only strengthen the management of their published health information quality but also understand users’ actual attitudes toward information quality and then try to reduce the gap between the perceived and actual quality of information.

Background In general, medical regimens and treatments are more likely to be effective if patients follow their physicians’ advice. However, limited studies have focused on the relationship between regulatory focus and patient adherence. This study explores the antecedents of patient adherence employing regulatory focus theory. Methods This study established a research model consisting of two independent variables, two mediators, one dependent variable, two moderators, three control variables, and six hypotheses. An online survey involving 336 valid responses was conducted to collect data in China. We used structural equation modelling and confirmatory factor analysis to test the hypotheses and to develop the research model. Results The reliability and validity of the measures were accepted. In terms of control variables, age had a positive effect on conservative treatment-related health information seeking behaviour, and patients with different resident statuses held different attitudes towards seeking conservative treatment-related health information. However, educational level did not have any effect on the variables of the research model. The hypothesis testing results corroborate that promotion focus had a positive impact on patients’ emerging treatment-related health information seeking behaviour; prevention focus had a positive impact on patients’ conservative treatment-related health information seeking behaviour, which had a positive impact on patient adherence. In addition, media campaigns had a positive impact on the relationship between promotion focus and emerging treatment-related health information seeking behaviour, and website reputation had a positive impact on the relationship between prevention focus and conservative treatment-related health information seeking behaviour. Conclusions Individuals can be encouraged to seek health information and share health-related knowledge through mass media, such as the Internet, when the quality of information, especially information from online sources, is guaranteed. In addition, physicians need to improve their professionalism and expand their knowledge of conservative healthcare. As a further application of our work, an Internet information recommendation system can be designed to recommend different types of health information for users according to their regulatory focus. Electronic supplementary material The online version of this article (10.1186/s12913-019-4127-9) contains supplementary material, which is available to authorized users.

Background The number of electronic cigarette (e-cigarette) users has been increasing rapidly in recent years, especially among youth and young adults. More e-cigarette products have become available, including e-liquids with various brands and flavors. Various e-liquid flavors have been frequently discussed by e-cigarette users on social media. Objective This study aimed to examine the longitudinal prevalence of mentions of electronic cigarette liquid (e-liquid) flavors and user perceptions on social media. Methods We applied a data-driven approach to analyze the trends and macro-level user sentiments of different e-cigarette flavors on social media. With data collected from web-based stores, e-liquid flavors were classified into categories in a flavor hierarchy based on their ingredients. The e-cigarette–related posts were collected from social media platforms, including Reddit and Twitter, using e-cigarette–related keywords. The temporal trend of mentions of e-liquid flavor categories was compiled using Reddit data from January 2013 to April 2019. Twitter data were analyzed using a sentiment analysis from May to August 2019 to explore the opinions of e-cigarette users toward each flavor category. Results More than 1000 e-liquid flavors were classified into 7 major flavor categories. The fruit and sweets categories were the 2 most frequently discussed e-liquid flavors on Reddit, contributing to approximately 58% and 15%, respectively, of all flavor-related posts. We showed that mentions of the fruit flavor category had a steady overall upward trend compared with other flavor categories that did not show much change over time. Results from the sentiment analysis demonstrated that most e-liquid flavor categories had significant positive sentiments, except for the beverage and tobacco categories. Conclusions The most updated information about the popular e-liquid flavors mentioned on social media was investigated, which showed that the prevalence of mentions of e-liquid flavors and user perceptions on social media were different. Fruit was the most frequently discussed flavor category on social media. Our study provides valuable information for future regulation of flavored e-cigarettes.

The increasing incidence of metabolic syndrome requires more functional food products with low cost and excellent effects to assist treatment. The crude extract of Moringa oleifera Lam. showed excellent hypoglycemic activity. The current study was designed to investigate the effects and mechanism of niazirin, a bioactive component from Moringa oleifera Lam. seed, on diabetic metabolic syndrome. C57BL/6J mice were treated daily with 5 mL/kg/body weight (BW) of saline, while db/db mice were similarly treated with 5 mL/kg/BW of saline, 10 and 20 mg/kg/BW of niazirin, respectively. Results indicated that niazirin could significantly reduce body weight, water and food intake, improve hyperglycemia, insulin resistance, inflammation, carbohydrate and lipid metabolism, non-alcoholic fatty liver. Furthermore, niazirin improved the hepatic energy metabolism via AMPK signaling pathway. Our study provides an evidence of an edible plant product, niazirin, may help in the treatment of metabolic syndrome.

Background: The internet has become a major mean for acquiring health information; however, Web-based health information is of mixed quality and may markedly affect patients’ health-related behavior and decisions. According to the social information processing theory, patients’ trust in their physicians may potentially change due to patients’ health-information-seeking behavior. Therefore, it is important to identify the relationship between internet health information and patient compliance from the perspective of trust. Objective: The objective of our study was to investigate the effects of the quality and source of internet health information on patient compliance using an empirical study based on the social information processing theory and social exchange theory. Methods: A Web-based survey involving 336 valid participants was conducted in China. The study included independent variables (internet health information quality and source of information), 2 mediators (cognition-based trust [CBT] and affect-based trust [ABT]), 1 dependent variable (patient compliance), and 3 control variables (gender, age, and job). All variables were measured using multiple-item scales from previously validated instruments, and confirmative factor analysis as well as structural equation modeling was used to test hypotheses. Results: The questionnaire response rate was 77.16% (375/486), validity rate was 89.6% (336/375), and reliability and validity were acceptable. We found that the quality and source of internet health information affect patient compliance through the mediation of CBT and ABT. In addition, internet health information quality has a stronger influence on patient compliance than the source of information. However, CBT does not have any direct effect on patient compliance, but it directly affects ABT and then indirectly impacts patient compliance. Therefore, the effect of ABT seems stronger than that of CBT. We found an unexpected, nonsignificant relationship between the source of internet health information and ABT. Conclusions: From patients’ perspective, internet health information quality plays a stronger role than its source in impacting their trust in physicians and the consequent compliance with physicians. Therefore, patient compliance can be improved by strengthening the management of internet health information quality. The study findings also suggest that physicians should focus on obtaining health information from health websites, thereby expanding their understanding of patients’ Web-based health-information-seeking preferences, and enriching their knowledge structure to show their specialization and reliability in the communication with patients. In addition, the mutual demonstration of care and respect in the communication between physicians and patients is important in promoting patients’ ABT in their physicians.

Years of clinical trials have proven the maturity and safety of certain treatments, however, some of these mature treatments may not be highly effective. Several treatments have emerged through technological innovations, but their long-term safety, efficacy, and adverse effects remain unknown. At present, many patients seek information related to their treatments on the Internet, which may impact their attitudes towards different treatments and their trust in physicians. In this study, a research model was developed to examine how patients&rsquo, trust in their physicians is influenced by related online information on mature or emerging treatments. The hypotheses were tested using confirmatory factor analysis (CFA) and structural equation modelling (SEM). A total of 336 valid responses were collected through an online survey. Mature treatments related health information was found to significantly improve patients&rsquo, trust. Thus, physicians should pay more attention to mature treatments, and encourage their patients to seek related information online. Moreover, the quality of online information should be developed further to increase patients&rsquo, satisfaction. Physicians should also consider their patients&rsquo, psychological safety in communication with patients to strengthen their trust.

Human endogenous retrovirus subfamily H (HERVH) is a class of transposable elements expressed preferentially in human embryonic stem cells (hESCs). Here, we report that the long terminal repeats of HERVH function as enhancers and that HERVH is a nuclear long noncoding RNA required to maintain hESC identity. Furthermore, HERVH is associated with OCT4, coactivators and Mediator subunits. Together, these results uncover a new role of species-specific transposable elements in hESCs. ASTAR (Agency for Sci., Tech. and Research, S’pore)

Detection of new genomic control elements is critical in understanding transcriptional regulatory networks in their entirety. We studied the genome-wide binding locations of three key regulatory proteins (POU5F1, also known as OCT4; NANOG; and CTCF) in human and mouse embryonic stem cells. In contrast to CTCF, we found that the binding profiles of OCT4 and NANOG are markedly different, with only approximately 5% of the regions being homologously occupied. We show that transposable elements contributed up to 25% of the bound sites in humans and mice and have wired new genes into the core regulatory network of embryonic stem cells. These data indicate that species-specific transposable elements have substantially altered the transcriptional circuitry of pluripotent stem cells.

Primary biliary cirrhosis (PBC) is a progressive autoimmune liver disease in which monocytes/macrophages infiltration and skewed T helper type (Th) 1 and Th17 cell responses participate in the development of the disease. Human peripheral blood monocytes are heterogeneous and can be divided into classical CD14

About half of the human genome consists of highly repetitive elements, most of which are considered dispensable for human life. Here, we report that repetitive elements originating from endogenous retroviruses (ERVs) are systematically transcribed during human early embryogenesis in a stage-specific manner. Our analysis highlights that the long terminal repeats (LTRs) of ERVs provide the template for stage-specific transcription initiation, thereby generating hundreds of co-expressed, ERV-derived RNAs. Conversion of human embryonic stem cells (hESCs) to an epiblast-like state activates blastocyst-specific ERV elements, indicating that their activity dynamically reacts to changes in regulatory networks. In addition to initiating stage-specific transcription, many ERV families contain preserved splice sites that join the ERV segment with non-ERV exons in their genomic vicinity. In summary, we find that ERV expression is a hallmark of cellular identity and cell potency that characterizes the cell populations in early human embryos. ASTAR (Agency for Sci., Tech. and Research, S’pore)

SON is a nuclear protein involved in multiple cellular processes including transcription, pre-messenger RNA (mRNA) splicing, and cell cycle regulation. Although SON was discovered 25 years ago, the importance of SON's function was only realized recently when its roles in nuclear organization and pre-mRNA splicing as well as the influence of these activities in maintaining cellular health were unveiled. Furthermore, SON was implicated to have a key role in stem cells as well as during the onset of various diseases such as cancer, influenza, and hepatitis. Here we review the progress that has been made in studying this multifunctional protein and discuss questions that remain to be answered about SON. ASTAR (Agency for Sci., Tech. and Research, S’pore)

SummaryHuman embryonic stem cells (hESCs) are derived from the inner cell mass of the blastocyst. Despite sharing the common property of pluripotency, hESCs are notably distinct from epiblast cells of the preimplantation blastocyst. Here we use a combination of three small-molecule inhibitors to sustain hESCs in a LIF signaling-dependent hESC state (3iL hESCs) with elevated expression of NANOG and epiblast-enriched genes such as KLF4, DPPA3, and TBX3. Genome-wide transcriptome analysis confirms that the expression signature of 3iL hESCs shares similarities with native preimplantation epiblast cells. We also show that 3iL hESCs have a distinct epigenetic landscape, characterized by derepression of preimplantation epiblast genes. Using genome-wide binding profiles of NANOG and OCT4, we identify enhancers that contribute to rewiring of the regulatory circuitry. In summary, our study identifies a distinct hESC state with defined regulatory circuitry that will facilitate future analysis of human preimplantation embryogenesis and pluripotency.

PRDM14 is an important determinant of the human embryonic stem cell (ESC) identity and works in concert with the core ESC regulators to activate pluripotency-associated genes. PRDM14 has been previously reported to exhibit repressive activity in mouse ESCs and primordial germ cells; and while PRDM14 has been implicated to suppress differentiation genes in human ESCs, the exact mechanism of this repressive activity remains unknown. In this study, we provide evidence that PRDM14 is a direct repressor of developmental genes in human ESCs. PRDM14 binds to silenced genes in human ESCs and its global binding profile is enriched for the repressive trimethylation of histone H3 lysine 27 (H3K27me3) modification. Further investigation reveals that PRDM14 interacts directly with the chromatin regulator polycomb repressive complex 2 (PRC2) and PRC2 binding is detected at PRDM14-bound loci in human ESCs. Depletion of PRDM14 reduces PRC2 binding at these loci and the concomitant reduction of H3K27me3 modification. Using reporter assays, we demonstrate that gene loci bound by PRDM14 exhibit repressive activity that is dependent on both PRDM14 and PRC2. In reprogramming human fibroblasts into induced pluripotent stem cells (iPSCs), ectopically expressed PRDM14 can repress these developmental genes in fibroblasts. In addition, we show that PRDM14 recruits PRC2 to repress a key mesenchymal gene ZEB1, which enhances mesenchymal-to-epithelial transition in the initiation event of iPSC reprogramming. In summary, our study reveals a repressive role of PRDM14 in the maintenance and induction of pluripotency and identifies PRDM14 as a new regulator of PRC2.

Human embryonic stem cells (hESCs) harbour the ability to undergo lineage-specific differentiation into clinically relevant cell types. Transcription factors and epigenetic modifiers are known to play important roles in the maintenance of pluripotency of hESCs. However, little is known about regulation of pluripotency through splicing. In this study, we identify the spliceosome-associated factor SON as a factor essential for the maintenance of hESCs. Depletion of SON in hESCs results in the loss of pluripotency and cell death. Using genome-wide RNA profiling, we identified transcripts that are regulated by SON. Importantly, we confirmed that SON regulates the proper splicing of transcripts encoding for pluripotency regulators such as OCT4, PRDM14, E4F1 and MED24. Furthermore, we show that SON is bound to these transcripts in vivo. In summary, we connect a splicing-regulatory network for accurate transcript production to the maintenance of pluripotency and self-renewal of hESCs. ASTAR (Agency for Sci., Tech. and Research, S’pore)

The derivation of human ES cells (hESCs) from human blastocysts represents one of the milestones in stem cell biology. The full potential of hESCs in research and clinical applications requires a detailed understanding of the genetic network that governs the unique properties of hESCs. Here, we report a genome-wide RNA interference screen to identify genes which regulate self-renewal and pluripotency properties in hESCs. Interestingly, functionally distinct complexes involved in transcriptional regulation and chromatin remodelling are among the factors identified in the screen. To understand the roles of these potential regulators of hESCs, we studied transcription factor PRDM14 to gain new insights into its functional roles in the regulation of pluripotency. We showed that PRDM14 regulates directly the expression of key pluripotency gene POU5F1 through its proximal enhancer. Genome-wide location profiling experiments revealed that PRDM14 colocalized extensively with other key transcription factors such as OCT4, NANOG and SOX2, indicating that PRDM14 is integrated into the core transcriptional regulatory network. More importantly, in a gain-of-function assay, we showed that PRDM14 is able to enhance the efficiency of reprogramming of human fibroblasts in conjunction with OCT4, SOX2 and KLF4. Altogether, our study uncovers a wealth of novel hESC regulators wherein PRDM14 exemplifies a key transcription factor required for the maintenance of hESC identity and the reacquisition of pluripotency in human somatic cells.