Enhancing lettuce yield via Cu/Fe-layered double hydroxide nanoparticles spraying.

Layered double hydroxides (LDHs) have been widely used in the field of plant engineering, such as DNA/RNA transformation and enhancing plant disease resistance. However, few studies have examined the direct effects of LDHs on plants and their potential utility as nanofertilizers. In this study, the retention capacity of Cu/Fe-layered double hydroxide nanoparticles (CuFe-LDHs) was assessed by comparative experiments on vegetables. The results showed that the retention of CuFe-LDHs in leafy vegetables was high, such as lettuce. Phenotypic analysis revealed that the fresh and dry weights of lettuce leaves were both increased by spraying 10-100 µg/mL CuFe-LDHs. Using the optimal concentration of 10 µg/mL, we conducted further experiments to elucidate the mechanism of CuFe-LDHs promoting lettuce growth. It was found that the application of CuFe-LDHs had a significant effect on growth and induced physiological, transcriptomic, and metabolomic changes, including an increase in the chlorophyll b content, net photosynthetic rate, and intercellular carbon dioxide concentration, as well as modifications in gene expression patterns and metabolite profiles. This work provides compelling evidence that CuFe-LDHs can efficiently adsorb on the surface of lettuce leaves through hydrogen bonding, promote lettuce growth, mitigate the toxicity of heavy metal ions compared to their raw materials at the same concentration and offer a molecular-scale insight into the response of leafy vegetables to CuFe-LDHs.

Fibrinogen-like protein 2 regulates macrophage glycolytic reprogramming by directly targeting PKM2 and exacerbates alcoholic liver injury.

BACKGROUND & AIMS: Switching of the macrophage activation phenotype affects the pathogenesis of alcoholic liver diseases, and metabolic reprogramming can provide the energy demand for macrophage phenotypes shift. However, the molecular mechanism by which immune metabolism regulates the activation of proinflammatory macrophages remains unclear. APPROACH: Expression of Fgl2 was examined in patients with alcoholic hepatitis and healthy controls. Mice were fed with a Lieber-DeCarli diet. Livers from mice were used to observe liver injury and macrophage activation. Fgl2 overexpressing THP-1 cell was used to find interacting partners through immunoprecipitation plus mass spectrometry. Naive bone marrow derived macrophages stimulated with LPS and ethanol were used for cell experiments. RESULTS: Expression of Fgl2 was elevated in macrophages of livers from mice with chronic-binge ethanol feeding or patients with alcoholic hepatitis. Fgl2 depletion ameliorated ethanol diet-induced hepatic steatosis and oxidative injury as well as the levels of proinflammatory cytokines. Fgl2-/- mice exhibited suppressed M1 polarization and glycolysis pathway activation. Fgl2 interacted with the M2 isoform of pyruvate kinase (PKM2) in macrophages and facilitated PKM2 nuclear translocation, thus promoting glycolysis in M1 macrophages and the secretion of proinflammatory cytokines. Furthermore, Fgl2 overexpression in THP-1 cells enhances PKM2-dependent glycolysis and inflammation, which could be reversed by activation of enzymatic PKM2 using DASA58. CONCLUSIONS: Taken together, Fgl2 hastens the development of alcoholic liver injury by mediating PKM2 dependent aerobic glycolysis in proinflammatory macrophages. Strategies that inhibiting proinflammatory macrophage activation by silencing Fgl2 might be a potential therapeutic intervention for alcoholic liver injury.

An fNIRS investigation of novel expressed emotion stimulations in schizophrenia.

Living in high expressed emotion (EE) environments tends to increase the relapse rate in schizophrenia (SZ). At present, the neural substrates responsible for high EE in SZ remain poorly understood. Functional near-infrared spectroscopy (fNIRS) may be of great use to quantitatively assess cortical hemodynamics and elucidate the pathophysiology of psychiatric disorders. In this study, we designed novel low- (positivity and warmth) and high-EE (criticism, negative emotion, and hostility) stimulations, in the form of audio, to investigate cortical hemodynamics. We used fNIRS to measure hemodynamic signals while participants listened to the recorded audio. Healthy controls (HCs, [Formula: see text]) showed increased hemodynamic activation in the major language centers across EE stimulations, with stronger activation in Wernicke's area during the processing of negative emotional language. Compared to HCs, people with SZ ([Formula: see text]) exhibited smaller hemodynamic activation in the major language centers across EE stimulations. In addition, people with SZ showed weaker or insignificant hemodynamic deactivation in the medial prefrontal cortex. Notably, hemodynamic activation in SZ was found to be negatively correlated with the negative syndrome scale score at high EE. Our findings suggest that the neural mechanisms in SZ are altered and disrupted, especially during negative emotional language processing. This supports the feasibility of using the designed EE stimulations to assess people who are vulnerable to high-EE environments, such as SZ. Furthermore, our findings provide preliminary evidence for future research on functional neuroimaging biomarkers for people with psychiatric disorders.

Fibrinogen-like protein 2 promotes proinflammatory macrophage polarization and mitochondrial dysfunction in liver fibrosis.

Fibrinogen-like protein 2 (Fgl2) robustly activates macrophages in response to infection or inflammatory cytokine challenge and is markedly increased in the liver tissues of liver cirrhosis patientswithhepatitisCvirus(HCV) infection. However, the molecular mechanism underlying the involvement of Fgl2 in macrophage function in the pathogenesis of liver fibrosis remains unclear. In this study, we demonstrated that increased hepatic Fgl2 expression was associated with hepatic inflammation and high-grade liver fibrosis in patients with hepatitis B virus (HBV) infection and experimental models. Genetic ablation of Fgl2 alleviated hepatic inflammation and fibrosis progression. Fgl2 promoted M1 macrophage polarization and increased the production of proinflammatory cytokines that contribute to inflammatory damage and fibrosis development. In addition, Fgl2 augmented mitochondrial reactive oxygen species (ROS) production and modulated mitochondrial functions. Fgl2-mediated mtROS were involved in macrophage activation and polarization. We further demonstrated that in macrophages, Fgl2 localized to not only the cytosol but also mitochondria, where it bound to cytosolic and mitochondrial heat shock protein 90 (HSP90). Mechanistically, Fgl2 interacted with HSP90, hindering the interaction of HSP90 with its target protein Akt, significantly inhibiting Akt phosphorylation and downstream FoxO1 phosphorylation. These results reveal different layers of regulation of Fgl2 that are necessary for inflammatory damage and mitochondrial dysfunction in M1-polarized macrophages. Therefore, Fgl2 may be a potent target in liver fibrosis treatment.

To Vaccinate or Not to Vaccinate-Reasons of Willingness and Reluctance of Students against SARS-CoV-2 Vaccination-An International Experience.

Despite the vaccine against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) being reported to be safe and effective, the unwillingness to vaccinate and doubts are still common. The aim of this international study was to assess the major reasons for the unwillingness to vaccinate in a group of students from Poland (n = 1202), Bangladesh (n = 1586), India (n = 484), Mexico (n = 234), Egypt (n = 566), Philippines (n = 2076), Pakistan (n = 506), Vietnam (n = 98) and China (n = 503). We conducted an online cross-sectional study that aimed to assess (1) the percentage of vaccinated and unvaccinated students and (2) the reasons associated with willingness/unwillingness to the vaccine. The study included 7255 respondents from 9 countries with a mean age of 21.85 ± 3.66 years. Only 22.11% (n = 1604) of students were vaccinated. However, the majority (69.25%, n = 5025) expressed a willingness to be vaccinated. More willing to vaccinate were students in informal relationships who worked mentally, used psychological/psychiatric services before the pandemic, and studied medicine. There are cultural differences regarding the reasons associated with the unwillingness to vaccinate, but some 'universal' might be distinguished that apply to the whole group.

Fibrinogen-like protein 2 deficiency inhibits virus-induced fulminant hepatitis through abrogating inflammatory macrophage activation.

BACKGROUND: Heterogeneous macrophages play an important role in multiple liver diseases, including viral fulminant hepatitis (VFH). Fibrinogen-like protein 2 (FGL2) is expressed on macrophages and regulates VFH pathogenesis; however, the underlying mechanism remains unclear. AIM: To explore how FGL2 regulates macrophage function and subsequent liver injury during VFH. METHODS: Murine hepatitis virus strain 3 (MHV-3) was used to induce VFH in FGL2-deficient (Fgl2-/-) and wild-type (WT) mice. The dynamic constitution of hepatic macrophages was examined. Adoptive transfer of Fgl2-/- or WT bone marrow-derived macrophages (BMDMs) into WT recipients with macrophages depleted prior to infection was carried out and the consequent degree of liver damage was compared. The signaling cascades that may be regulated by FGL2 were detected in macrophages. RESULTS: Following MHV-3 infection, hepatic macrophages were largely replenished by proinflammatory monocyte-derived macrophages (MoMFs), which expressed high levels of FGL2. In Fgl2-/- mice, the number of infiltrating inflammatory MoMFs was reduced compared with that in WT mice after viral infection. Macrophage depletion ameliorated liver damage in WT mice and further alleviated liver damage in Fgl2-/- mice. Adoptive transfer of Fgl2-/- BMDMs into macrophage-removed recipients significantly reduced the degree of liver damage. Inhibition of monocyte infiltration also significantly ameliorated liver damage. Functionally, Fgl2 deletion impaired macrophage phagocytosis and the antigen presentation potential and attenuated the proinflammatory phenotype. At the molecular level, FGL2 deficiency impaired IRF3, IRF7, and p38 phosphorylation, along with NF-κB activation in BMDMs in response to viral infection. CONCLUSION: Infiltrated MoMFs represent a major source of hepatic inflammation during VFH progression, and FGL2 expression on MoMFs maintains the proinflammatory phenotype via p38-dependent positive feedback, contributing to VFH pathogenesis.

Insufficient immunity led to virologic breakthrough in NAs-treated chronic hepatitis B patients switching to Peg-IFN-ɑ.

BACKGROUND: Virologic breakthrough (VBT) may occur in chronic hepatitis B (CHB) patients after switching from nucleos(t)ide analogues (NAs) to pegylated interferon alpha (Peg-IFN-ɑ). This study aimed to characterize the clinical and immunological features of VBT. METHODS: In NAs-treated patients switching to Peg-IFN-ɑ, innate and adaptive immune cell proportions were examined in peripheral blood and liver biopsy specimens. In vitro effect of IFN-ɑ on the expressions of toll-like receptors 2 (TLR2) and programmed cell death ligand 1 (PDL1) on monocytes, programmed cell death 1 (PD1) on CD8+T cells was examined. Peripheral blood mononuclear cells (PBMCs) were treated with TLR2 agonist and/or PDL1 blockade to evaluate their effect on HBV replication. RESULTS: 33 of 166 patients switching to Peg-IFN-ɑ experienced VBT after NA cessation, with majority being hepatitis B e antigen (HBeAg) positive or having higher hepatitis B core-related antigen (HBcrAg) levels. Patients with VBT exhibited lower proportions of TLR2+monocyte and increased PD1+HBV-specific CD8+T cell during the early phase of Peg-IFN-ɑ therapy after NA cessation in peripheral blood, as well as fewer TLR2+CD68+macrophages but more PDL1+CD68+macrophages and PD1+CD8+T cells in liver tissues. Simultaneous use of TLR2 agonist and PDL1 blockage ex vivo suppressed HBV replication by promoting cytokines production and CD8+T cells cytotoxicity. Upon in vitro IFN-ɑ stimulation, PDL1+monocytes and PD1+CD8+T cells were upregulated, whereas TLR2+monocytes were not increased in PBMC isolated from HBeAg-positive patients, or those with high HBcrAg titers. CONCLUSIONS: In NAs-treated patients, lower TLR2+monocyte and increased PD1+HBV-specific CD8+T cell proportions potentially contribute to VBT after switching to Peg-IFN-ɑ therapy. This insufficient immunity may be associated with the HBeAg status and HBcrAg levels.

The Impact of the COVID-19 Pandemic on Physical and Mental Health in China and Spain: Cross-sectional Study.

BACKGROUND: Differences in physical and mental health impact across continents during the COVID-19 pandemic are unknown. OBJECTIVE: This study compared the levels of impact of COVID-19 on mental health among people from Spain and China and correlated mental health parameters with variables relating to symptoms similar to COVID-19, COVID-19 knowledge, and precautionary measures. METHODS: We collected information on demographic data, physical symptoms, contact history with persons with a confirmed COVID-19 diagnosis, COVID-19 knowledge, and precautionary measures. Participants completed the Impact of Event Scale-Revised (IES-R) and the Depression, Anxiety and Stress Scale-21 Items (DASS-21). To analyze the differences in the mental health parameters, the mean scores between Chinese and Spanish respondents were compared using the independent samples t test. The differences in categorical variables between the two samples were analyzed by the chi-square test. Linear regression was used to calculate the univariate associations between the independent variables and mental health parameters for both groups separately, with adjustments made for age, gender, and education. RESULTS: A total of 1528 participants (Spain: n=687; China: n=841) were recruited. The mean age of the Chinese respondents was 24.73 years (SD 7.60; range 18-65 years), and the mean age of the Spanish respondents was 43.06 years (SD 11.95; range 18-76 years). Spanish participants reported significantly more symptoms similar to COVID-19 infection (eg, fever, sore throat, and breathing difficulties), contact history with COVID-19, higher perceived risk of contracting COVID-19, frequent use of medical services, and less confidence in medical services compared with their Chinese counterparts (P<.001). Spanish participants reported significantly higher DASS-21 stress and depression scores, while Chinese participants reported significantly higher IES-R scores (P<.001). Chinese participants encountered more discrimination from other countries (P<.001). Significantly more Chinese participants reported using face masks than Spanish ones (P<.001). More exposure to health information was associated with adverse mental health in Spain (depression: P=.02; anxiety: P=.02; stress: P=.001). CONCLUSIONS: Our study found that Spanish respondents reported higher levels of stress and depression as well as more symptoms and use of medical services. In preparation for the next pandemic, Spain needs to establish a prompt policy to implement rapid response and enhance medical services to safeguard physical and mental health.

Ghrelin modulates dopaminergic neuron formation and attention deficit hyperactivity disorder-like behaviors: From animals to human models.

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in children. The orexigenic hormone ghrelin is important in neuroprotection and neurodevelopment, which may play an important role in psychopathogenesis of ADHD. This study aimed to systematically investigate the genomic and pharmacological manipulations of ghrelin functioning in ADHD-like symptoms in zebrafish models and validated the effects of ghrelin polymorphisms in human subjects with ADHD. We firstly generated ghrelinΔ/Δ zebrafish mutant, which displayed hyperactive, attention deficit-like and impulsive-like behaviors, as well as endophenotypes, mimicking human ADHD. GhrelinΔ/Δ zebrafish exhibited downregulated expression levels of wnt1, wnt3a, wnt5a that are critical for dopaminergic neuron development to possibly regulate their number and spatial organization. Pharmacological blockade of wnt signaling with XAV939 induced a reduced moving activity and less dopaminergic neurons; whereas, wnt agonist SB415286 rescued hyperactivity and dopaminergic neuron loss in ghrelinΔ/Δ zebrafish. In addition, we further identified and validated a SNP, rs696217, on orexigenic hormone preproghrelin/ghrelin (T408T, Met72Met) to be associated with a higher risk of ADHD in a case-controlled association study with 248 subjects with ADHD and 208 subjects of healthy controls. Together, our results reveal a novel endogenous role for orexigenic hormone ghrelin in ADHD, which provides insights into genetic regulation and drug screens for the identification of novel treatments of ADHD.

Interferon-Induced Macrophage-Derived Exosomes Mediate Antiviral Activity Against Hepatitis B Virus Through miR-574-5p.

BACKGROUND: Interferon alfa (IFN-α) has been proved effective in treating chronic hepatitis B (CHB), owing to its ability to suppress hepatitis B surface antigen and hepatitis B virus (HBV) covalently closed circular DNA. However, the underlying mechanisms are unclear. METHODS: We investigated the antiviral activities of exosomes from responders and nonresponders to pegylated IFN-α (PegIFN-α) as well as the supernatants of IFN-α-treated macrophages derived from THP-1 (the human leukemia monocyte cell line). Then the expression profiles of exosomal microRNAs (miRNAs) were analyzed using miRNA sequencing. The luciferase reporter assay was used to locate the binding position of HBV genomic sequence targeted by the identified miRNA. RESULTS: Exosomes from PegIFN-α-treated patients, particularly responders, as well as the supernatants of IFN-α-treated macrophages exhibited anti-HBV activities, as manifested by the suppression of hepatitis B surface antigen, hepatitis B e antigen, HBV DNA, and covalently closed circular DNA levels in HBV-related cell lines. PegIFN-α treatment up-regulated exosomal hsa-miR-193a-5p, hsa-miR-25-5p, and hsa-miR-574-5p, which could partially inhibit HBV replication and transcription, and hsa-miR-574-5p reduced pregenomic RNA and polymerase messenger RNA levels by binding to the 2750-2757 position of the HBV genomic sequence. CONCLUSIONS: Exosomes can transfer IFN-α-related miRNAs from macrophages to HBV-infected hepatocytes, and they exhibit antiviral activities against HBV replication and expression.

The Association Between Physical and Mental Health and Face Mask Use During the COVID-19 Pandemic: A Comparison of Two Countries With Different Views and Practices.

BACKGROUND: The physical and mental health of citizens living in a country that encouraged face masks (China) and discouraged face masks (Poland) during the initial stage of the COVID-19 pandemic remained unknown. We conducted a cross-country study to compare the psychological impact of the COVID-19 pandemic on Poles and Chinese. This study aimed to compare the levels of psychological impact of pandemic and levels of anxiety and depression between China and Poland. METHODS: The survey collected information on demographic data, physical symptoms, contact history, and precautionary measures. The psychological impact was assessed using the Impact of Event Scale-Revised (IES-R), and mental health status was assessed by the Depression, Anxiety and Stress Scale (DASS-21). The chi-squared test was used to analyze the differences in categorical variables between the two populations. Linear regression was used to calculate the bivariate associations between independents variables (e.g., physical symptoms and precautionary measures) and dependent variables (e.g., mental health outcomes). RESULTS: This study included a total of 2,266 respondents from both countries (1,056 Poles and 1,210 Chinese). There were significantly less Polish respondents who wore face masks (Poles: 35.0%; Chinese: 96.8% p < 0.001). Significantly more Polish respondents reported physical symptoms resembling COVID-19 infection (p < 0.001), recent medical consultation (p < 0.01), recent COVID-19 testing (p < 0.001), and hospitalization (p < 0.01). Furthermore, Polish respondents had significantly higher levels of anxiety, depression and stress (p < 0.001) than Chinese. The mean IES-R scores of Poland and China were above the cut-off for post-traumatic stress disorder (PTSD) symptoms. Besides precautionary measures, unemployment, retirement, physical symptoms resembling COVID-19 infection, recent medical consultation or COVID-19 testing, and long daily duration of home confinement were risk factors for PTSD symptoms, anxiety, depression, or stress for Polish respondents. CONCLUSION: Use of face masks at the community level may safeguard better physical and mental health during the COVID-19 pandemic. There is a need of health education with scientific information from Polish health authority on the proper use of face masks and reduce social stigma. This study was limited by the respondent sampling method that had compromised the representativeness of samples.

General Issues in Clinical Research of Acupuncture and In Vitro Fertilization.

In vitro fertilization-embryo transfer (IVF-ET), a well-developed technology, provides the last possibility or hope for infertile women. However, the live birth rate per IVF cycle is still not satisfactory. Acupuncture is a frequently used adjunctive therapy drawing wide attention on improvement of IVF. Although so many randomized controlled trials have been evaluating the effect of acupuncture on IVF in the past 20 years, the exact efficacy of acupuncture on IVF is still controversy mainly because of no consensus on placebo control and acupuncture scheme. This paper focused on the general issues in clinical research of acupuncture and IVF and gave some suggestions for future directions.

A longitudinal study on the mental health of general population during the COVID-19 epidemic in China.

In addition to being a public physical health emergency, Coronavirus disease 2019 (COVID-19) affected global mental health, as evidenced by panic-buying worldwide as cases soared. Little is known about changes in levels of psychological impact, stress, anxiety and depression during this pandemic. This longitudinal study surveyed the general population twice - during the initial outbreak, and the epidemic's peak four weeks later, surveying demographics, symptoms, knowledge, concerns, and precautionary measures against COVID-19. There were 1738 respondents from 190 Chinese cities (1210 first-survey respondents, 861 s-survey respondents; 333 respondents participated in both). Psychological impact and mental health status were assessed by the Impact of Event Scale-Revised (IES-R) and the Depression, Anxiety and Stress Scale (DASS-21), respectively. IES-R measures PTSD symptoms in survivorship after an event. DASS -21 is based on tripartite model of psychopathology that comprise a general distress construct with distinct characteristics. This study found that there was a statistically significant longitudinal reduction in mean IES-R scores (from 32.98 to 30.76, p < 0.01) after 4 weeks. Nevertheless, the mean IES-R score of the first- and second-survey respondents were above the cut-off scores (>24) for PTSD symptoms, suggesting that the reduction in scores was not clinically significant. During the initial evaluation, moderate-to-severe stress, anxiety and depression were noted in 8.1%, 28.8% and 16.5%, respectively and there were no significant longitudinal changes in stress, anxiety and depression levels (p > 0.05). Protective factors included high level of confidence in doctors, perceived survival likelihood and low risk of contracting COVID-19, satisfaction with health information, personal precautionary measures. As countries around the world brace for an escalation in cases, Governments should focus on effective methods of disseminating unbiased COVID-19 knowledge, teaching correct containment methods, ensuring availability of essential services/commodities, and providing sufficient financial support.

Immediate Psychological Responses and Associated Factors during the Initial Stage of the 2019 Coronavirus Disease (COVID-19) Epidemic among the General Population in China.

Background: The 2019 coronavirus disease (COVID-19) epidemic is a public health emergency of international concern and poses a challenge to psychological resilience. Research data are needed to develop evidence-driven strategies to reduce adverse psychological impacts and psychiatric symptoms during the epidemic. The aim of this study was to survey the general public in China to better understand their levels of psychological impact, anxiety, depression, and stress during the initial stage of the COVID-19 outbreak. The data will be used for future reference. Methods: From 31 January to 2 February 2020, we conducted an online survey using snowball sampling techniques. The online survey collected information on demographic data, physical symptoms in the past 14 days, contact history with COVID-19, knowledge and concerns about COVID-19, precautionary measures against COVID-19, and additional information required with respect to COVID-19. Psychological impact was assessed by the Impact of Event Scale-Revised (IES-R), and mental health status was assessed by the Depression, Anxiety and Stress Scale (DASS-21). Results: This study included 1210 respondents from 194 cities in China. In total, 53.8% of respondents rated the psychological impact of the outbreak as moderate or severe; 16.5% reported moderate to severe depressive symptoms; 28.8% reported moderate to severe anxiety symptoms; and 8.1% reported moderate to severe stress levels. Most respondents spent 20-24 h per day at home (84.7%); were worried about their family members contracting COVID-19 (75.2%); and were satisfied with the amount of health information available (75.1%). Female gender, student status, specific physical symptoms (e.g., myalgia, dizziness, coryza), and poor self-rated health status were significantly associated with a greater psychological impact of the outbreak and higher levels of stress, anxiety, and depression (p < 0.05). Specific up-to-date and accurate health information (e.g., treatment, local outbreak situation) and particular precautionary measures (e.g., hand hygiene, wearing a mask) were associated with a lower psychological impact of the outbreak and lower levels of stress, anxiety, and depression (p < 0.05). Conclusions: During the initial phase of the COVID-19 outbreak in China, more than half of the respondents rated the psychological impact as moderate-to-severe, and about one-third reported moderate-to-severe anxiety. Our findings identify factors associated with a lower level of psychological impact and better mental health status that can be used to formulate psychological interventions to improve the mental health of vulnerable groups during the COVID-19 epidemic.

Impact of the COVID-19 Pandemic on Physical and Mental Health in Lower and Upper Middle-Income Asian Countries: A Comparison Between the Philippines and China.

Objective: The differences between the physical and mental health of people living in a lower-middle-income country (LMIC) and upper-middle-income country (UMIC) during the COVID-19 pandemic was unknown. This study aimed to compare the levels of psychological impact and mental health between people from the Philippines (LMIC) and China (UMIC) and correlate mental health parameters with variables relating to physical symptoms and knowledge about COVID-19. Methods: The survey collected information on demographic data, physical symptoms, contact history, and knowledge about COVID-19. The psychological impact was assessed using the Impact of Event Scale-Revised (IES-R), and mental health status was assessed by the Depression, Anxiety, and Stress Scale (DASS-21). Findings: The study population included 849 participants from 71 cities in the Philippines and 861 participants from 159 cities in China. Filipino (LMIC) respondents reported significantly higher levels of depression, anxiety, and stress than Chinese (UMIC) during the COVID-19 (p < 0.01) while only Chinese respondents' IES-R scores were above the cut-off for PTSD symptoms. Filipino respondents were more likely to report physical symptoms resembling COVID-19 infection (p < 0.05), recent use of but with lower confidence on medical services (p < 0.01), recent direct and indirect contact with COVID (p < 0.01), concerns about family members contracting COVID-19 (p < 0.001), dissatisfaction with health information (p < 0.001). In contrast, Chinese respondents requested more health information about COVID-19. For the Philippines, student status, low confidence in doctors, dissatisfaction with health information, long daily duration spent on health information, worries about family members contracting COVID-19, ostracization, and unnecessary worries about COVID-19 were associated with adverse mental health. Physical symptoms and poor self-rated health were associated with adverse mental health in both countries (p < 0.05). Conclusion: The findings of this study suggest the need for widely available COVID-19 testing in MIC to alleviate the adverse mental health in people who present with symptoms. A health education and literacy campaign is required in the Philippines to enhance the satisfaction of health information.

Soluble fibrinogen-like protein 2 promotes the growth of hepatocellular carcinoma via attenuating dendritic cell-mediated cytotoxic T cell activity.

BACKGROUND: Soluble fibrinogen-like protein 2 (sFGL2), a secretory protein expressed by regulatory T cells (Tregs) with immunosuppressive activity, is highly expressed in both the peripheral blood and tumor tissue of patients with hepatocellular carcinoma (HCC); however, sFGL2 function in HCC remains largely unknown. Here, we elucidated the potential role of sFGL2 in HCC progression. METHODS: T cells, dendritic cells (DCs), and related cytokines in the tumor microenvironment were comparatively analyzed in BALB/c and C57BL/6 mice bearing transplanted hepatomas harboring Fgl2-knockout or receiving sFGL2-antibody treatment. Additionally, the effects of sFGL2 on DCs and T cells were evaluated in vivo and ex vivo. RESULTS: The growth of both subcutaneously and orthotopically transplanted hepatomas was inhibited in Fgl2-knockout mice and those treated with the sFGL2 antibody, respectively, as compared with controls. Moreover, sFGL2 depletion enhanced the proportion and cytotoxicity of cytotoxic T cells, promoted DC maturation, and improved DC activity to proliferate T cells in the tumor microenvironment. Furthermore, we detected lower levels of interleukin (IL)-35 in both types of transplanted hepatomas and higher level of IL-6 in orthotopically transplanted hepatomas following sFGL2 depletion. Mechanistically, we found that sFGL2 impaired bone-marrow-derived DC (BMDCs) function by inhibiting phosphorylation of Akt, nuclear factor-kappaB, cAMP response element binding protein, and p38 and downregulating the expression of major histocompatibility complex II, CD40, CD80, CD86, and CD83 on BMDCs in vitro. CONCLUSIONS: Our data suggest that sFGL2 promotes hepatoma growth by attenuating DC activity and subsequent CD8+ T cell cytotoxicity, suggesting sFGL2 as a novel potential therapeutic target for HCC treatment.

Sequential combination therapy with interferon, interleukin-2 and therapeutic vaccine in entecavir-suppressed chronic hepatitis B patients: the Endeavor study.

BACKGROUND: Switching from nucleos(t)ide analogues to interferon (IFN) improves hepatitis B surface antigen (HBsAg) loss. We aimed to evaluate whether combining immunomodulators such as interleukin-2 (IL-2) and therapeutic vaccine with IFN enhances HBsAg loss in entecavir (ETV)-suppressed patients. METHODS: Ninety-four patients exhibiting virological suppression and hepatitis B e antigen (HBeAg) loss following ETV treatment were randomized 1:1:1 to receive ETV (group I) or IFN (group II) for 48 weeks, or IFN and vaccine for 48 weeks plus IL-2 for 12 weeks (group III). The primary endpoint was HBsAg loss at week 48. Peripheral natural killer (NK) cells and regulatory T cells (Treg) were measured as immune checkpoint indicators. RESULTS: Mean HBsAg decline at week 48 was significantly greater in group III (0.85 log 10 IU/mL) and group II (0.74 log 10 IU/mL), than in group I (0.13 log 10 IU/mL). At week 48, 9.38%, 3.03%, and 3.70% of subjects in group III, II, and I, respectively, achieved HBsAg loss. Among patients with baseline HBsAg titers ranging from 100 to 1500 IU/mL, HBsAg loss rate was 27.3, 7.1, and 0% in group III, II, and I, respectively. Responders in group III showed a significantly higher increase in CD56bright CD16-NK cells from week 24 to 36, and a significant decline in Treg from week 12 to 24 than non-responders. CONCLUSION: For ETV-suppressed patients, particularly those with low baseline HBsAg levels, combination therapy with IFN and other immunomodulators may enhance HBsAg loss, while successful response correlates with partial restoration of NK cells and Tregs.

Kctd9 Deficiency Impairs Natural Killer Cell Development and Effector Function.

We previously showed that potassium channel tetramerization domain containing 9 (KCTD9) is aberrantly expressed in natural killer (NK) cells in patients with hepatitis B virus-associated acute-on-chronic liver failure and mice with experimental fulminant hepatitis. However, the mechanism underlying the regulation of NK cell function and fulminant hepatitis progression by KCTD9 is unknown. Here, we investigated the role of Kctd9 in regulation of early development, maturation, and function of NK cells using Kctd9-knockout mice. Compared to wild-type mice, Kctd9-deficient mice exhibited impaired NK cell lineage commitment, as evidenced by selective reduction in the refined NK progenitors, and incomplete NK cell maturation, as manifested by a higher proportion of CD11b- NK cells and a lower percentage of CD11b+ NK cells with high proliferative potential. Moreover, Kctd9-depleted NK cells displayed insufficient IFN-γ production, degranulation, and granzyme B production in response to cytokine stimulation, and attenuated cytotoxicity to tumor cells in vitro. The defect in NK cells was further supported by ameliorated liver damage and improved survival in Kctd9-deficient mice following murine hepatitis virus strain-3 (MHV-3) infection, which otherwise leads to immune-mediated fulminant hepatitis, a phenotype homologous to that caused by NK cell depletion in wild-type mice. Further investigation to identify the underlying mechanism revealed that Kctd9 deficiency hindered the expression of transcription factors, including Ets1, Nfil3, Eomes, and Id2 in NK cells. Collectively, our data reveal that Kctd9 acts as a novel regulator for NK cell commitment, maturation, and effector function.

Regulatory T cells suppress excessive lipid accumulation in alcoholic liver disease.

Sensitization of hepatic immune cells from chronic alcohol consumption gives rise to inflammatory accumulation, which is considered a leading cause of liver damage. Regulatory T cells (Tregs) are an immunosuppressive cell subset that plays an important role in a variety of liver diseases; however, data about pathological involvement of Tregs in liver steatosis of alcoholic liver disease (ALD) is insufficient. In mouse models of ALD, we found that increased lipid accumulation by chronic alcohol intake was accompanied by oxidative stress, inflammatory accumulation, and Treg decline in the liver. Adoptive transfer of Tregs relieved lipid metabolic disorder, oxidative stress, inflammation, and, consequently, ameliorated the alcoholic fatty liver. Macrophages are a dominant source of inflammation in ALD. Aberrant macrophage activation and cytokine production were activated during chronic alcohol consumption, but were significantly inhibited after Treg transfer. In vitro, macrophages were co-activated by alcohol and lipopolysaccharide to mimic a condition for alcoholic liver microenvironment. Tregs suppressed monocyte chemoattractant protein-1 and TNF-α production from these macrophages. However, such effects of Tregs were remarkably neutralized when interleukin (IL)-10 was blocked. Altogether, our data uncover a novel role of Tregs in restoring liver lipid metabolism in ALD, which partially relies on IL-10-mediated suppression of hepatic pro-inflammatory macrophages.