Jpx RNA regulates CTCF anchor site selection and formation of chromosome loops.

Chromosome loops shift dynamically during development, homeostasis, and disease. CCCTC-binding factor (CTCF) is known to anchor loops and construct 3D genomes, but how anchor sites are selected is not yet understood. Here, we unveil Jpx RNA as a determinant of anchor selectivity. Jpx RNA targets thousands of genomic sites, preferentially binding promoters of active genes. Depleting Jpx RNA causes ectopic CTCF binding, massive shifts in chromosome looping, and downregulation of >700 Jpx target genes. Without Jpx, thousands of lost loops are replaced by de novo loops anchored by ectopic CTCF sites. Although Jpx controls CTCF binding on a genome-wide basis, it acts selectively at the subset of developmentally sensitive CTCF sites. Specifically, Jpx targets low-affinity CTCF motifs and displaces CTCF protein through competitive inhibition. We conclude that Jpx acts as a CTCF release factor and shapes the 3D genome by regulating anchor site usage.

SMCHD1 Merges Chromosome Compartments and Assists Formation of Super-Structures on the Inactive X.

Mammalian chromosomes are partitioned into A/B compartments and topologically associated domains (TADs). The inactive X (Xi) chromosome, however, adopts a distinct conformation without evident compartments or TADs. Here, through exploration of an architectural protein, structural-maintenance-of-chromosomes hinge domain containing 1 (SMCHD1), we probe how the Xi is reconfigured during X chromosome inactivation. A/B compartments are first fused into "S1" and "S2" compartments, coinciding with Xist spreading into gene-rich domains. SMCHD1 then binds S1/S2 compartments and merges them to create a compartment-less architecture. Contrary to current views, TADs remain on the Xi but in an attenuated state. Ablating SMCHD1 results in a persistent S1/S2 organization and strengthening of TADs. Furthermore, loss of SMCHD1 causes regional defects in Xist spreading and erosion of heterochromatic silencing. We present a stepwise model for Xi folding, where SMCHD1 attenuates a hidden layer of Xi architecture to facilitate Xist spreading.

TERRA RNA Antagonizes ATRX and Protects Telomeres.

Through an integration of genomic and proteomic approaches to advance understanding of long noncoding RNAs, we investigate the function of the telomeric transcript, TERRA. By identifying thousands of TERRA target sites in the mouse genome, we demonstrate that TERRA can bind both in cis to telomeres and in trans to genic targets. We then define a large network of interacting proteins, including epigenetic factors, telomeric proteins, and the RNA helicase, ATRX. TERRA and ATRX share hundreds of target genes and are functionally antagonistic at these loci: whereas TERRA activates, ATRX represses gene expression. At telomeres, TERRA competes with telomeric DNA for ATRX binding, suppresses ATRX localization, and ensures telomeric stability. Depleting TERRA increases telomerase activity and induces telomeric pathologies, including formation of telomere-induced DNA damage foci and loss or duplication of telomeric sequences. We conclude that TERRA functions as an epigenomic modulator in trans and as an essential regulator of telomeres in cis.

Differential effects of digital media platforms on climate change risk information-sharing intention: A moderated mediation model.

This study analyzes the mechanisms through which risk messages about climate change lead to people's risk information-sharing intention, and how digital media platform type serves as a context that moderates those mechanisms. Our analysis is informed by the influence of presumed influence (IPI) model, and we adapt and expand that model in three ways. First, we apply the concept of perceived media reach to the context of digital media platforms, specifically news aggregators and social networking sites. Second, we integrate the two mediators of risk perception and presumed influence. Third, we examine potential moderating roles of digital media platforms in the IPI model. An online survey was conducted among 1000 South Korean adults, and a moderated mediation model (PROCESS Macro Model 59) generated the following results. (1) Perceived media reach was positively related to both mediators-risk perception and presumed influence. (2) By way of those two mediators, perceived reach significantly led to information-sharing intention. (3) Presumed influence, but not risk perception, was significantly related to information-sharing intention. (4) Digital media platforms moderated the relation between perceived reach and risk perception: the role of content-related risk perception was more pronounced in news aggregators, while the role of context-related presumed influence was greater in social networking sites. Theoretical and practical implications for risk communication are discussed.

When Do People Verify and Share Health Rumors on Social Media? The Effects of Message Importance, Health Anxiety, and Health Literacy.

This study explores the roles of perceived message importance, health anxiety, and health literacy in the relationship between message factors (message label and message valence) and behavioral intentions for rumor verification and sharing. 660 Twitter users responded to unverified information regarding the influenza vaccine. A 3 (label: none vs. news vs. rumor) × 2 (valence: positive vs. negative) online semi-experiment, with a survey to measure health anxiety and health literacy, showed the following results: First, perceived message importance mediated the relationship between message factors and behavioral intentions: only in the condition of the negative message, participants considered a news-labeled message more important than a rumor-labeled or a no-label message. Perceived message importance was associated with intentions to verify and share the message. Second, health anxiety interacted with perceived message importance only when predicting an intention to share the message. Last, healthy literacy interacted with perceived message importance when predicting intentions to both verify and share the message. The results will provide implications for health communication research and practices, especially on managing and controlling rumor dissemination on social media.

Daxx mediates activation-induced cell death in microglia by triggering MST1 signalling.

Microglia, the resident macrophages of the mammalian central nervous system, migrate to sites of tissue damage or infection and become activated. Although the persistent secretion of inflammatory mediators by the activated cells contributes to the pathogenesis of various neurological disorders, most activated microglia eventually undergo apoptosis through the process of activation-induced cell death (AICD). The molecular mechanism of AICD, however, has remained unclear. Here, we show that Daxx and mammalian Ste20-like kinase-1 (MST1) mediate apoptosis elicited by interferon-γ (IFN-γ) in microglia. IFN-γ upregulated the expression of Daxx, which in turn mediated the homodimerization, activation, and nuclear translocation of MST1 and apoptosis in microglial cells. Depletion of Daxx or MST1 by RNA interference also attenuated IFN-γ-induced cell death in primary rat microglia. Furthermore, the extent of IFN-γ-induced death of microglia in the brain of MST1-null mice was significantly reduced compared with that apparent in wild-type mice. Our results thus highlight new functions of Daxx and MST1 that they are the key mediators of microglial cell death initiated by the proinflammatory cytokine IFN-γ.

Tell Me a Story About Healthy Snacking and I Will Follow: Comparing the Effectiveness of Self-Generated Versus Message-Aided Implementation Intentions on Promoting Healthy Snacking Habits Among College Students.

In the context of healthy snacking, this study examines whether the quality of mental imagery determines the effectiveness of combining the implementation intention (II) intervention with mental imagery. This study further explores whether providing narrative healthy snacking scenarios prior to forming an II enhances people's mental imagery experience when they are not motivated to snack healthfully. A 2 × 2 factorial design was employed to test the main effect of providing healthy snacking scenarios prior to II formation, and whether such effect depends on people's motivation level. The results from the experiment (N =148) showed significant main as well as interaction effects of the manipulation (with vs. without reading healthy snacking scenarios prior to II formation) and motivation level on ease and vividness of mental imagery. The regression model with the experiment and follow-up survey data (n = 128) showed a significant relationship between ease of mental imagery and actual snacking behavior after controlling for habit strength. The findings suggest that adding a narrative message to the II intervention can be useful, especially when the intervention involves mental imagery and invites less motivated people.

Assessment of a healthy corner store program (FIT Store) in low-income, urban, and ethnically diverse neighborhoods in Michigan.

This study evaluated a community-based and social marketing healthy corner store program (FIT store) to improve the affordability and availability of healthy foods in low-income, urban, and ethnically diverse neighborhoods in Michigan. The Nutrition Environment Measures Survey in Stores data were analyzed for the FIT (N = 4) stores. Two cross-sectional surveys were conducted among the FIT store customers before (N = 401) and after (N = 318) the intervention. Three FIT stores improved their total Nutrition Environment Measures Survey in Stores availability score from before to after the intervention. A significantly higher level of FIT awareness and monthly bean and nut consumption was reported in the postintervention.

Purification of a novel peptide derived from Mytilus coruscus and in vitro/in vivo evaluation of its bioactive properties.

Excess oxidant can promote inflammatory responses. Moreover, chronic inflammation accompanied by oxidative stress is connected various steps involved in many diseases. From the aspect, we investigated an antioxidant peptide to prevent inflammatory response against oxidant overexpression. To prepare the peptide, eight proteases were employed for enzymatic hydrolysis, and the antioxidant properties of the hydrolysates were investigated using free radical scavenging activity by electron spin resonance (ESR) spectrometry. Papain hydrolysates, which showed clearly superior free radical scavenging activity, were further purified using consecutive chromatographic methods. Finally, a novel antioxidant peptide was obtained, and the sequence was identified as Ser-Leu-Pro-Ile-Gly-Leu-Met-Ile-Ala-Met at N-terminal. Oral administration of the peptide to mice effectively inhibited malondialdehyde (MDA) levels in a thiobarbituric acid reactive substances (TBARS) assay, and we also confirmed the antioxidative enzyme activities in superoxide dismutase (SOD) and glutathione-s-transferase (GST) assays. This is the first report of an antioxidant peptide derived from the hydrolysate of Mytilus coruscus, and also these results suggest that the peptide possesses potent antioxidant activity, and potential to enhance anti-inflammatory response.

The Role of Social Presence in Relationships Among Gender Stereotypes, Sexism, and In-Game Sexual Harassment Among Young Korean Gamers.

Despite the rapidly increasing number of female gamers worldwide, female players are still experiencing discrimination, stereotyping, and objectification in digital games. The present study examined the relationships among gender stereotypes, sexism, and sexual harassment in online games, and further investigated how enhanced social presence contributes to intensifying the effects of gender stereotypes and sexism on sexual harassment. An online survey was conducted among 521 young male Korean gamers who regularly play two genres of online games: role-playing games and first-person shooter games. The results of moderated-mediation analyses using Hayes PROCESS macro models confirmed that gender stereotypes had significant effects on hostile and benevolent in-game sexism. A significant interaction was also observed between in-game sexism and social presence in predicting sexual harassment in online games. The findings from this study confirm the role of social presence as an amplifier that reinforces gender stereotypes and discrimination in competitive and violent online game environments.

Zinc balance is critical for NFI-C mediated regulation of odontoblast differentiation.

Zinc is trace element essential for diverse metabolic and cellular signaling pathways for the growth, development, and maintenance. Zinc deficiency is involved in bone malformations and oral disease. Mice deficient in zinc transporter Zip13 show connective tissue and skeletal disorders, abnormal incisor teeth, and reduced root dentin formation in the molar teeth and share a morphologically similar phenotype to nuclear factor I-C (NFI-C)-deficient mice. However, the precise function of zinc in NFI-C signaling-mediated odontoblast differentiation and dentin formation remains unclear. Here, we show that zinc stimulated the expression of metal transcription factor-1, but decreased NFI-C expression in odontoblastic MDPC-23 cells. Zinc also enhanced the phosphorylation of Smad2/3 (p-Smad2/3) and increased the binding efficiency of NFI-C and p-Smad2/3 in the cytoplasm. In contrast, zinc deficiency resulted in the accumulation of NFI-C into nucleus. Consequently, NFI-C had the biologic properties of a transcription factor, including DNA binding affinity for metallothionein-1 and the dentin sialophosphoprotein (DSPP) promoter, and transcriptional activation of the DSPP gene. Furthermore, zinc deficiency condition promoted DSPP expression in odontoblasts and dentin mineralization, while zinc sufficiency condition decreased DSPP expression and slightly delayed dentin mineralization. These data suggest that zinc equilibrium is required for odontoblast differentiation and dentin formation during dentinogenesis through the nuclear accumulation and modulation of NFI-C.

The Laennec staging system for histological sub-classification of cirrhosis is useful for stratification of prognosis in patients with liver cirrhosis.

BACKGROUNDS & AIMS: The clinical severity of cirrhosis varies widely. We investigated whether histological sub-classification of cirrhosis using the Laennec system can discriminate different outcomes among patients with cirrhosis. METHODS: One hundred and seventy-five patients with chronic liver disease who underwent liver biopsy and showed stage 3 or 4 fibrosis between January 2001 and December 2008 were prospectively enrolled. Cirrhosis was sub-classified into three groups (4A, 4B, and 4C) according to the Laennec system. The end point was liver-related event (LRE) occurrence, including decompensation, hepatocellular carcinoma, and liver-related death. RESULTS: The median age of the patients (110 men, 65 women) was 55 years. Stages 3, 4A, 4B, and 4C were identified in 46 (26.3%), 16 (9.1%), 82 (46.9%), and 31 (17.7%) patients, respectively. During the follow-up period, LREs occurred in 32 (18.3%) patients: 4 (8.7%) with stage 3, 2 (12.5%) with stage 4A, 17 (20.7%) with stage 4B, and 9 (29.0%) with stage 4C. In a multivariate analysis, histological sub-classification of cirrhosis independently predicted LRE occurrence. While patients with stage 4A tended to be at higher risk of LRE occurrence than those with stage 3, patients with stages 4B and 4C had significantly higher risks of LRE occurrence, with hazard ratios of 6.158 (p=0.016) and 8.945 (p=0.004), respectively. CONCLUSIONS: Histological sub-classification of cirrhosis using the Laennec system can be used to assess the risk of LRE occurrence among patients with cirrhosis. Our study provides a solid basis for further studies of non-invasive methods for monitoring the risk of LRE occurrence and will help physicians to establish optimum treatment strategies.

The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex.

The tumour suppressor p53, which accumulates in response to DNA damage and induces cell-cycle arrest and apoptosis, has a key function in the maintenance of genome integrity. Under normal conditions, the antiproliferative effects of p53 are inhibited by MDM2, a ubiquitin ligase that promotes p53 ubiquitination and degradation. MDM2 is also self-ubiquitinated and degraded. Here, we show that the tumour suppressor RASSF1A regulates G(1)-S cell-cycle progression in a p53-dependent manner by promoting MDM2 self-ubiquitination and preventing p53 degradation. Importantly, RASSF1A associates with MDM2 and death-domain-associated protein (DAXX) in the nucleus, thereby disrupting the interactions between MDM2, DAXX, and the deubiquitinase, HAUSP, and enhancing the self-ubiquitin ligase activity of MDM2. Moreover, RASSF1A partially contributes to p53-dependent checkpoint activation at early time points in response to DNA damage. These findings reveal a new and important function for RASSF1A in regulating the p53-MDM2 pathway.

A crucial role of WW45 in developing epithelial tissues in the mouse.

The role and molecular mechanisms of a new Hippo signalling pathway are not fully understood in mammals. Here, we generated mice that lack WW45 and revealed a crucial role for WW45 in cell-cycle exit and epithelial terminal differentiation. Many organs in the mutant mouse embryos displayed hyperplasia accompanied by defects in terminal differentiation of epithelial progenitor cells owing to impaired proliferation arrest rather than intrinsic acceleration of proliferation during differentiation. Importantly, the MST1 signalling pathway is specifically activated in differentiating epithelial cells. Moreover, WW45 is required for MST1 activation and translocation to the nucleus for subsequent LATS1/2 activation upon differentiation signal. LATS1/2 phosphorylates YAP, which, in turn, translocates from the nucleus into the cytoplasm, resulting in cell-cycle exit and terminal differentiation of epithelial progenitor cells. Collectively, these data provide compelling evidence that WW45 is a key mediator of MST1 signalling in the coordinate coupling of proliferation arrest with terminal differentiation for proper epithelial tissue development in mammals.

How media campaigns influence children's physical activity: expanding the normative mechanisms of the theory of planned behavior.

This study explicates mechanisms of media campaign effectiveness in the context of children's physical activity. The authors' model expands the theory of planned behavior by integrating injunctive and descriptive norms into its normative mechanism. Analysis of a 3-wave nationally representative evaluation survey among 1,623 tweens indicates that campaign exposure is significantly related, but only indirectly, to both physical activity intention and physical activity behavior. Instead, campaign exposure seems more strongly related to perceived behavioral control and attitudes toward physical activity. By contrast, perceived behavioral control and descriptive norms are strongly related to behavioral intention. The findings suggest that integrating normative mechanisms with the theory of planned behavior can improve efforts to predict and explain a health behavior.

The effect of computer-mediated social support in online communities on patient empowerment and doctor-patient communication.

In the context of diabetes, this study tested a mechanism through which Korean diabetes patients' exchange of computer-mediated social support (CMSS) in diabetes online communities influences their sense of empowerment and intention to actively communicate with the doctor. Analysis of data from 464 Korean diabetes patients indicates significant relationships among diabetes patients' online community activities, perceived CMSS, sense of empowerment, and their intention to actively communicate with the doctor. Diabetes patients who have engaged more in online community activities perceived greater social support from other members of the community. Perceived CMSS significantly predicted their intention to actively communicate with the doctor through sense of empowerment. Sense of empowerment was a valid underlying mechanism that explains how patients' perceived CMSS influences their intention to actively communicate with the doctor. The implications for health communication research and practice are discussed.

Pesticide Exposure in Relation to the Incidence of Abnormal Glucose Regulation: A Retrospective Cohort Study.

Diabetes and prediabetes (called abnormal glucose regulation (AGR)) are adverse health effects associated with exposure to pesticides. However, there are few epidemiological studies on the relationship between pesticide use and the incidence of AGR. We examined the causal relationship between pesticide use and AGR incidence in a rural population using data from a Korean Farmers' Cohort study of 1076 participants. Poisson regression with robust error variance was used to calculate the relative risks (RR) and 95% confidence intervals (CI) to estimate the relationship between pesticide exposure and AGR. The incidence of AGR in the pesticide-exposed group was 29.1%. Pesticide use increased the RR of AGR (RR 1.32, 95% CI 1.03-1.69). We observed a low-dose effect related to exposure of pesticides to AGR and a U-shaped dose-response relationship in men. Pesticide exposure is related to the incidence of AGR, and the causal relationship differs between men and women.

Let-7 microRNA inhibits the proliferation of human glioblastoma cells.

MicroRNAs (miRNAs) are small noncoding RNAs comprising 21-23 nucleotides that regulate gene expression by transcriptionally repressing their complementary mRNAs. In particular, let-7 miRNA has been postulated to function as a tumor suppressor in various cancer cells, but not yet in glioblastoma. In this study, we investigated the anti-tumorigenic effect of let-7 miRNA in glioblastoma cells. Human glioblastoma cells (U251 or U87 cells) were transfected with let-7 miRNA and assayed for in-vitro proliferation, migration, and in-vivo tumor formation. Transfection of let-7 miRNA reduced expression of pan-RAS, N-RAS, and K-RAS in the glioblastoma cells. Let-7 miRNA also reduced the in-vitro proliferation and migration of the cells, and reduced the sizes of the tumors produced after transplantation into nude mice. However, let-7 miRNA exerted no effect on the proliferation of normal human astrocytes. These results indicate that let-7 miRNA has an anti-tumorigenic effect on glioblastoma cells, and suggest possible use of let-7 miRNA for treating glioblastoma.

Role of the tumor suppressor RASSF2 in regulation of MST1 kinase activity.

The tumor suppressor, RASSF2 (Ras association domain family 2), is frequently downregulated in a number of cancers. Although exogenously expressed RASSF2 induces apoptotic cell death, the precise roles of RASSF2 under pro-apoptotic conditions remain largely unknown. Here, we demonstrate that MST1 (mammalian sterile 20-like kinase 1) regulates RASSF2 protein stability. Knockdown of MST1 in cancer cells markedly destabilizes RASSF2, and Mst1-deficient mice show reduced Rassf2 protein levels in several organs. Conversely, RASSF2 activates MST1 kinase activity through formation of a RASSF2-MST1 complex, which inhibits the MST-FOXO3 signaling pathway. RASSF2 also engages the JNK pathway and induces apoptosis in an MST1-independent manner. Collectively, these findings indicate that MST1 is a major determinant of RASSF2 protein stability, and suggest that RASSF2 acts in a complex manner that extends beyond simple protein-protein association to play an important role in MST1 regulation.

Long Noncoding RNA Functionality Beyond Sequence: The Jpx Model: Commentary on "Functional Conservation of lncRNA JPX Despite Sequence and Structural Divergence" by Karner et al. (2019).

The mouse lncRNA Jpx has been shown as an essential regulator in X-chromosome inactivation (XCI). Jpx RNA activates Xist expression through its trans-acting ability to evict CTCF from Xist promoter. Karner et al. (2019) reveals the intriguing finding that human JPX and mouse Jpx are functionally conserved although they have low similarity in the primary sequence and the secondary structure. This study provides an excellent model for studying lncRNA's evolution and epigenetic function.