Runx1 and Runx3 Are Involved in the Generation and Function of Highly Suppressive IL-17-Producing T Regulatory Cells

CD4+Foxp3+ T regulatory cells (Tregs) display phenotypic and functional plasticity that is regulated by cytokines and other immune cells. Previously, we determined that during co-culture with CD4+CD25− T cells and antigen presenting cells, Tregs produced IL-17. Here, we investigated the mechanisms underlying the differentiation of IL-17-producing Treg (Tr17) cells and their molecular and functional properties. We determined that during stimulation via TCR/CD3 and CD28, the combination of IL-1β and IL-2 was necessary and sufficient for the generation of Tr17 cells. Tr17 cells expressed Runx1 transcription factor, which was required for sustained expression of Foxp3 and RORγt and for production of IL-17. Surprisingly, Tr17 cells also expressed Runx3, which regulated transcription of perforin and granzyme B thereby mediating cytotoxic activity. Our studies indicate that Tr17 cells concomitantly express Foxp3, RORγt, Runx1 and Runx3 and are capable of producing IL-17 while mediating potent suppressive and cytotoxic function

Obesity in Pregnancy – Implications on Pregnancy Events

BACKGROUND: Overweight and obesity are serious health problems in most developed countries. The percentage of young women with excessive weight who get pregnant continues to grow every year. This raises a concern about the risks of the mother and the baby during pregnancy and after birth. AIM: This study aims to determine health risk for overweight mothers and especially the risk for preterm birth. MATERIALS AND METHODS: This is a prospective and retrospective study taking place in the outpatient clinic of the University Hospital “Maichin Dom”. Our study included 105 pregnant women with BMI ≥25 kg/m2 as a case group and 91 pregnant women with BMI within normal limits as a control group. RESULTS: Mean BMI in the case group was 34.79 ± 3.71 kg/m2 and 20.20 ± 2.24 kg/m2 in the control group. Among 105 women in the case group, we registered 24.8% (n = 26) who gave birth before term. Preterm births among 91 women in the control group were registered in 17.6% (n = 16) patients. We found a significant correlation between increased BMI and the risk of increased systolic and diastolic blood pressure. Moreover, we found comorbidities in 43.8% of cases and 24.2% of controls. CONCLUSION: Maternal overweight and obesity during pregnancy are associated with increased risks of preterm delivery and complications of pregnancy. Extra efforts should be made to help women lose weight before this important period of life

Evidence on the extent of harms experienced by children as a result of online risks: Implications for policy and research

This is an Accepted Manuscript of an article published by Taylor & Francis in Information, Communication and Society on 8/7/2014, available online: http://wwww.tandfonline.com/10.1080/1369118X.2014.934387Intense media and policy focus on issues of online child protection have prompted a resurgence of moral panics about children and adolescents' Internet use, with frequent confounding of different types of risk and harm and little reference to empirical evidence of actual harm. Meanwhile, within the academic literature, the quantity and quality of studies detailing the risks and opportunities of online activity for children and young people has risen substantially in the past 10 years, but this is also largely focused on risk rather than evidence of harm. Whilst this is understandable given the methodological and ethical challenges of studying Internet-related harms to minors, the very concept of risk is dependent on some prior understanding of harm, meaning that without efforts to study what harms are connected with children's online experiences, discussions of risk lack a strong foundation. This article makes a key contribution to the field by reviewing available evidence about the scale and scope of online harms from across a range of disciplines and identifying key obstacles in this research area as well as the major policy implications. The findings are based on a review of 148 empirical studies. Results were found in relation to main types of harms: health-related harms as a result of using pro-eating disorder, self-harm or pro-suicide websites; sex-related harms such as Internet-initiated sexual abuse of minors and cyber-bullying

Predictive imaging of chemotherapeutic response in a transgenic mouse model of pancreatic cancer: Imaging of Chemotherapeutic Response

The underglycosylated mucin 1 tumor antigen (uMUC1) is a biomarker that forecasts the progression of adenocarcinomas. In this study, we evaluated the utility of a dual-modality molecular imaging approach based on targeting uMUC1 for monitoring chemotherapeutic response in a transgenic murine model of pancreatic cancer (KCM triple transgenic mice). An uMUC1-specific contrast agent (MN-EPPT) was synthesized for use with magnetic resonance imaging (MRI) and fluorescence optical imaging. It consisted of dextran-coated iron oxide nanoparticles conjugated to the near infrared fluorescent dye Cy5.5 and to a uMUC1-specific peptide (EPPT). KCM triple transgenic mice were given gemcitabine as chemotherapy while control animals received saline injections following the same schedule. Changes in uMUC1 levels following chemotherapy were monitored using T2-weighted MRI and optical imaging before and 24 hr after injection of the MN-EPPT. uMUC1 expression in tumors from both groups was evaluated by histology and qRT-PCR. We observed that the average delta-T2 in the gemcitabine-treated group was significantly reduced compared to the control group indicating lower accumulation of MN-EPPT, and correspondingly, a lower level of uMUC1 expression. In vivo optical imaging confirmed the MRI findings. Fluorescence microscopy of pancreatic tumor sections showed a lower level of uMUC1 expression in the gemcitabine-treated group compared to the control, which was confirmed by qRT-PCR. Our data proved that changes in uMUC1 expression after gemcitabine chemotherapy could be evaluated using MN-EPPT-enhanced in vivo MR and optical imaging. These results suggest that the uMUC1-targeted imaging approach could provide a useful tool for the predictive assessment of therapeutic response

Prognostic impact of acute pulmonary triggers in patients with takotsubo syndrome: new insights from the International Takotsubo Registry

AIMS Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes. METHODS AND RESULTS Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes. Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In-hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long-term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long-term mortality (hazard ratio 2.12, 95% confidence interval 1.33-3.38; P = 0.002). CONCLUSIONS The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in-hospital course and a worse long-term outcome

PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation

During activation, T cells undergo metabolic reprogramming, which imprints distinct functional fates. We determined that on PD-1 ligation, activated T cells are unable to engage in glycolysis or amino acid metabolism but have an increased rate of fatty acid β-oxidation (FAO). PD-1 promotes FAO of endogenous lipids by increasing expression of CPT1A, and inducing lipolysis as indicated by elevation of the lipase ATGL, the lipolysis marker glycerol and release of fatty acids. Conversely, CTLA-4 inhibits glycolysis without augmenting FAO, suggesting that CTLA-4 sustains the metabolic profile of non-activated cells. Because T cells utilize glycolysis during differentiation to effectors, our findings reveal a metabolic mechanism responsible for PD-1-mediated blockade of T-effector cell differentiation. The enhancement of FAO provides a mechanistic explanation for the longevity of T cells receiving PD-1 signals in patients with chronic infections and cancer, and for their capacity to be reinvigorated by PD-1 blockade

Happiness around the world: A combined etic-emic approach across 63 countries.

What does it mean to be happy? The vast majority of cross-cultural studies on happiness have employed a Western-origin, or "WEIRD" measure of happiness that conceptualizes it as a self-centered (or "independent"), high-arousal emotion. However, research from Eastern cultures, particularly Japan, conceptualizes happiness as including an interpersonal aspect emphasizing harmony and connectedness to others. Following a combined emic-etic approach (Cheung, van de Vijver & Leong, 2011), we assessed the cross-cultural applicability of a measure of independent happiness developed in the US (Subjective Happiness Scale; Lyubomirsky & Lepper, 1999) and a measure of interdependent happiness developed in Japan (Interdependent Happiness Scale; Hitokoto & Uchida, 2015), with data from 63 countries representing 7 sociocultural regions. Results indicate that the schema of independent happiness was more coherent in more WEIRD countries. In contrast, the coherence of interdependent happiness was unrelated to a country's "WEIRD-ness." Reliabilities of both happiness measures were lowest in African and Middle Eastern countries, suggesting these two conceptualizations of happiness may not be globally comprehensive. Overall, while the two measures had many similar correlates and properties, the self-focused concept of independent happiness is "WEIRD-er" than interdependent happiness, suggesting cross-cultural researchers should attend to both conceptualizations

Neonatal Fc Receptor: From Immunity to Therapeutics

The neonatal Fc receptor (FcRn), also known as the Brambell receptor and encoded by Fcgrt, is a MHC class I like molecule that functions to protect IgG and albumin from catabolism, mediates transport of IgG across epithelial cells, and is involved in antigen presentation by professional antigen presenting cells. Its function is evident in early life in the transport of IgG from mother to fetus and neonate for passive immunity and later in the development of adaptive immunity and other functions throughout life. The unique ability of this receptor to prolong the half-life of IgG and albumin has guided engineering of novel therapeutics. Here, we aim to summarize the basic understanding of FcRn biology, its functions in various organs, and the therapeutic design of antibody- and albumin-based therapeutics in light of their interactions with FcRn