Idax and Rinf facilitate expression of Tet enzymes to promote neural and suppress trophectodermal programs during differentiation of embryonic stem cells.

The Inhibitor of disheveled and axin (Idax) and its ortholog the Retinoid inducible nuclear factor (Rinf) are DNA binding proteins with nuclear and cytoplasmic functions. Rinf is expressed in embryonic stem cells (ESCs) where it regulates transcription of the Ten-eleven translocation (Tet) enzymes, promoting neural and suppressing mesendoderm/trophectoderm differentiation. Here, we find that Idax, which is not expressed in ESCs, is induced upon differentiation. Like Rinf, Idax facilitates neural and silences trophectodermal programs. Individual or combined loss of Idax and Rinf led to downregulation of neural and upregulation of trophectoderm markers during differentiation of ESCs to embryoid bodies as well as during directed differentiation of ESCs to neural progenitor cells (NPCs) and trophoblast-like cells. These defects resemble those of Tet-deficient ESCs. Consistently, Tet genes are direct targets of Idax and Rinf, and loss of Idax and Rinf led to downregulation of Tet enzymes during ESC differentiation to NPCs and trophoblast-like cells. While Idax and Rinf single and double knockout (DKO) mice were viable and overtly normal, DKO embryos had reduced expression of several NPC markers in embryonic forebrains and deregulated expression of selected trophoblast markers in placentas. NPCs derived from DKO forebrains had reduced self-renewal while DKO placentas had increased junctional zone and reduced labyrinth layers. Together, our findings establish Idax and Rinf as regulators of Tet enzymes for proper differentiation of ESCs.

Tet-mediated DNA demethylation regulates specification of hematopoietic stem and progenitor cells during mammalian embryogenesis.

Ten-eleven translocation (Tet) enzymes promote DNA demethylation by oxidizing 5-methylcytosine. They are expressed during development and are essential for mouse gastrulation. However, their postgastrulation functions are not well established. We find that global or endothelial-specific loss of all three Tet enzymes immediately after gastrulation leads to reduced number of hematopoietic stem and progenitor cells (HSPCs) and lethality in mid-gestation mouse embryos. This is due to defects in specification of HSPCs from endothelial cells (ECs) that compromise primitive and definitive hematopoiesis. Mechanistically, loss of Tet enzymes in ECs led to hypermethylation and down-regulation of NFκB1 and master hematopoietic transcription factors (Gata1/2, Runx1, and Gfi1b). Restoring Tet catalytic activity or overexpression of these factors in Tet-deficient ECs rescued hematopoiesis defects. This establishes Tet enzymes as activators of hematopoiesis programs in ECs for specification of HSPCs during embryogenesis, which is distinct from their roles in adult hematopoiesis, with implications in deriving HSPCs from pluripotent cells.

Moderated Mediation Model from Stress to Burnout among Health Professionals.

Objectives: It is unclear whether poor health is a contributing factor or a consequence of burn-out. We aimed to explore the relationship among job stress, physical health, mental health, burnout, and coping strategies among health professionals using a moderated mediation model. Methods: Health professionals in Taiwan were invited using a stratified and probability proportional to size sampling. A structure equation model (SEM) was used to examine relationships among job stress, burnout, and physical/mental health. The bootstrapping approach for moderated mediation analysis was then used to explore the role of coping strategies. Results: Totally 935 health professionals participated. The SEM model revealed that job stress was inversely associated with physical and mental health. The direct association between job stress and burn-out was insignificant. Moderated mediation analysis revealed that job stress influenced burnout through physical health and mental health, and that the coping strategy of support-seeking moderated the indirect effect only through mental health. Conclusions: Support-seeking is a good coping strategy for health professionals to buffer the harmful effects of job stress on mental health.

Quantitative analysis by reversed-phase high-performance liquid chromatography and retinal neuroprotection after topical administration of moxonidine.

AIM: To determine moxonidine in aqueous humor and iris-ciliary body by reversed-phase high performance liquid chromatography (RP-HPLC), and to evaluate the retinal neuroprotective effect after topical administration with moxonidine in a high intraocular pressure (IOP) model. METHODS: The eyes of albino rabbits were administered topically and ipsilaterally with 0.2% moxonidine. A RP-HPLC method was employed for the identification and quantification of moxonidine between 2 and 480min, which presented in the aqueous humor and iris-ciliary body. Flash electroretinography (F-ERG) amplitude and superoxide dismutase (SOD) level were measured between day 1 and day 15 after topical administration with moxonidine in a rabbit model of high IOP. Histological and ultrastructural observation underwent to analyze the changes of retinal morphology, the inner retinal layers (IRL) thickness, and retinal ganglion cell (RGC) counting. RESULTS: Moxonidine was detectable between 2 and 480min after administration, and the peak concentration developed both in the two tissues at 30min, 0.51 µg/mL in aqueous humor and 1.03 µg/g in iris-ciliary body. In comparison to control, F-ERG b-wave amplitude in moxonidine eyes were significantly differences between day 3 and day 15 (P<0.01) in the high IOP model; SOD levels were significantly higher at all time-points (P<0.01) with a maximum level of 20.29 U/mgprot at day 15; and RGCs were significantly higher (P<0.05). CONCLUSION: Moxonidine is a viable neuroprotective agent with application to high IOP model. All layers of retina, including RGC layer, retinal nerve fiber layer and INL, are more preserved after moxonidine administration. SOD plays a neuroprotective role in ocular hypertension-mediated RGC death.

Status of healthcare workers after comprehensive reform of urban public hospitals in Beijing, China: sustainable supply, psychological perception, and work outcomes.

BACKGROUND: Healthcare reform in China has attracted worldwide interest and reached a new juncture. In an attempt to improve healthcare quality and patient satisfaction, the government of Beijing introduced comprehensive reform of urban public hospitals in 2016 and implemented new policies on personnel, compensation, management, and diagnosis and treatment. As the agents of healthcare service, and a target of reform measures, healthcare workers were greatly affected by these reforms but have not been carefully studied. METHODS: This study used mean value analysis, variance analysis, and qualitative content analysis to investigate the status of healthcare workers after comprehensive reform of urban public hospitals in Beijing. RESULTS: We found a gradual but constant increase in the number of healthcare workers in poor health in Beijing public hospitals. After the reforms, this population reported high challenge stress, public service motivation, job satisfaction, job performance and quality of healthcare, moderate presenteeism, and low hindrance stress and turnover intention. The status of healthcare workers differed by subgroup and changed during the reform process. CONCLUSIONS: Our study provides data useful for policy recommendations regarding the implementation and extension of future reforms and offers important lessons for developing and developed countries that are reforming public hospitals to improve efficiency and reduce costs.

Public service motivation as a mediator of the relationship between job stress and presenteeism: a cross-sectional study from Chinese public hospitals.

BACKGROUND: Job stress is a strong indicator of presenteeism, but few studies have examined its diverse effects and mediators on presenteeism. This study explored the relationships between job stress, public service motivation (PSM) and presenteeism and how job stress and PSM influence presenteeism in a large national sample of Chinese healthcare workers. METHODS: A cross-sectional survey including 1392 healthcare workers from 11 Class A tertiary hospitals in eastern, central and western China was used in the analysis. Descriptive statistical analysis, correlation analysis and structural equation modeling were used to test the research hypothesis. RESULTS: Hindrance stress was inversely associated with PSM (ß = - 0.27; P < 0.001) but significantly positively associated with presenteeism (ß = 0.35; P < 0.001). PSM was directly inversely associated with presenteeism (ß = - 0.35; P < 0.001). PSM partially mediated the relation of hindrance stress with presenteeism. CONCLUSIONS: The findings suggest that efforts to prevent presenteeism among healthcare workers in China should emphasize PSM improvement and reduction of hindrance stress.

Rinf Regulates Pluripotency Network Genes and Tet Enzymes in Embryonic Stem Cells.

The Retinoid inducible nuclear factor (Rinf), also known as CXXC5, is a nuclear protein, but its functions in the context of the chromatin are poorly defined. We find that in mouse embryonic stem cells (mESCs), Rinf binds to the chromatin and is enriched at promoters and enhancers of Tet1, Tet2, and pluripotency genes. The Rinf-bound regions show significant overlapping occupancy of pluripotency factors Nanog, Oct4, and Sox2, as well as Tet1 and Tet2. We found that Rinf forms a complex with Nanog, Oct4, Tet1, and Tet2 and facilitates their proper recruitment to regulatory regions of pluripotency and Tet genes in ESCs to positively regulate their transcription. Rinf deficiency in ESCs reduces expression of Rinf target genes, including several pluripotency factors and Tet enzymes, and causes aberrant differentiation. Together, our findings establish Rinf as a regulator of the pluripotency network genes and Tet enzymes in ESCs.

Effect of Stress on the Work Ability of Aging American Workers: Mediating Effects of Health.

We examined how stress affects the work ability of an aging workforce, how health mediates this relationship, and how the effects of stress on work ability differ in relation to social status. We analyzed data from the Health and Retirement Survey, namely, 2921 observations in 2010, 2289 observations in 2012, and 2276 observations in 2014. Ongoing chronic stress, social status, health status, and associations with individual work ability were assessed with ordinary least squares regression. Stress was significantly inversely associated with work ability. Health may function as a mediator between individual stress and work ability. The effects of stress and health on work ability decreased as social status increased. To cope with the challenges of aging workforces, future policy-makers should consider job resources and social status.

Job Stress and Healthcare Quality among Chinese Healthcare Workers: The Mediating Effects of Public Service Motivation.

Objectives: This study explored the relationships between challenge stress, hindrance stress, and healthcare quality, and the mediating effect of public service motivation (PSM), among healthcare workers in Chinese public hospitals. Methods: Using widely adopted scales to measure all variables, we used descriptive statistical analysis, analysis of variance, correlation analysis, structural equation modeling and subgroup analysis to investigate data from 2066 healthcare workers in 68 Chinese public hospitals. Results: Challenge stress and hindrance stress were strongly correlated among the participants (ß = 0.59; p < .001). Challenge stress was significantly and positively associated with PSM (ß = 0.14; p < .001) and healthcare quality (ß = 0.16; p < .001), and hindrance stress was significantly and negatively associated with PSM (ß = -0.29; p < .001) and healthcare quality (ß = -0.10; p < .001). PSM was directly positively associated with healthcare quality (ß = 0.59; p < .001) and indirectly mediated the relationship of hindrance stress with healthcare quality. Conclusions: Healthcare quality might be improved by limiting hindrance stress, increasing PSM, and controlling challenge stress.

Supervisor Support, Coworker Support and Presenteeism among Healthcare Workers in China: The Mediating Role of Distributive Justice.

Healthcare workers in China are exposed to extremely high job stress and inequitable work conditions, and the Healthy China 2030 blueprint has made them an important focus of policymakers. To examine the importance of distributive justice in Chinese medical reform, we analyzed data from 1542 healthcare workers employed in 64 primary, secondary and tertiary hospitals in 28 Chinese cities in Western, Central and Eastern China in 2018. Supervisor support, coworker support, distributive justice, and presenteeism were assessed with the supervisor support scale, coworker support scale, distributive justice scale and perceived ability to work scale, respectively. Structural equation modeling was used to examine relationships among variables. The mediating effect of distributive justice on associations between supervisor support, coworker support, and presenteeism was examined with the Sobel test. The results revealed that significant indirect effects between supervisor support and presenteeism and between coworker support and presenteeism were significantly mediated by distributive justice. Better supervisor and coworker support might improve distributive justice among healthcare workers in Chinese hospitals, thereby increasing their performance.

G-Protein α-Subunit Gsα Is Required for Craniofacial Morphogenesis.

The heterotrimeric G protein subunit Gsα couples receptors to activate adenylyl cyclase and is required for the intracellular cAMP response and protein kinase A (PKA) activation. Gsα is ubiquitously expressed in many cell types; however, the role of Gsα in neural crest cells (NCCs) remains unclear. Here we report that NCCs-specific Gsα knockout mice die within hours after birth and exhibit dramatic craniofacial malformations, including hypoplastic maxilla and mandible, cleft palate and craniofacial skeleton defects. Histological and anatomical analysis reveal that the cleft palate in Gsα knockout mice is a secondary defect resulting from craniofacial skeleton deficiencies. In Gsα knockout mice, the morphologies of NCCs-derived cranial nerves are normal, but the development of dorsal root and sympathetic ganglia are impaired. Furthermore, loss of Gsα in NCCs does not affect cranial NCCs migration or cell proliferation, but significantly accelerate osteochondrogenic differentiation. Taken together, our study suggests that Gsα is required for neural crest cells-derived craniofacial development.

Transferrin Receptor Controls AMPA Receptor Trafficking Efficiency and Synaptic Plasticity.

Transferrin receptor (TFR) is an important iron transporter regulating iron homeostasis and has long been used as a marker for clathrin mediated endocytosis. However, little is known about its additional function other than iron transport in the development of central nervous system (CNS). Here we demonstrate that TFR functions as a regulator to control AMPA receptor trafficking efficiency and synaptic plasticity. The conditional knockout (KO) of TFR in neural progenitor cells causes mice to develop progressive epileptic seizure, and dramatically reduces basal synaptic transmission and long-term potentiation (LTP). We further demonstrate that TFR KO remarkably reduces the binding efficiency of GluR2 to AP2 and subsequently decreases AMPA receptor endocytosis and recycling. Thus, our study reveals that TFR functions as a novel regulator to control AMPA trafficking efficiency and synaptic plasticity.