No abstract

The differentiation of stem cells into smooth muscle cells (SMCs) plays an important role in vascular development and remodeling. In addition, stem cells represent a potential source of SMCs for regenerative medicine applications such as constructing vascular grafts. Previous studies have suggested that various biochemical factors, including transforming growth factor-β (TGF-β) and the Notch pathway, may play important roles in vascular differentiation. However, the interactions of these two signaling pathways in the differentiation of bone marrow mesenchymal stem cells (MSCs) have not been clearly defined. In this study, we profiled the gene expression in MSCs in response to TGF-β, and showed that TGF-β induced Notch ligand Jagged 1 (JAG1) and SMC markers, including smooth muscle α-actin (ACTA2), calponin 1 (CNN1), and myocardin (MYOCD), which were dependent on the activation of SMAD3 and Rho kinase. In addition, knocking down JAG1 expression partially blocked ACTA2 and CNN1 expression and completely blocked MYOCD expression, suggesting that JAG1 plays an important role in TGF-β-induced expression of SMC markers. On the other hand, the activation of Notch signaling induced the expression of SMC markers in MSCs and human embryonic stem cells (hESCs). Notch activation in hESCs also resulted in an increase of neural markers and a decrease of endothelial markers. These results suggest that Notch signaling mediates TGF-β regulation of MSC differentiation and that Notch signaling induces the differentiation of MSCs and hESCs into SMCs, which represents a novel mechanism involved in stem cell differentiation.

Renal ischemia-reperfusion injury (IRI) after kidney transplantation is a major cause of delayed graft function. Even though IRI is recognized as a highly coordinated and specific process, the pathways and mechanisms through which the innate response is activated are poorly understood. In this study, we used a mouse model of acute kidney IRI to examine whether the interactions of costimulatory receptor CD137 and its ligand (CD137L) are involved in the early phase of acute kidney inflammation caused by IRI. We report here that the specific expressions of CD137 on natural killer cells and of CD137L on tubular epithelial cells (TECs) are required for acute kidney IRI. Reverse signaling through CD137L in TECs results in their production of the chemokine (C-X-C motif) receptor 2 ligands CXCL1 and CXCL2 and the subsequent induction of neutrophil recruitment, resulting in a cascade of proinflammatory events during kidney IRI. Our findings identify an innate pathogenic pathway for renal IRI involving the natural killer cell-TECneutrophil axis, whereby CD137-CD137L interactions provide the causal contribution of epithelial cell dysregulation to renal IRI. The CD137L reverse signaling pathway in epithelial cells therefore may represent a good target for blocking the initial stage of inflammatory diseases, including renal IRI.acute inflammation | costimulatory ligand

The aim of this study was to determine whether intra-amniotic infection/inflammation (IAI) was associated with subsequent ruptured membranes in women with preterm labor and intact membranes who had a clinically indicated amniocentesis. This retrospective cohort study included 237 consecutive women with preterm labor (20-34.6 weeks) who underwent amniocentesis. The clinical and laboratory parameters evaluated included demographic variables, gestational age, C-reactive protein (CRP) and amniotic fluid (AF) white blood cell, interleukin-6 (IL-6) and culture results. IAI was defined as a positive AF culture and/or an elevated AF IL-6 level (>2.6 ng/mL). The primary outcome was ruptured membranes in the absence of active labor occurring within 48 hours of amniocentesis. Preterm premature rupture of membranes subsequently developed in 10 (4.2%) women within 48 hr of amniocentesis. Multivariate analysis demonstrated that only IAI was independently associated with the ruptured membranes occurring within 48 hr of amniocentesis. In the predictive model based on variables assessed before amniocentesis, only CRP level was retained. IAI is an independent risk factor for subsequent ruptured membranes after clinically indicated amniocentesis in preterm labor. Prior to amniocentesis, measurement of serum CRP level can provide a risk assessment for the subsequent development of ruptured membranes after the procedure.

Toxoplasma gondii (T. gondii) microneme protein 8 (MIC8) represents a novel, functional distinct invasion factor. In this study, we generated virus-like particles (VLPs) targeting Toxoplasma gondii MIC8 for the first time, and investigated the protection against highly virulent RH strain of T. gondii in a mouse model. We found that VLP vaccination induced Toxoplasma gondii-specific IgG and IgG1 antibody responses in the sera. Upon challenge infection with RH strain of T. gondii tachyzoites, vaccinated mice showed a significant increase of both IgG antibodies in sera and IgA antibodies in feces compared to those before challenge, and a rapid expansion of both germinal center B cell (B220+, GL7+) and T cell (CD4+, CD8+) populations. Importantly, intranasally immunized mice showed higher neutralizing antibodies and displayed no proinflammatory cytokine IFN-γ in the spleen. Mice were completely protected from a lethal challenge infection with the highly virulent T. gondii (RH) showing no body weight loss (100% survival). Our study shows the effective protection against T. gondii infection provided by VLPs containing microneme protein 8 of T. gondii, thus indicating a potential T. gondii vaccine candidate.

Emerging research suggests overrepresentation of gender diversity among autistic youth. Previous gender diversity research with autistic children has relied on parent-report based on a single question. The Gender Diversity Screening Questionnaire–Self-Report and Parent-Report assessed gender diversity experiences from 244 children (140 autism spectrum disorder and 104 typically developing), between 10 and 13 years, and their parents. Parent-report Child Behavior Checklist Item-110, “Wishes to be the opposite sex,” was also collected. Autistic children endorsed higher Gender Diversity Screening Questionnaire–Self-Report Binary Gender Diversity, t(223.21) = –2.83, adjusted p = 0.02, d = –0.35, and Nonbinary Gender Diversity, t(191.15) = –3.79, adjusted p = 0.001, d = –0.46, than typically developing children. Similarly, for Gender Diversity Screening Questionnaire–Parent-Report, there was a significant gender-body incongruence difference between the groups, t(189.59) = –2.28, adjusted p = 0.05, d = –0.30. Within-group analyses revealed that parents of autistic females-assigned-at-birth reported significantly more gender-body incongruence than males-assigned-at-birth, t(32.91) = –3.78, p < 0.001, d = –1.11. Moreover, distinct within-group profiles of gender experiences and internalizing symptoms were revealed, showing associations between gender profiles and symptoms of anxiety, depression, and suicidality. Results extend reports showing increased rates of gender diversity in autistic children based on both self-report and parent-report, underscoring the need to better understand and support the unique and complex needs of autistic children who experience gender diversity. Lay abstract Gender diversity broadly refers to the way in which an individual experiences (expressions and/or identities) their gender distinctly to that which would be expected based upon social norms for their gender assigned at birth. Recent research has shown a higher representation of gender diversity among autistic youth. Previous research in this area has relied on parent-report based on a single question from the Child Behavior Checklist Item-110, asking whether their child “Wishes to be the opposite sex.” The Gender Diversity Screening Questionnaire Self-Report and Parent-Report were used to assess the experience of gender diversity in 244 children (140 autism spectrum disorder and 104 typically developing) between 10 and 13 years. The Item-110 was also collected. Results showed that autistic children endorsed much higher rates of Binary Gender Diversity (less identification with their designated sex and more with the other binary sex) and Nonbinary Gender Diversity (identification as neither male nor female) than typically developing children. Similarly, parents of autistic children reported significantly more gender-body incongruence experienced by their child than parents of typically developing children. Specifically, parents of autistic females-assigned-at-birth reported significantly more gender-body incongruence than autistic males-assigned-at-birth. Parent- and self-report measures were largely related. Moreover, statistical comparisons between and within the groups revealed associations between gender profiles and symptoms of anxiety, depression, and suicidality. Results extend previous reports showing increased rates of gender diversity in autistic children, now based on both self-report and parent-report, and highlight the need to better understand and support the unique and complex needs of autistic children who experience gender diversity.

Sensitivity to noise, particularly road traffic noise, can increase cortisol levels and result in changes in immune system biomarkers. Therefore, continuous exposure to noise can have an effect on immune function, hormonal levels, and cardiovascular function, leading to hypertension and stress. The purpose of this study was to investigate the changes in stress-and immune system-related biomarkers according to the self-reported sensitivity to noise and exposure to road traffic noise, to ultimately determine the potential effects of noise on health. A survey was conducted through questionnaire (ISO/TS 15666) sent to 172 female subjects in Korea, including 128 from Ulsan and 44 from Seoul. The average noise level was calculated, and blood samples were collected for measurements of cortisol levels, Natural killer (NK) / Natural killer T (NKT) cell populations, and NK cell activity (through measurements of interleukin-12 (IL-12) and interferon-gamma (INF-γ) concentrations). Multivariate linear regression analysis of the measured biomarkers according to the road traffic noise level and self-reported noise sensitivity was conducted adjusting for the effects of age, alcohol status, smoking status, regular exercise, and residence period. IL-12 levels increased, whereas the NKT cell population decreased with increasing noise levels. The results further suggested that cortisol levels are more influenced by the subject’s sensitivity to noise than to the level of chronic road traffic noise. Therefore, noise appears to have the largest effect on IL-12 levels as well as the population and activity of NKT cells. In conclusion, our results suggest that low-level road traffic noise and sensitivity to noise can affect health by causing changes in the immune response through mechanisms other than increased cortisol.

Maternal neutrophil-to-lymphocyte ratio, parity, and birth weight can independently predict the risk of NEC in very preterm infants, whereas clinical and histological chorioamnionitis and funisitis are not predictive of NEC.