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We here present a new anti-tumor mechanism of all-trans retinoic acid (ATRA). ATRA induced several biomarkers of cellular senescence including irreversible G1 arrest, morphological changes, senescence-associated β-galactosidase, and heterochromatin foci in HepG2 cells. ATRA also upregulated levels of p16, p21, and p27 which lead to activation of Rb and subsequent inactivation of E2F1. These effects were abolished by the RNA interference-mediated silencing of p16, p21, and p27. Moreover, ATRA failed to induce cellular senescence in Huh7 and HCT116, in which p16, p21, and p27 were not upregulated by ATRA, confirming that ATRA induces cellular senescence via upregulation of p16, p21, and p27. [ABSTRACT FROM AUTHOR]

Some studies of the event-related potentials demonstrated a reduction of the voluntary component P3 (P300 or P3b) in youngsters with the attention deficit/hyperactivity disorder (ADHD) or in conduct disorders (CD), and a reduction of the automatic processing component, mismatch negativity, in patients with both ADHD and CD (ADHD+CD). Recently, a passive auditory P3 potential has been elicited by a single stimulus. We therefore tried this potential study in 20 healthy subjects and 20 teenagers with ADHD+CD to search for further evidence of the altered automatic cerebral processing in the latter. Subjects also answered a self-report Dimensional Assessment of Personality Pathology (DAPP). The patient group scored significantly higher on most DAPP traits that reflect problems of emotion control, showed significantly prolonged P2, N2, and P3, and reduced P3. In all subjects Stimulus Seeking was positively correlated with P3 latencies at Fz, Cz, and Pz, and with P3 amplitude at Cz. This study suggests that youngsters with ADHD+CD had pronounced emotion dysregulation, and prominent deficit in passive attention, as reflected by the automatic processing of auditory stimuli. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV), particularly through the HBx protein, induces oxidative stress during liver infections. This study reveals that HBx increases reactive oxygen species (ROS) via two distinct mechanisms. The first mechanism is p53-independent, likely involving mitochondrial dysfunction, as demonstrated by elevated ROS levels in p53-deficient Hep3B cells and p53-knocked-down HepG2 cells after HBx expression or HBV infection. The increase in ROS persisted even when p53 transcriptional activity was inhibited by pifithrin-α (PFT-α), a p53 inhibitor. The second mechanism is p53-dependent, wherein HBx activates p53, which then amplifies ROS production through a feedback loop involving ROS and p53. The ability of HBx to elevate ROS levels was higher in HepG2 than in Hep3B cells. Knocking down p53 in HepG2 cells lowered ROS levels, while ectopic p53 expression in Hep3B cells raised ROS. HBx-activated p53 downregulated catalase and upregulated manganese-dependent superoxide dismutase, contributing to ROS amplification. The transcriptional activity of p53 was crucial for these effects, as cells with a p53 R175H mutation or those treated with PFT-α generated less ROS. Additionally, HBx variants with Ser-101 increased p53 and ROS levels, whereas variants with Pro-101 did not. These dual mechanisms of HBx-induced ROS generation are likely significant in the pathogenesis of HBV and may contribute to liver diseases, including hepatocellular carcinoma.

Proton exchange membrane fuel cells (PEMFCs) for automotive applications are required to achieve mechanical reliability at various temperatures ranging from subfreezing to 80 °C. The thermal behavior of the electrode should be considered at the initial design stage to design a robust automotive fuel cell electrode. Recently, a behavior different from that of the bulk state has been reported for ionomers with a few nanometers of thickness. Therefore, the intrinsic thermal behavior of ionomer films with thicknesses from micrometers to nanometers is quantitatively investigated in this study. By introducing the fabrication of a pseudo-freestanding Nafion thin film and in-plane thermal strain measurement method on the water surface, the thermal expansion of the freestanding Nafion thin film was successfully measured with minimizing substrate constraints. Thermal strain measurement and X-ray scattering studies revealed that the weakening of intermolecular interaction within the hydrophobic and hydrophilic domains in the Nafion thin film caused thermal expansion, and well-structured hydrophobic domains could suppress thermal expansion. The thermal expansion behavior with different heat treatments provides evidence of the thin-film-to-bulk transition of the fully hydrated Nafion film. Intrinsic thermal behavior without substrate interactions can facilitate an understanding of the thermal behavior of electrodes and provide insight into designing a robust PEMFC in temperature-varying environments.

Hepatitis B virus (HBV) infects approximately 300 million people worldwide, causing chronic infections. The HBV X protein (HBx) is crucial for viral replication and induces reactive oxygen species (ROS), leading to cellular damage. This study explores the relationship between HBx-induced ROS, p53 activation, and HBV replication. Using HepG2 and Hep3B cell lines that express the HBV receptor NTCP, we compared ROS generation and HBV replication relative to p53 status. Results indicated that HBV infection significantly increased ROS levels in p53-positive HepG2-NTCP cells compared to p53-deficient Hep3B-NTCP cells. Knockdown of p53 reduced ROS levels and enhanced HBV replication in HepG2-NTCP cells, whereas p53 overexpression increased ROS and inhibited HBV replication in Hep3B-NTCP cells. The ROS scavenger N-acetyl-L-cysteine (NAC) reversed these effects. The study also found that ROS-induced degradation of the HBx is mediated by the E3 ligase Siah-1, which is activated by p53. Mutations in p53 or inhibition of its transcriptional activity prevented ROS-mediated HBx degradation and HBV inhibition. These findings reveal a p53-dependent negative feedback loop where HBx-induced ROS increases p53 levels, leading to Siah-1-mediated HBx degradation and HBV replication inhibition. This study offers insights into the molecular mechanisms of HBV replication and identifies potential therapeutic targets involving ROS and p53 pathways.

All-trans retinoic acid (ATRA), recognized as the principal and most biologically potent metabolite of vitamin A, has been identified for its inhibitory effects on hepatitis B virus (HBV) replication. Nevertheless, the underlying mechanism remains elusive. The present study reveals that ATRA induces E6-associated protein (E6AP)-mediated proteasomal degradation of HBx to suppress HBV replication in human hepatoma cells in a p53-dependent pathway. For this effect, ATRA induced promoter hypomethylation of E6AP in the presence of HBx, which resulted in the upregulation of E6AP levels in HepG2 but not in Hep3B cells, emphasizing the p53-dependent nature of this effect. As a consequence, ATRA augmented the interaction between E6AP and HBx, resulting in substantial ubiquitination of HBx and consequent reduction in HBx protein levels in both the HBx overexpression system and the in vitro HBV replication model. Additionally, the knockdown of E6AP under ATRA treatment reduced the interaction between HBx and E6AP and decreased the ubiquitin-dependent proteasomal degradation of HBx, which prompted a recovery of HBV replication in the presence of ATRA, as confirmed by increased levels of intracellular HBV proteins and secreted HBV levels. This study not only contributes to the understanding of the complex interactions between ATRA, p53, E6AP, and HBx but also provides an academic basis for the clinical employment of ATRA in the treatment of HBV infection., Competing Interests: No authors have competing interests., (Copyright: © 2024 Han, Jang. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Hepatitis C virus (HCV) is constantly exposed to considerable oxidative stress, characterized by elevated levels of reactive oxygen species, including hydrogen peroxide (H 2 O 2 ), during acute and chronic infection in the hepatocytes of patients. However, the effect of oxidative stress on HCV replication is largely unknown. In the present study, we demonstrated that H 2 O 2 downregulated HCV Core levels to inhibit HCV replication. For this purpose, H 2 O 2 upregulated p53 levels, resulting in the downregulation of both the protein and enzyme activity levels of DNA methyltransferase 1 (DNMT1), DNMT3a, and DNMT3b, and activated the expression of E6-associated protein (E6AP) through promoter hypomethylation in the presence of HCV Core. E6AP, an E3 ligase, induced the ubiquitin-dependent proteasomal degradation of HCV Core in a p53-dependent manner. The inhibitory effect of H 2 O 2 on HCV replication was almost completely nullified either by treatment with a representative antioxidant, N-acetyl-L-cysteine, or by knockdown of p53 or E6AP using a specific short hairpin RNA, confirming the roles of p53 and E6AP in the inhibition of HCV replication by H 2 O 2 . This study provides insights into the mechanisms that regulate HCV replication under conditions of oxidative stress in patients.

The hepatitis B virus (HBV) is constantly exposed to significant oxidative stress characterized by elevated levels of reactive oxygen species (ROS), such as H 2 O 2 , during infection in hepatocytes of patients. In this study, we demonstrated that H 2 O 2 inhibits HBV replication in a p53-dependent fashion in human hepatoma cell lines expressing sodium taurocholate cotransporting polypeptide. Interestingly, H 2 O 2 failed to inhibit the replication of an HBV X protein (HBx)-null HBV mutant, but this defect was successfully complemented by ectopic expression of HBx. Additionally, H 2 O 2 upregulated p53 levels, leading to increased expression of seven in absentia homolog 1 (Siah-1) levels. Siah-1, an E3 ligase, induced the ubiquitination-dependent proteasomal degradation of HBx. The inhibitory effect of H 2 O 2 was nearly abolished not only by treatment with a representative antioxidant, N-acetyl-L-cysteine but also by knockdown of either p53 or Siah-1 using specific short hairpin RNA, confirming the role of p53 and Siah-1 in the inhibition of HBV replication by H 2 O 2 . The present study provides insights into the mechanism that regulates HBV replication under conditions of oxidative stress in patients.

All- trans retinoic acid (ATRA), the most biologically active metabolite of vitamin A, is known to abolish the potential of HBx to downregulate the levels of p14, p16, and p21 and to stimulate cell growth during hepatitis B virus (HBV) infection, contributing to its chemopreventive and therapeutic effects against HBV-associated hepatocellular carcinoma. Here, we demonstrated that ATRA antagonizes HBx to inhibit HBV replication. For this effect, ATRA individually or in combination with HBx upregulated p53 levels, resulting in upregulation of seven in absentia homolog 1 (Siah-1) levels. Siah-1, an E3 ligase, induces ubiquitination and proteasomal degradation of HBx in the presence of ATRA. The ability of ATRA to induce Siah-1-mediated HBx degradation and the subsequent inhibition of HBV replication was proven in an in vitro HBV replication model. The effects of ATRA became invalid when either p53 or Siah-1 was knocked down by a specific shRNA, providing direct evidence for the role of p53 and Siah-1 in the negative regulation of HBV replication by ATRA., Competing Interests: The authors declare no conflict of interest.

Most clinical and experimental studies have suggested that hepatitis C virus (HCV) is dominant over hepatitis B virus (HBV) during coinfection, although the underlying mechanism remains unclear. In this study, we found that the HBV X protein (HBx) upregulates the levels of the HCV core protein to stimulate HCV replication during coinfection in human hepatoma cells. For this purpose, HBx upregulated both the protein levels and enzyme activities of cellular DNA methyltransferase 1 (DNMT1) and DNMT3b, and this subsequently reduced the expression levels of the E6-associated protein (E6AP), an E3 ligase of the HCV core protein, via DNA methylation. The ubiquitin-dependent proteasomal degradation of the HCV core protein was severely impaired in the presence of HBx, whereas this effect was not observed when E6AP was either ectopically expressed or restored by treatment with 5-aza-2'dC or DNMT1 knockdown. The effect of HBx on the HCV core protein was accurately reproduced in HBV/HCV coinfection systems, which were established by either monoinfection by HCV in Huh7D cells transfected with a 1.2-mer HBV replicon or coinfection by HBV and HCV in Huh7D-Na + -taurocholate cotransporting polypeptide cells, providing evidence for the stimulation of HCV replication by HBx. The present study may provide insights into understanding HCV dominance during HBV/HCV coinfection in patients. IMPORTANCE Hepatitis B virus (HBV) and hepatitis C virus (HCV) are major human pathogens that cause a substantial proportion of liver diseases worldwide. As the two hepatotropic viruses have the same modes of transmission, coinfection is often observed, especially in areas and populations where HBV is endemic. High-risk populations include people who inject drugs. Both clinical and experimental studies have shown that HCV is more dominant than HBV during coinfection, but the underlying mechanism remains unclear. In this study, we show that HBV X protein (HBx) stimulates HCV replication by inhibiting the expression of E6-associated protein ( E6AP ) via DNA methylation, thereby protecting the HCV core protein from proteasomal degradation, which can contribute to HCV dominance during HBV/HCV coinfection.

HBx, a multifunctional regulatory protein, plays an essential role in the replication and pathogenesis of the hepatitis B virus (HBV). In this study, we found that in human hepatoma cells, the tumor suppressor p53 downregulates HBx via ubiquitin-dependent proteasomal degradation. p53 transcriptional activity that results from HBV infection was not essential for this effect. This was shown by treatment with a potent p53 inhibitor, pifithrin-α. Instead, we found that p53 facilitated the binding of E6-associated protein (E6AP), which is an E3 ligase, to HBx and induced E6AP-mediated HBx ubiquitination in a ternary complex of p53, E6AP, and HBx. The ability of p53 to induce E6AP-mediated downregulation of HBx and inhibit HBV replication was demonstrated in an in vitro HBV infection system. This study may provide insights into the regulation of HBx and HBV replication, especially with respect to p53 status, which may also help in understanding HBV-associated tumorigenesis in patients.

The tumour suppressor p53 has been implicated in the host defence system against hepatitis C virus (HCV) infection, although the detailed mechanism remains unknown. Here, we found that p53 inhibits HCV replication by downregulating HCV Core protein levels in human hepatoma cells. For this effect, p53 potentiated the role of E6-associated protein (E6AP) as an E3 ligase to induce ubiquitination and proteasomal degradation of HCV Core. Specifically, p53 facilitated the binding of E6AP to HCV Core through direct interactions with the two proteins. In addition, E6AP failed to induce ubiquitination of HCV Core in the absence of p53, suggesting that p53 increases the E3 ligase activity of E6AP in a triple complex consisting of p53, E6AP and HCV Core., (© 2022 Federation of European Biochemical Societies.)

Aim: Approximately half of the population in Egypt is under the age of 25. Globally, mental illness represents the highest burden of disease in this age group. Yet in Egypt, there is still no youth-specific mental health system in place and the vast majority of young people do not have access to any professional mental health support. The objective of this study was to describe the mental health needs of Egyptian youth and the resources they use when seeking help., Methods: An online cross-sectional survey was distributed among medical students at Tanta University in Egypt. Of the 707 individuals who completed the survey (90.9% response rate), 60.5% were female, 62.0% lived in urban and suburban areas, and the mean age of the sample was 20.5 (±1.8) years old., Results: More than half (54%) of the students reported that they had been affected by mental health problems at some point in their lives. Anxiety and depression were the most common problems. Regarding help-seeking behaviours, participants mainly searched the web or spoke to peers and relatives; few reported approaching medical professionals. The majority of participants (59.7%) reported being disappointed with the current mental health care system in Egypt., Conclusions: There is a high prevalence of mental challenges among Egyptian youth and the health care system is not adequately prepared to respond to their needs. E-Mental Health and online interventions seem to be a promising solution that could increase access to mental health services for Egyptian youth., (© 2021 John Wiley & Sons Australia, Ltd.)

Dual infection of hepatitis B virus (HBV) and hepatitis C virus (HCV) is closely associated with an increased risk of hepatocellular carcinoma; however, the underlying mechanism is poorly understood. In the present study, we found that HBV X protein (HBx) and HCV core protein work together to inhibit E-cadherin expression in human hepatoma cells. For this effect, they additively increased both the level and activity of enzymes, DNA methyltransferase 1, 3a, and 3b to induce promoter hypermethylation of E-cadherin in a p53-dependent fashion. Their additive effect on E-cadherin levels was reproduced in an in vitro HBV/HCV dual infection system using Huh7D-NTCP cells. As a result, HBV and HCV additively upregulated mesenchymal marker such as N-cadherin, Snail, Twist and Vimentin but cooperatively downregulated epithelial markers such as E-cadherin, Slug and Plakoglobin. In addition, the coinfected cells exhibited faster cell migration and higher invasion ability, as compared with monoinfection, which are hallmarks of epithelial-mesenchymal transition required for the initiation of metastasis in cancer progression., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Here, we found that all-trans retinoic acid (ATRA), the most biologically active metabolite of vitamin A, strengthens the anti-viral defense mechanism of E6-associated protein (E6AP) that downregulates hepatitis C virus (HCV) Core levels via ubiquitin-dependent proteasomal degradation. For this effect, ATRA downregulated both protein and enzyme activity levels of DNA methyltransferase 1 and 3b and activated E6AP expression via promoter hypomethylation in HepG2 cells but not in Hep3B cells, in which p53 was absent. Ectopic p53 expression but not E6AP overexpression restored the ability of ATRA to downregulate HCV Core levels in Hep3B cells, suggesting a direct role of p53 in the E6AP-mediated ubiquitination of HCV Core. ATRA also downregulated HCV Core levels during HCV infection in Huh7D cells to inhibit virus replication, providing theoretical basis for the clinical application of ATRA against HCV infection., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Individuals experiencing absolute homelessness have complex needs but limited access to services, contributing to high rates of morbidity and mortality. The aim of this article is to describe the perceived unmet service needs of individuals experiencing absolute homelessness, identify their barriers to care, and examine factors associated with specific unmet service needs., Methods: Using a cross-sectional survey, 150 individuals experiencing absolute homelessness were recruited from Edmonton's inner city and adjoining areas. The majority of participants were male (71.3%) and self-identified as Indigenous (74.0%). An adapted version of the Perceived Need for Care Questionnaire was used to measure past-year unmet needs for 4 types of services: hospital care, counselling, skills training, and harm reduction. Descriptive statistics and bivariate analyses were used; odds ratio and confidence intervals were calculated for statistically significant outcomes., Results: Overall, 89.3% of participants perceived a need for care for one or more general health and social services during the past year regarding their substance use and/or mental health problems; participants reported the highest levels of unmet need for counselling (42.9%) and skills training (39.2%). Though 73.3% of participants reported receiving any service, only 8.0% of participants reported having their perceived needs fully met., Conclusion: In this study, individuals reported a high percentage of unmet needs. By interacting and engaging with these hard-to-reach individuals, healthcare systems will be more equipped to service them and address their barriers to care. Better patient-centred care, housing and supports for this neglected and underserved population is needed., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Most clinical and experimental studies have suggested that hepatitis C virus (HCV) is dominant over hepatitis B virus (HBV) during coinfection, although the mechanism remains unclear. Here, we found that HCV core protein inhibits HBV replication by downregulating HBx levels during coinfection in human hepatoma cells. For this effect, HCV core protein increased reactive oxygen species levels in the mitochondria and activated the ataxia telangiectasia mutated-checkpoint kinase two pathway in the nucleus, resulting in an upregulation of p53 levels. Accordingly, HCV core protein induced p53-dependent activation of seven in absentia homolog one expression, an E3 ligase of HBx, resulting in the ubiquitination and proteasomal degradation of HBx. The effect of the HCV core protein on HBx levels was accurately reproduced in both a 1.2-mer HBV replicon and in vitro HBV infection systems, providing evidence for the inhibition of HBV replication by HCV core protein. The present study may provide insights into the mechanism of HCV dominance in HBV- and HCV-coinfected patients.

Proteasomal activator 28 gamma (PA28γ) upregulates the levels of HBx, a regulatory protein of hepatitis B virus (HBV) to stimulate HBV replication; however, the detailed mechanism remains unknown. Here, we found that PA28γ impaired the ability of seven in absentia homolog 1 (Siah-1) as an E3 ubiquitin ligase of HBx. PA28γ competitively inhibited the binding of Siah-1 to HBx in human hepatoma cells. Accordingly, PA28γ increased the stability of HBx and decreased HBx ubiquitination, abolishing the potential of Siah-1 to downregulate HBx levels. PA28γ also executed its role as an antagonist of Siah-1 during HBV replication, as demonstrated by an in vitro HBV replication system. The present study may provide insights into the mechanisms underlying the regulation of HBV replication., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Among individuals experiencing homelessness, the prevalence of alcohol use disorder is extremely high. Alcohol-related harms are compounded by the use of non-beverage alcohol (NBA; e.g. rubbing alcohol, cooking wine). The dangers of NBA consumption pose significant risks to the individual and to others when consumed in large quantities and when mixed with other substances. The objectives of this paper are to describe the alcohol consumption patterns of individuals experiencing homelessness, identify substance use patterns, psychological stressors, and related harms associated with NBA consumption, and compare NBA consumers to non-NBA consumers in relation to their use of services and perceived barriers to care., Methods: Using a cross-sectional survey, 150 individuals experiencing homelessness were recruited from Edmonton's inner city and adjoining areas. Frequency, quantity, and volume of alcohol consumption were used to assess patterns of alcohol use in the last 6 months. Descriptive statistics and bivariate analyses were used to compare participants reporting NBA consumption and non-NBA consumption (p ≤ 0.05)., Results: The majority of participants were male (71.3%) and self-identified as Indigenous (74.0%). Overall, 24% (n = 36) reported NBA consumption within the last six months. NBA consumers were older than non-NBA consumers (p = 0.005), reported different perceived living stability (p = 0.022), and had higher psychological distress (p = 0.038). The majority of NBA consumers reported not receiving harm reduction services while also not needing such services (n = 18, 51.4%), which differed from non-NBA consumers (p = 0.003). Structural barriers (e.g. availability, location, cost) were most frequently reported as reasons for unmet harm reduction (60.9%) and hospital care (58.3%) needs, while barriers to skills training (58.5%) and counselling services (53.6%) were mostly motivational (e.g. personal beliefs)., Conclusions: Within such an already marginalized population experiencing homelessness, individuals who consume NBA represent a vulnerable subpopulation who require adapted and distinct health and social services to stabilize and recover. Current harm reduction services are not prepared to effectively assist this group of individuals, and specific treatment programs are rare. Managed alcohol programs are a feasible approach but must be tailored to the specific needs of those who consume NBA, which is especially important for Indigenous people. More comprehensive assessments of NBA consumption are needed for program development and policy recommendations., (© 2021. The Author(s).)

Proteasomal activator 28 gamma (PA28γ), an essential constituent of the 20S proteasome, is frequently overexpressed in hepatocellular carcinoma. Hepatitis C virus (HCV) core protein is recently known to activate PA28γ expression in human hepatocytes via upregulation of p53 levels; however, its role in HCV tumorigenesis remains unknown. Here, we found that HCV core-activated PA28γ downregulates p16 levels via ubiquitin-independent proteasomal degradation. As a result, HCV core protein activated the Rb-E2F pathway to stimulate cell cycle progression from G 1 to S phase, resulting in an increase in cell proliferation. The potential of HCV core protein to induce these effects was almost completely abolished by either PA28γ knockdown or p16 overexpression, confirming the role of the PA28γ-mediated p16 degradation in HCV tumorigenesis., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s).)

Background: There is a growing body of evidence regarding eHealth interventions that target substance use disorders. Development and funding decisions in this area have been challenging, due to a lack of understanding of what parts of an intervention work in which context., Objective: We conducted a realist review of the literature on electronic cognitive behavioral therapy (eCBT) programs for substance use with the goal of answering the following realist question: "How do different eCBT interventions for substance use interact with different contexts to produce certain outcomes?", Methods: A literature search of published and gray literature on eHealth programs targeting substance use was conducted. After data extraction, in order to conduct a feasible realist review in a timely manner, the scope had to be refined further and, ultimately, only included literature focusing on eCBT programs targeting substance use. We synthesized the available evidence from the literature into Context-Mechanism-Outcome configurations (CMOcs) in order to better understand when and how programs work., Results: A total of 54 papers reporting on 24 programs were reviewed. Our final results identified eight CMOcs from five unique programs that met criteria for relevance and rigor., Conclusions: Five strategies that may be applied to future eCBT programs for substance use are discussed; these strategies may contribute to a better understanding of mechanisms and, ultimately, may help design more effective solutions in the future. Future research on eCBT programs should try to understand the mechanisms of program strategies and how they lead to outcomes in different contexts., (©Farhud Shams, James S H Wong, Mohammadali Nikoo, Ava Outadi, Ehsan Moazen-Zadeh, Mostafa M Kamel, Michael Jae Song, Kerry L Jang, Reinhard Michael Krausz. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 21.01.2021.)

Proteasomal activator 28 gamma (PA28γ), an essential constituent of the 20S proteasome responsible for ubiquitin-independent degradation of target proteins, is frequently overexpressed in hepatocellular carcinoma. Recently, we have reported that hepatitis B virus (HBV) X protein (HBx) activates PA28γ expression in human hepatocytes via upregulation of p53 levels; however, its role in HBV tumorigenesis remains unknown. Here, we found that HBx - activated PA28γ downregulates p16 levels via ubiquitin-independent proteasomal degradation. As a result, HBx activated the Rb-E2F pathway and stimulated G 1 /S cell cycle progression, resulting in an increase in cell proliferation. The potential of HBx to induce these effects was reproduced in a 1.2-mer HBV replicon and in in vitro HBV infection systems and was almost completely abolished by either PA28γ knockdown or p16 overexpression, demonstrating the critical role of the PA28γ - mediated p16 degradation in HBV tumorigenesis.

The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural-geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.

Proteasomal activator 28 gamma (PA28γ) is frequently overexpressed in hepatocellular carcinoma; however, its underlying mechanism and role in hepatitis B virus (HBV) replication are largely unknown. Here, we found that HBV X protein (HBx) natural variants containing Ser-101 instead of Pro-101 increase reactive oxygen species levels in the mitochondria and activate the ataxia telangiectasia mutated/checkpoint kinase 2 pathway in the nucleus, resulting in the phosphorylation of p53 at Ser-15 and Ser-20 and the subsequent upregulation of its protein levels. Therefore, HBx variants containing Ser-101 induced p53-dependent activation of PA28γ expression in human hepatoma cells. The elevated PA28γ levels upregulated HBx levels through the inhibition of seven in absentia homologue 1-dependent proteasomal degradation. The self-amplifying ability of HBx variants containing Ser-101 via a positive feedback loop involving p53 and PA28γ was accurately reproduced in both a 1.2-mer HBV replicon and in vitro HBV infection systems, which also provided evidence for the stimulation of HBV replication by these HBx variants. In conclusion, the ability of HBx to upregulate PA28γ levels via p53 activation, in a Ser-101-dependent pathway, is critical for the stimulation of HBV replication.

Mõttus and colleagues (2017) reported evidence that the unique variance in specific personality characteristics captured by single descriptive items often displayed trait-like properties of cross-rater agreement, rank-order stability, and heritability. They suggested that the personality hierarchy should be extended below facets to incorporate these specific characteristics, called personality nuances. The present study attempted to replicate these findings, employing data from 6,287 individuals from 6 countries (Australia, Canada, Czech Republic, Denmark, Japan, and United States). The same personality measure-240-item Revised NEO Personality Inventory-and statistical procedures were used. The present findings closely replicated the original results. When the original and current results were meta-analyzed, the unique variance of nearly all items (i.e., items' scores residualized for all broader personality traits) showed statistically significant cross-rater agreement (median = .12) and rank-order stability over an average of 12 years (median = .24), and the unique variance of the majority of items had a significant heritable component (median = .14). These 3 item properties were intercorrelated, suggesting that items systematically differed in the degree of reflecting valid unique variance. Also, associations of items' unique variance with age, gender, and body mass index (BMI) replicated across samples and tracked with the original findings. Moreover, associations between item residuals and BMI obtained from one group of people allowed for a significant incremental prediction of BMI in an independent sample. Overall, these findings reinforce the hypotheses that nuances constitute the building blocks of the personality trait hierarchy, their properties are robust and they can be useful. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Coefficient of thermal expansion (CTE) for thin film has been measured only from change in thickness because thin film has to be constrained on a solid substrate. However, thin film CTE shows different values depending on the supporting solid substrate. Here, a novel measurement method is suggested to quantitatively measure the in-plane thermal expansion of thin films floating on a water surface. In-plane thermal expansion of thin films on water surface is achieved by heating the water. The CTE is measured through a digital image correlation (DIC) technique. The DIC tracks displacement marks deposited on the film surface, and the in-plane thermal strain is defined as the change in distance between the patterns. The method can be applied to measure the CTE of polymer, metal, and graphene with a thickness ranging from a micrometer to one-atom-thickness. The in-plane thermal expansion of the polystyrene (PS) thin film decreased as the film thickness decreased. The negative CTE of graphene is also successfully explored without any substrate effects or complicated calculations. The CTE measurement method can provide understanding of the intrinsic thermal expansion behavior of thin films including emerging two-dimensional materials.

Methylation of HBV cccDNA has been detected in vivo and in vitro ; however, the mechanism and its effects on HBV replication remain unclear. HBx derived from a 1.2-mer HBV replicon upregulated protein levels and enzyme activities of DNA methyltransferase 1 (DNMT1), 3a, and 3b, resulting in methylation of the negative regulatory region (NRE) in cccDNA, while none of these effects were observed with an HBx-null mutant. The HBx-positive HBV cccDNA expressed higher levels of HBc and produced about 4-fold higher levels of HBV particles than those from the HBx-null counterpart. For these effects, HBx interrupted the action of NRE binding protein via methylation of the C-1619 within NRE, resulting in activation of the core promoter. Treatment with 5-Aza-2'dC or DNMT1 knock-down drastically impaired the ability of HBx to activate the core promoter and stimulate HBV replication in 1.2-mer HBV replicon and in vitro infection systems, indicating the positive role of HBx-mediated cccDNA methylation in HBV replication.

Introduction: Homeless individuals are often mischaracterized as members of a homogeneous population that suffers from a wide mental health and addiction issues, with little consideration of potentially important differences within or between samples. The aim of the present study was to investigate the comorbidy of alcohol and/or substance dependence (ASD) and major psychiatric diagnoses (bipolar disorder, unipolar depression, and psychotic disorder) in a large Canadian sample of homeless individuals, and to examine potential sources of variability including location and ethnicity. Materials and Methods: A sample of 1,585 homeless individuals were assessed for alcohol and/or substance dependence and bipolar disorder, unipolar depression and psychotic disorder with the Mini-International Neuropsychiatric Interview (version 6.0). Regional and ethnic differences in major psychiatric diagnoses between homeless with and without ASD were examined using univariate (i.e., chi-square) and multivariate (i.e., logistic regression) statistics. Results: Members of the sample with ASD were found to be younger, Aboriginal, less well-educated, and born in the Americas. They were more significantly more prevalent in Western Canada and less prevalent in Central and Eastern Canada. The odds of having ASD were higher among people affected by bipolar disorder and (to a less extent) unipolar depression. Limitations: Data collected were self-reported and no urinalyses were performed. We considered diagnosis of ASD according to the previous 12 months only. Conclusions: Homeless people with major mental illness are at high risk for concurrent ASD, however the prevalence of ASD varies significantly between cities, and based on ethnicity and specific psychiatric diagnosis (with greater prevalence in individuals affected by bipolar disorder and, to a less extent, unipolar depression). Clinicians, administrators and policy makers should develop and deliver services based on careful assessment of the local population.

Proteasomal activator gamma (PA28γ), frequently overexpressed in hepatocellular carcinoma, is believed to play important roles in tumourigenesis. However, the underlying mechanism of PA28γ overexpression and its possible roles in hepatitis B virus (HBV) replication are largely unknown. In the present study, we found that hepatitis B virus X protein (HBx) activates PA28γ expression by upregulating p53 levels in human hepatoma cells. The elevated PA28γ levels in turn repressed seven in absentia homologue 1 expression via downregulation of p53 levels, thereby inhibiting ubiquitin-dependent proteasomal degradation of HBx, which ultimately led to upregulation of HBx levels. The correlation among HBx, p53 and PA28γ was exactly reproduced in a 1.2-mer HBV replicon system, mimicking the natural course of HBV infection. In particular, knockdown of either p53 or PA28γ in HepG2 cells downregulated HBx levels and thereby inhibited HBV replication, whereas overexpression of p53 or PA28γ in Hep3B cells upregulated HBx levels, which stimulated HBV replication, indicating that p53 and PA28γ act as activators of HBV replication. In conclusion, HBx levels are upregulated via a positive feedback loop involving p53 and PA28γ to stimulate HBV propagation.

All-trans retinoic acid (ATRA), the most biologically active metabolite of vitamin A, is known to activate p14 expression via promoter hypermethylation to induce p53-dependent apoptosis in human hepatocytes. In this study, we found that the oncogenic hepatitis B virus (HBV) X protein (HBx) of HBV, derived from both overexpression and 1.2-mer replicon systems, suppresses ATRA-induced apoptosis in p53-positive human hepatocytes. For this effect, HBx upregulated both protein and enzyme activity levels of DNA methyltransferase 1, 3a and 3b, in the presence of ATRA and thereby inhibited p14 expression via promoter hypermethylation, resulting in inactivation of the p14-mouse double minute 2 pathway and subsequent downregulation of p53 levels. As a result, HBx was able to impair the potential of ATRA to activate apoptosis-related molecules, including Bax, p53-upregulated modulator of apoptosis, caspase-9, caspase-3 and poly (ADP-ribose) polymerase. In conclusion, the present study provides a new oncogenic action mechanism of HBx, namely by suppressing the anticancer potential of ATRA to induce p53-dependent apoptosis in HBV-infected hepatocytes.

All- trans retinoic acid (ATRA), the most biologically active metabolite of vitamin A, is known to induce p14 expression via promoter hypomethylation to activate the p14-MDM2-p53 pathway, which leads to activation of the p53-dependent apoptotic pathway and subsequent induction of apoptosis in human hepatoma cells. In the present study, we found that hepatitis C virus (HCV) Core derived from ectopic expression or HCV infection overcomes ATRA-induced apoptosis in p53-positive hepatoma cells. For this effect, HCV Core upregulated both protein levels and enzyme activities of DNA methyltransferase 1 (DNMT1), DNMT3a, and DNMT3b and thereby repressed p14 expression via promoter hypermethylation, resulting in inactivation of the pathway leading to p53 accumulation in the presence of ATRA. As a result, HCV Core prevented ATRA from activating several apoptosis-related molecules, including Bax, p53 upregulated modulator of apoptosis, caspase-9, caspase-3, and poly (ADP-ribose) polymerase. In addition, complementation of p14 in the Core-expressing cells by either ectopic expression or treatment with 5-Aza-2'dC almost completely abolished the potential of HCV Core to suppress ATRA-induced apoptosis. Based on these observations, we conclude that HCV Core executes its oncogenic potential by suppressing the p53-dependent apoptosis induced by ATRA in human hepatoma cells., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Background: Genes and the environment contribute to variation in adult body mass index [BMI (in kg/m 2 )], but factors modifying these variance components are poorly understood. Objective: We analyzed genetic and environmental variation in BMI between men and women from young adulthood to old age from the 1940s to the 2000s and between cultural-geographic regions representing high (North America and Australia), moderate (Europe), and low (East Asia) prevalence of obesity. Design: We used genetic structural equation modeling to analyze BMI in twins ≥20 y of age from 40 cohorts representing 20 countries (140,379 complete twin pairs). Results: The heritability of BMI decreased from 0.77 (95% CI: 0.77, 0.78) and 0.75 (95% CI: 0.74, 0.75) in men and women 20-29 y of age to 0.57 (95% CI: 0.54, 0.60) and 0.59 (95% CI: 0.53, 0.65) in men 70-79 y of age and women 80 y of age, respectively. The relative influence of unique environmental factors correspondingly increased. Differences in the sets of genes affecting BMI in men and women increased from 20-29 to 60-69 y of age. Mean BMI and variances in BMI increased from the 1940s to the 2000s and were greatest in North America and Australia, followed by Europe and East Asia. However, heritability estimates were largely similar over measurement years and between regions. There was no evidence of environmental factors shared by co-twins affecting BMI. Conclusions: The heritability of BMI decreased and differences in the sets of genes affecting BMI in men and women increased from young adulthood to old age. The heritability of BMI was largely similar between cultural-geographic regions and measurement years, despite large differences in mean BMI and variances in BMI. Our results show a strong influence of genetic factors on BMI, especially in early adulthood, regardless of the obesity level in the population., (© 2017 American Society for Nutrition.)

The seven in absentia homologue 1 (Siah-1) protein is an E3 ubiquitin ligase that induces ubiquitin-dependent proteasomal degradation of HBx, the principal regulatory protein of hepatitis B virus (HBV); however, its role in HBV propagation remains unknown. Here, we found that HBx upregulates Siah-1 levels in HepG2 but not in Hep3B cells, in which p53 is absent. For this effect, HBx sequentially activated ataxia telangiectasia mutated kinase and checkpoint kinase 2 via phosphorylation at the Ser-1981 and Thr-68 residues, respectively, which led to the activation of p53 via phosphorylation at the Ser-15 and Ser-20 residues. As a result, HBx was heavily ubiquitinated by Siah-1 and degraded by the ubiquitin-proteasome system in HepG2 cells, whereas this effect was marginal or undetectable in Hep3B cells. Knock-down of p53 in HepG2 cells downregulated Siah-1 levels and subsequently upregulated HBx levels, whereas ectopic p53 expression in Hep3B cells upregulated Siah-1 levels and subsequently downregulated HBx levels. In addition, Siah-1 knock-down impaired the ubiquitination and proteasomal degradation of HBx in HepG2 cells, whereas ectopic Siah-1 expression induced ubiquitin-dependent proteasomal degradation of HBx in Hep3B cells. The effects of HBx on p53 and Siah-1 were exactly reproduced in a 1.2-mer HBV replicon system, mimicking the natural course of HBV infection. In particular, Siah-1 knock-down upregulated the levels of HBx derived from the HBV replicon, resulting in an increase in HBV production. In conclusion, HBx modulates its own protein level via a negative feedback loop involving p53 and Siah-1 to control HBV propagation.