Association between family conflict resolution methods and depressive symptoms in South Korea: a longitudinal study.

We investigated the relationship between family conflict resolution and depression, focusing on each component of family conflict resolution to determine which factors have stronger associations with depression. We used data from 2008 to 2015 of the Korea Welfare Panel Study. Our final sample included 3565 participants. For each participant, we included at least 2-8 years of follow-up data with a mean follow-up time of 4.05 ± 2.52 years. To identify the relationship between new-onset depressive symptoms and participants' family conflict resolution styles, we performed generalized estimating equation analysis with autoregressive working correlations to estimate adjusted odds ratios for new-onset depressive symptoms adjusted for covariates. Compared with positive family conflict resolution, negative family conflict resolution had a higher odds ratio for depressive symptoms (aOR 1.80, 95% CI 1.42-2.29). This relationship was strongly founded on participants who were women (aOR 2.35, 95% CI 1.55-3.94) with experience of verbal aggression (aOR 1.84, 95% CI 1.42-2.37) and threatening behaviors (aOR 1.89, 95% CI 1.25-2.85). Negative family conflict resolution has long-term associations with an elevated risk of depressive symptoms. In particular, we observed higher risks of depression with verbal and psychological conflict than with physical conflict. Health care providers and health policymakers should support the management and development of methods for dealing with family conflict to improve mental health at a family level, as well as an individual level.

Effect of Changes in Sleep Quantity and Quality on Depressive Symptoms Among Korean Children.

This study aims to determine whether changes in sleep quantity and quality in childhood are associated with incidence of depressive symptoms. We used the three waves of the Korean Children & Youth Panel Survey (2011-2013). Statistical analysis using a generalized estimating equation model was performed. The 2,605 subjects analyzed included 1,453 students in 2012 and 1,152 students in 2013 without depressive symptoms in the prior year. We found that deteriorated or consistently poor sleep quality were important risk factors for depressive symptoms in children. We suggest that early detection and intervention of poor sleep quality in elementary school is required to reduce early onset depressive symptoms.

Continuous exposure to 60 Hz magnetic fields induces duration- and dose-dependent apoptosis of testicular germ cells.

To evaluate duration- and dose-dependent effects of continuous exposure to a 60 Hz magnetic field (MF) on the testes in mice, BALB/c male mice were exposed to a 60 Hz MF at 100 µT for 24 h a day for 2, 4, 6, or 8 weeks, and at 2, 20, or 200 µT for 24 h a day for 8 weeks. Any exposures to MF did not significantly affect body or testicular masses. However, the apoptotic cells among testicular germ cells were increased duration-dependent at exposures of 100 µT for 6 and 8 weeks and dose-dependent at exposures of 20 and 200 µT for 8 weeks. The number of sperm in epididymis and the diameter of seminiferous tubule decreased in mice exposed to 100 and 200 µT for 8 weeks, respectively. To induce the apoptosis of testicular germ cell in mice, the minimum dose is 20 µT at continuous exposure to a 60 Hz MF for 8 weeks and the minimum duration is 6 weeks at continuous exposure of 100 µT. Taken together, these results suggest that continuous exposure to a 60 Hz MF might affect, duration- and dose-dependent biological processes including apoptotic cell death and spermatogenesis in the male reproductive system of mice.

Tumors recycle glucocorticoids to drive Treg-mediated immunosuppression.

Suppression of antitumor immunity is a prominent feature of the tumor microenvironment. In this issue of the JCI, Taves, Otsuka, and authors show that glucocorticoids (GCs), which are potent immunosuppressive hormones mainly produced by the adrenals, can be reconverted from their inactive form to active metabolites via the 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme expressed by murine tumor cell lines. In the tumor microenvironment, GCs acted on CD4+ regulatory T cells to enhance their immunosuppressive function and promote tumor growth. The findings suggest that targeting GC recycling as a strategy for modulating tumor immunosuppression has the potential to improve therapeutic efficacy of immune checkpoint blockade.

Thinking (Metastasis) outside the (Primary Tumor) Box.

The metastasis of tumor cells into vital organs is a major cause of death from diverse types of malignancies [...].

Bacteriophage EK99P-1 alleviates enterotoxigenic Escherichia coli K99-induced barrier dysfunction and inflammation.

Bacteriophages, simply phages, have long been used as a potential alternative to antibiotics for livestock due to their ability to specifically kill enterotoxigenic Escherichia coli (ETEC), which is a major cause of diarrhea in piglets. However, the control of ETEC infection by phages within intestinal epithelial cells, and their relationship with host immune responses, remain poorly understood. In this study, we evaluated the effect of phage EK99P-1 against ETEC K99-infected porcine intestinal epithelial cell line (IPEC-J2). Phage EK99P-1 prevented ETEC K99-induced barrier disruption by attenuating the increased permeability mediated by the loss of tight junction proteins such as zonula occludens-1 (ZO-1), occludin, and claudin-3. ETEC K99-induced inflammatory responses, such as interleukin (IL)-8 secretion, were decreased by treatment with phage EK99P-1. We used a IPEC-J2/peripheral blood mononuclear cell (PBMC) transwell co-culture system to investigate whether the modulation of barrier disruption and chemokine secretion by phage EK99P-1 in ETEC K99-infected IPEC-J2 would influence immune cells at the site of basolateral. The results showed that phage EK99P-1 reduced the mRNA expression of ETEC K99-induced pro-inflammatory cytokines, IL-1ß and IL-8, from PBMC collected on the basolateral side. Together, these results suggest that phage EK99P-1 prevented ETEC K99-induced barrier dysfunction in IPEC-J2 and alleviated inflammation caused by ETEC K99 infection. Reinforcement of the intestinal barrier, such as regulation of permeability and cytokines, by phage EK99P-1 also modulates the immune cell inflammatory response.

Change of Dendritic Cell Subsets Involved in Protection Against Listeria monocytogenes Infection in Short-Term-Fasted Mice.

The gastrointestinal tract is the first organ directly affected by fasting. However, little is known about how fasting influences the intestinal immune system. Intestinal dendritic cells (DCs) capture antigens, migrate to secondary lymphoid organs, and provoke adaptive immune responses. We evaluated the changes of intestinal DCs in mice with short-term fasting and their effects on protective immunity against Listeria monocytogenes (LM). Fasting induced an increased number of CD103+CD11b- DCs in both small intestinal lamina propria (SILP) and mesenteric lymph nodes (mLN). The SILP CD103+CD11b- DCs showed proliferation and migration, coincident with increased levels of GM-CSF and C-C chemokine receptor type 7, respectively. At 24 h post-infection with LM, there was a significant reduction in the bacterial burden in the spleen, liver, and mLN of the short-term-fasted mice compared to those fed ad libitum. Also, short-term-fasted mice showed increased survival after LM infection compared with ad libitum-fed mice. It could be that significantly high TGF-ß2 and Aldh1a2 expression in CD103+CD11b- DCs in mice infected with LM might affect to increase of Foxp3+ regulatory T cells. Changes of major subset of DCs from CD103+ to CD103- may induce the increase of IFN-γ-producing cells with forming Th1-biased environment. Therefore, the short-term fasting affects protection against LM infection by changing major subset of intestinal DCs from tolerogenic to Th1 immunogenic.

Inactivated Vibrio cholerae Strains That Express TcpA via the toxT-139F Allele Induce Antibody Responses against TcpA.

Cholera remains a major global public health problem, for which oral cholera vaccines (OCVs) being a valuable strategy. Patients, who have recovered from cholera, develop antibody responses against LPS, cholera toxin (CT), toxin-coregulated pilus (TCP) major subunit A (TcpA) and other antigens; thus, these responses are potentially important contributors to immunity against Vibrio cholerae infection. However, assessments of the efficacy of current OCVs, especially inactivated OCVs, have focused primarily on O-antigen-specific antibody responses, suggesting that more sophisticated strategies are required for inactivated OCVs to induce immune responses against TCP, CT, and other antigens. Previously, we have shown that the toxT-139F allele enables V. cholerae strains to produce CT and TCP under simple laboratory culture conditions. Thus, we hypothesized that V. cholerae strains that express TCP via the toxT-139F allele induce TCP-specific antibody responses. As anticipated, V. cholerae strains that expressed TCP through the toxT-139F allele elicited antibody responses against TCP when the inactivated bacteria were delivered via a mouse model. We have further developed TCP-expressing V. cholerae strains that have been used in inactivated OCVs and shown that they effect an antibody response against TcpA in vivo, suggesting that V. cholerae strains with the toxT-139F allele are excellent candidates for cholera vaccines.

Self-reactivity controls functional diversity of naive CD8+ T cells by co-opting tonic type I interferon.

The strength of the T cell receptor interaction with self-ligands affects antigen-specific immune responses. However, the precise function and underlying mechanisms are unclear. Here, we demonstrate that naive CD8+ T cells with relatively high self-reactivity are phenotypically heterogeneous owing to varied responses to type I interferon, resulting in three distinct subsets, CD5loLy6C-, CD5hiLy6C-, and CD5hiLy6C+ cells. CD5hiLy6C+ cells differ from CD5loLy6C- and CD5hiLy6C- cells in terms of gene expression profiles and functional properties. Moreover, CD5hiLy6C+ cells demonstrate more extensive antigen-specific expansion upon viral infection, with enhanced differentiation into terminal effector cells and reduced memory cell generation. Such features of CD5hiLy6C+ cells are imprinted in a steady-state and type I interferon dependence is observed even for monoclonal CD8+ T cell populations. These findings demonstrate that self-reactivity controls the functional diversity of naive CD8+ T cells by co-opting tonic type I interferon signaling.

STAT1 maintains naïve CD8+ T cell quiescence by suppressing the type I IFN-STAT4-mTORC1 signaling axis.

Naïve CD8+ T cell quiescence is maintained at a steady state. Although this state of quiescence involves various cell-intrinsic and cell-extrinsic regulators, the mechanisms underlying this regulation remain incompletely understood. Here, we found that signal transducer and activator of transcription 1 (STAT1), a key transcription factor downstream of interferon receptor (IFNR) signaling, plays a cell-intrinsic role in maintaining naïve CD8+ T cell quiescence. STAT1-deficient mice showed enhanced proliferation of peripheral naïve CD8+ T cells, which resulted in an abnormal increase in the number of CD44hi memory/activated phenotype cells and an enlargement of secondary lymphoid tissues. This phenomenon was not observed in IFNR-deficient mice but was paradoxically dependent on type I interferon and its alternative signaling pathway via the STAT4­RagD­lysosomal mTORC1 axis. Collectively, these findings underline the importance of STAT1 in regulating the homeostasis of peripheral naïve CD8+ T cells by suppressing their responsiveness to homeostatic cues at a steady state.

Intranasal Vaccination with Outer-Membrane Protein of Orientia tsutsugamushi induces Protective Immunity Against Scrub Typhus.

Scrub typhus develops after the individual is bitten by a trombiculid mite infected with Orientia tsutsugamushi. Since it has been reported that pneumonia is frequently observed in patients with scrub typhus, we investigated whether intranasal (i.n.) vaccination with the outer membrane protein of O. tsutsugamushi (OMPOT) would induce a protective immunity against O. tsutsugamushi infection. It was particular interest that when mice were infected with O. tsutsugamushi, the bacteria disseminated into the lungs, causing pneumonia. The i.n. vaccination with OMPOT induced IgG responses in serum and bronchoalveolar lavage (BAL) fluid. The anti-O. tsutsugamushi IgA Abs in BAL fluid after the vaccination showed a high correlation of the protection against O. tsutsugamushi. The vaccination induced strong Ag-specific Th1 and Th17 responses in the both spleen and lungs. In conclusion, the current study demonstrated that i.n. vaccination with OMPOT elicited protective immunity against scrub typhus in mouse with O. tsutsugamushi infection causing subsequent pneumonia.

Pulp and paper mill effluents induce distinct gene expression changes linked to androgenic and estrogenic responses in the fathead minnow (Pimephales promelas).

Although effluent treatment systems within pulp and paper mills remove many toxicants and improve wastewater quality, there is a need to understand and quantify the effectiveness of the treatment process. At a combined news and kraft pulp and paper mill in northwestern Ontario, Canada, fathead minnow (FHM) reproduction and physiology were examined before, during, and after a short-term (6-d) exposure to 10% (v/v) untreated kraft mill effluent (UTK), 25% (v/v) secondary treated kraft mill effluent (TK), and 100% (v/v) combined mill outfall (CMO). Although UTK exposure significantly decreased egg production, neither TK nor CMO caused any reproductive changes. The expression of six genes responsive to endocrine-disrupting compounds, stress, or metals was then examined in livers of these fish using real-time polymerase chain reaction. In female FHMs, none of the three effluents induced significant expression changes in any genes investigated. By contrast, in males there were significant increases in the mRNA levels of androgen receptor, estrogen receptor (ER) beta, and cytochrome P4501A (CYP1A) upon UTK and TK exposure but no changes in ERalpha or vitellogenin (VTG) gene expression, whereas CMO exposure significantly increased the mRNA levels of ERalpha, VTG, and CYP1A. Together, these results suggest that kraft effluent before and after biological treatment contained compounds able to induce androgenic effects in FHMs, and that combination of kraft and newsmill effluents eliminated the androgenic compounds while inducing distinct and significant patterns of gene expression changes that were likely due to estrogenic compounds produced by the newsmill.

Supraphysiological Levels of IL-2 in Jak3-Deficient Mice Promote Strong Proliferative Responses of Adoptively Transferred Naive CD8+ T Cells.

The antigen-independent, strong proliferative responses of naive CD8+ T cells have been well demonstrated in a particular strain of mice lacking IL-2 receptors. This type of proliferation is mainly driven by common gamma-chain (γc) cytokines, such as IL-2, IL-7, and IL-15, present at abnormally high levels in these mice. Similarly, in the present study, we showed that mice lacking Janus kinase 3 (Jak3), a tyrosine kinase crucial for γc cytokine signaling, could induce strong proliferation of adoptively transferred naive CD8+ T cells. This proliferation was also independent of antigenic stimulation, but heavily dependent on IL-2, as evidenced by the failure of proliferation of adoptively transferred IL-2 receptor alpha- and beta-chain-deficient naive CD8+ T cells. Consistent with this, Jak3-/- mice showed elevated serum levels of IL-2 compared to wild-type mice, and interestingly, IL-2 production was due to high levels of accumulation of activated CD4+ T cells in Jak3-/- mice along with defective CD4+ T regulatory cells. Collectively, these findings reveal previously unidentified unique immune contexts of Jak3-/- mice that cause robust IL-2-driven T cell expansion and have a clinical implication for designing a treatment strategy for human patients with loss-of-function genetic mutations of Jak3.

Intranasal immunization with pneumococcal surface protein A in the presence of nanoparticle forming polysorbitol transporter adjuvant induces protective immunity against the Streptococcus pneumoniae infection.

Developing effective mucosal subunit vaccine for the Streptococcus pneumoniae has been unsuccessful mainly because of their poor immunogenicity with insufficient memory T and B cell responses. We thus address whether such limitation can be overcome by introducing effective adjuvants that can enhance immunity and show here that polysorbitol transporter (PST) serves as a mucosal adjuvant for a subunit vaccine against the Streptococcus pneumoniae. Pneumococcal surface protein A (PspA) with PST adjuvant induced protective immunity against S. pneumoniae challenge, especially long-term T and B cell immune responses. Moreover, we found that the PST preferentially induced T helper (Th) responses toward Th2 or T follicular helper (Tfh) cells and, importantly, that the responses were mediated through antigen-presenting cells via activating a peroxisome proliferator-activated receptor gamma (PPAR-γ) pathway. Thus, these data indicate that PST can be used as an effective and safe mucosal vaccine adjuvant against S. pneumoniae infection. STATE OF SIGNIFICANCE: In this study, we suggested the nanoparticle forming adjuvant, PST works as an effective adjuvant for the pneumococcal vaccine, PspA. The PspA subunit vaccine together with PST adjuvant efficiently induced protective immunity, even in the long-term memory responses, against Streptococcus pneumoniae lethal challenge. We found that PspA with PST adjuvant induced dendritic cell activation followed by follicular helper T cell responses through PPAR-γ pathway resulting long-term memory antibody-producing cells. Consequently, in this paper, we suggest the mechanism for safe nanoparticle forming subunit vaccine adjuvant against pneumococcal infection.

Galectin-9 Induced by Dietary Probiotic Mixture Regulates Immune Balance to Reduce Atopic Dermatitis Symptoms in Mice.

Probiotics can be an effective treatment for atopic dermatitis (AD), while their mechanism of action is still unclear. Here, we induced AD in mice with 2,4-dinitrochlorobenzene and administrated YK4, a probiotic mixture consisting of Lactobacillus acidophilus CBT LA1, L. plantarum CBT LP3, Bifidobacterium breve CBT BR3, and B. lactis CBT BL3. Then, we have validated the underlying mechanism for the alleviation of AD by YK4 from the intestinal and systematic immunological perspectives. Administration of YK4 in AD mice alleviated the symptoms of AD by suppressing the expression of skin thymic stromal lymphopoietin and serum immunoglobulin E eliciting excessive T-helper (Th) 2 cell-mediated responses. YK4 inhibited Th2 cell population through induce the proportion of Th1 cells in spleen and Treg cells in Peyer's patches and mesenteric lymph node (mLN). CD103+ dendritic cells (DCs) in mLN and the spleen were significantly increased in AD mice administered with YK4 when compared to AD mice. Furthermore, galectin-9 was significantly increased in the gut of AD mice administered with YK4. In vitro experiments were performed using bone marrow-derived DCs (BMDC) and CD4+ T cells to confirm the immune mechanisms of YK4 and galectin-9. The expression of CD44, a receptor of galectin-9, together with programmed death-ligand 1 was significantly upregulated in BMDCs following treatment with YK4. IL-10 and IL-12 were upregulated when BMDCs were treated with YK4. Cytokines together with co-receptors from DCs play a major role in the differentiation and activation of CD4+ T cells. Proliferation of Tregs and Th1 cell activation were enhanced when CD4+T cells were co-cultured with YK4-treated BMDCs. Galectin-9 appeared to contribute at least partially to the proliferation of Tregs. The results further suggested that DCs treated with YK4 induced the differentiation of naïve T cells toward Th1 and Tregs. At the same time, YK4 alleviated AD symptoms by inhibiting Th2 response. Thus, the present study suggested a potential role of YK4 as an effective immunomodulatory agent in AD patients.

The Relationship Between Physical Activity Level of Parents and That of Their Adolescent Children.

BACKGROUND: Intergenerational transmission, which refers to the similarity between parent and their children, is a possible explanation of adolescent physical activity (PA). However, only a few existing studies explore the relationship of parent-adolescent PA in East Asian countries. Therefore, this study aimed to investigate the association of parent-adolescent PA using a nationally representative data in Korea with a large sample size. METHODS: Data were collected from the Korean National Health and Nutrition Examination Survey conducted from 2010 to 2014. The authors performed a linear mixed effects regression analysis with 1342 cases after using log conversion of parent and adolescent moderate- to vigorous-intensity physical activity (MVPA) levels. RESULTS: In the study, the median MVPA of adolescents was 150 (interquartile range: 360) minutes per week. Adolescent MVPA levels were significantly correlated with their mother's MVPA (ß = 0.055, P = .02). Similar findings of greater association in girls and younger adolescents (age: 13-15 y) were found in subgroup analysis (girls: ß = 0.073, P = .05; younger adolescents: ß = 0.103, P = .001). CONCLUSION: Increasing maternal PA levels could stimulate their adolescent's PA levels. Therefore, intervention at the family level may lead to an increase in adolescent PA levels.

Utilization of professional mental health services according to recognition rate of mental health centers.

BACKGROUND: Despite the positive effect of community-based mental health centers, the utilization of professional mental health services appears to be low. Therefore, we analyzed the relationship between regional recognition of mental health centers and utilization of professional mental health services. METHODS: We used data from the Community Health Survey (2014) and e-provincial indicators. Only those living in Seoul, who responded that they were either feeling a lot of stress or depression, were included in the study. Multiple logistic regression analysis using generalized estimating equations was performed to examine both individual- and regional-level variables associated with utilization of professional mental health services. RESULTS: Among the 7338 participants who reported depression or stress, 646 (8.8%) had consulted a mental health professional for their symptoms. A higher recognition rate of mental health centers was associated with more utilization of professional mental health services (odds ratio [OR]=1.05, 95% confidence interval [CI]=1.03-1.07). CONCLUSIONS: Accessibility to professional mental health services could be improved depending on the general population's recognition and attitudes toward mental health centers. Therefore, health policy-makers need to plan appropriate strategies for changing the perception of mental health services and informing the public about both the benefits and functions of mental health centers.

Distinct pattern of immune tolerance in dendritic cells treated with lipopolysaccharide or lipoteichoic acid.

Cytokine induction is often critical for the host defense during acute immune responses while, if not tightly regulated, it may cause an immunological pathology coincident with tissue damage. Despite the fact that gram-positive bacterial infection has become increasingly prevalent, immune modulation induced by lipoteichoic acid (LTA), the major cell wall component of gram-positive bacteria has not been studied thoroughly at the cellular level. In the current study, tolerance induction in mouse bone marrow-derived dendritic cells (BMDCs) treated with single or repeated stimulation of Staphylococcus aureus LTA was compared with those of Escherichia coli lipopolysaccharide (LPS). The results showed that repeated LTA stimulation significantly suppressed pro-inflammatory cytokine (TNF-α and IL-6) production in BMDCs, comparable to that of LPS, but with less extent, down-regulated IL-10 and enhanced the inhibitory molecule, LAG-3-associated protein (LAP). Furthermore, we observed a sustained expression of unique negative regulators, Toll interacting protein (TOLLIP) and Indoleamine 2,3-dioxygenase (IDO), in BMDCs treated with LTA. A transient hyporesponsiveness period appeared when DCs were treated repeatedly with LTA or LPS showing a distinctive pattern. Intriguingly, LPS exposure induced cross tolerance to LTA while LTA exposure did not to LPS, implicating that a distinct signaling components are involved in response to LTA. Collectively, a distinct immune regulation appeared to be responsible for the LPS- and LTA-induced tolerance on cytokine production, expression of surface markers and intracellular proteins.

CD45-mediated control of TCR tuning in naïve and memory CD8+ T cells.

Continuous contact with self-major histocompatibility complex (MHC) ligands is essential for survival of naïve T cells but not memory cells. This surprising finding implies that T cell subsets may vary in their relative T-cell receptor (TCR) sensitivity. Here we show that in CD8+T cells TCR sensitivity correlates inversely with levels of CD5, a marker for strong self-MHC reactivity. We also show that TCR sensitivity is lower in memory CD8+ T cells than naïve cells. In both situations, TCR hypo-responsiveness applies only to short-term TCR signalling events and not to proliferation, and correlates directly with increased expression of a phosphatase, CD45 and reciprocal decreased expression of activated LCK. Inhibition by high CD45 on CD8+ T cells may protect against overt TCR auto-MHC reactivity, while enhanced sensitivity to cytokines ensures strong responses to foreign antigens.

Survival of porcine fibroblasts enhanced by human FasL and dexamethasone-treated human dendritic cells in vitro.

Cell-mediated and acute vascular rejections remain to be one of the primary hurdles to achieve successful xenotransplantation. Fas ligand is known to be an important molecule for the formation of 'immune-privileged' condition and dendritic cells treated with dexamethasone (Dex-DCs) acting like tolerogenic DCs (tDCs) which are known to protect transplanted cells and organs from unwanted immune responses. The present study investigated the possibility that porcine fibroblasts expressing human Fas ligand (PhF) together with human Dex-DCs could induce prolonged survival of porcine fibroblasts in vitro. PhF was collected from an ear of human Fas ligand transgenic porcine and cell-line was established by MGEM Inc. PhF labeled with CFSE co-cultured with human peripheral blood mononuclear cells (hPBMCs) were examined with respect to induction of tolerance and cell death when co-cultured with Dex-DCs for 3days. PhF induced the apoptosis in hPBMCs, especially CD4(+) T cells. Dex-DCs showed significant (P<0.05) reduction on the expression of CD80, CD86 and MHC class I/II, and the secretion of IL-12p70, TNF-α and IL-10, but increase of latency-associated peptide (LAP). Survival of PhF was significantly higher than that of WT and it was increased in the presence of Dex-DCs when compared to the other DCs (i.e.,DCs, LPS-treated DCs and LPS/Dex-treated DCs) in vitro. Survival of PhF did not change by co-culture with Dex-DCs due to apoptotic cell death of Dex-DCs. Dex-DCs reduced the death of porcine fibroblasts and, at the same time, PhF induced the apoptosis from hPBMCs, but it was not synergistic.