Feynman Rules in the Type III Natural Flavour-Conserving Two-Higgs Doublet Model

We consider a two Higgs-doublet model with $S_3$ symmetry, which implies a $\pi \over 2$ rather than 0 relative phase between the vacuum expectation values $$and$$. The corresponding Feynman rules are derived accordingly and the transformation of the Higgs fields from the weak to the mass eigenstates includes not only an angle rotation but also a phase transformation. In this model, both doublets couple to the same type of fermions and the flavour-changing neutral currents are naturally suppressed. We also demonstrate that the Type III natural flavour-conserving model is valid at tree-level even when an explicit $S_3$ symmetry breaking perturbation is introduced to get a reasonable CKM matrix. In the special case $\beta = \alpha$, as the ratio $\tan\beta = {v_2 \over v_1}$ runs from 0 to $\infty$, the dominant Yukawa coupling will change from the first two generations to the third generation. In the Feynman rules, we also find that the charged Higgs currents are explicitly left-right asymmetric. The ratios between the left- and right-handed currents for the quarks in the same generations are estimated.Comment: 16 pages (figures not included), NCKU-HEP/93-1

Is there a role for glucocorticoid receptor beta in asthma?

Glucocorticoids (GCs) are routinely used as anti-inflammatory drugs in the treatment of asthma. They act through binding to glucocorticoid receptor α (GRα), which represses numerous genes encoding pro-inflammatory mediators. A hormone binding deficient GR isoform named GRβ has been isolated in humans. When overexpressed by transfection, GRβ may function as a dominant negative modulator of GRα. However, to act as such, GRβ has to be more abundant than GRα, and conflicting data have been obtained concerning the relative levels of the two isoforms in cell lines and freshly isolated cells. Moreover, the dominant negative effect was not confirmed by independent laboratories. In GC-resistant asthmatics, GRβ was expressed by an increased number of peripheral blood mononuclear cells (PBMCs), airway T cells, and cells found in skin biopsies of tuberculin responses. However, the relative amounts of GRα and GRβ in these cells were not determined. In GC-dependent asthmatics, PBMCs expressed GRα predominantly. No cells containing higher levels of GRβ than GRα have yet been reported in asthmatics. Even if the existence of such cells is demonstrated, the role of GRβ in asthma will remain a matter of controversy because functional studies have given discrepant data

Research Recommendations Following the Discovery of Pain Sensitizing IgG Autoantibodies in Fibromyalgia Syndrome

BACKGROUND: Fibromyalgia syndrome (FMS) is the most common chronic widespread pain condition in rheumatology. Until recently, no clear pathophysiological mechanism for fibromyalgia had been established, resulting in management challenges. Recent research has indicated that serum IgGs may play a role in FMS. We undertook a research prioritisation exercise to identify the most pertinent research approaches that may lead to clinically implementable outputs. METHODS: Research priority setting was conducted in five phases: situation analysis; design; expert group consultation; interim recommendations; consultation and revision. A dialogue model was used, and an international multi-stakeholder expert group was invited. Clinical, patient, industry, funder, and scientific expertise was represented throughout. Recommendation-consensus was determined via a voluntary closed eSurvey. Reporting guideline for priority setting of health research were employed to support implementation and maximise impact. RESULTS: Arising from the expert group consultation (n = 29 participants), 39 interim recommendations were defined. A response rate of 81.5% was achieved in the consensus survey. Six recommendations were identified as high priority- and 15 as medium level priority. The recommendations range from aspects of fibromyalgia features that should be considered in future autoantibody research, to specific immunological investigations, suggestions for trial design in FMS, and therapeutic interventions that should be assessed in trials. CONCLUSIONS: By applying the principles of strategic priority setting we directed research towards that which is implementable, thereby expediating the benefit to the FMS patient population. These recommendations are intended for patients, international professionals and grant-giving bodies concerned with research into causes and management of patients with fibromyalgia syndrome

Agent based modelling helps in understanding the rules by which fibroblasts support keratinocyte colony formation

Background: Autologous keratincoytes are routinely expanded using irradiated mouse fibroblasts and bovine serum for clinical use. With growing concerns about the safety of these xenobiotic materials, it is desirable to culture keratinocytes in media without animal derived products. An improved understanding of epithelial/mesenchymal interactions could assist in this. Methodology/Principal Findings: A keratincyte/fibroblast o-culture model was developed by extending an agent-based keratinocyte colony formation model to include the response of keratinocytes to both fibroblasts and serum. The model was validated by comparison of the in virtuo and in vitro multicellular behaviour of keratinocytes and fibroblasts in single and co-culture in Greens medium. To test the robustness of the model, several properties of the fibroblasts were changed to investigate their influence on the multicellular morphogenesis of keratinocyes and fibroblasts. The model was then used to generate hypotheses to explore the interactions of both proliferative and growth arrested fibroblasts with keratinocytes. The key predictions arising from the model which were confirmed by in vitro experiments were that 1) the ratio of fibroblasts to keratinocytes would critically influence keratinocyte colony expansion, 2) this ratio needed to be optimum at the beginning of the co-culture, 3) proliferative fibroblasts would be more effective than irradiated cells in expanding keratinocytes and 4) in the presence of an adequate number of fibroblasts, keratinocyte expansion would be independent of serum. Conclusions: A closely associated computational and biological approach is a powerful tool for understanding complex biological systems such as the interactions between keratinocytes and fibroblasts. The key outcome of this study is the finding that the early addition of a critical ratio of proliferative fibroblasts can give rapid keratinocyte expansion without the use of irradiated mouse fibroblasts and bovine serum

Family History of Alcoholism and Childhood Adversity: Joint Effects on Alcohol Consumption and Dependence

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65494/1/j.1530-0277.1994.tb00085.x.pd

Transcriptional Changes in Schistosoma mansoni during Early Schistosomula Development and in the Presence of Erythrocytes

Schistosome blood flukes cause more mortality and morbidity than any other human worm infection, but current control methods primarily rely on a single drug. There is a desperate need for new approaches to control this parasite, including vaccines. People become infected when the free-swimming larva, the cercaria, enters through the skin and becomes the schistosomulum. Schistosomula are susceptible to immune responses during their first few days in the host before they become adult parasites. We characterised the genes that these newly transformed parasites switch on when they enter the host to identify molecules that are critical for survival in the human host. Some of these highly up-regulated genes can be targeted for future development of new vaccines and drugs

Minicircle-oriP-IFNγ: A Novel Targeted Gene Therapeutic System for EBV Positive Human Nasopharyngeal Carcinoma

) in which the transgene expression was under the transcriptional regulation of oriP promoter.. Immunohistochemistry was used to detect the expression and the activity of the IFNγ in tumor sections. Our results demonstrated that mc-oriP vectors mediated comparable gene expression and anti-proliferative effect in the EBV-positive NPC cell line C666-1 compared to mc-CMV vectors. Furthermore, mc-oriP vectors exhibited much lower killing effects on EBV-negative cell lines compared to mc-CMV vectors. The targeted expression of mc-oriP vectors was inhibited by EBNA1-siRNA in C666-1. This selective expression was corroborated in EBV-positive and -negative tumor models. as a safe and highly effective targeted gene therapeutic system for the treatment of EBV positive NPC

Selected sociodemographic factors and related differences in patterns of alcohol use among university students in Slovakia

Background: Alcohol use and misuse and their relation to sociodemograhic factors are well studied among university students in Western European countries and the USA, but less is known about students in Eastern Europe. The historical past as communistic countries might have affected the social life among these populations, which is again one of the main factors determining the alcohol consumption among university students. The aim of our study was to assess the association of selected sociodemographic factors with different patterns of alcohol use among university students in Slovakia. Methods: A sample of 813 young adults (mean age 21.1 years, 63.8% females; response rate of 71%) from four universities in Kosice answered questions about their sociodemographic background and about alcohol use. To obtain a detailed picture of different aspects, alcohol use was measured by four variables: frequency of alcohol use, heavy episodic drinking, frequency of drunkenness and problem drinking. Four separate logistic regression models were used to assess the association between sociodemographic and alcohol-related variables. To assess the potentially different effects in both genders, all two-way interactions with gender were tested. Results: While 41% of the students drank alcohol once a week or more often, 77% reported heavy episodic drinking and 49% had been drunk more than once in the last month. Problem drinking existed in 23.3% of the sample. Gender was consistently associated with all four alcohol-related variables, with males being at higher risk. A higher study year was associated only with lower levels of heavy episodic drinking, but displayed no association with the other studied variables. Living with parents during the semester was consistently associated with less frequent heavy episodic drinking, drunkenness episodes, and problem drinking while having an intimate relationship was associated with less problem drinking only. Conclusions: Our findings for the university students from Slovakia are in line with previous studies in Western Europe. Additionally, it appears that frequent alcohol use, excessive alcohol use (heavy episodic drinking and drunkenness) and problem drinking among university students represent a continuum and are influenced by the same sociodemographic factors

Pro-asthmatic cytokines regulate unliganded and ligand-dependent glucocorticoid receptor signaling in airway smooth muscle

To elucidate the regulation of glucocorticoid receptor (GR) signaling under pro-asthmatic conditions, cultured human airway smooth muscle (HASM) cells were treated with proinflammatory cytokines or GR ligands alone and in combination, and then examined for induced changes in ligand-dependent and -independent GR activation and downstream signaling events. Ligand stimulation with either cortisone or dexamethsone (DEX) acutely elicited GR translocation to the nucleus and, comparably, ligand-independent stimulation either with the Th2 cytokine, IL-13, or the pleiotropic cytokine combination, IL-1β/TNFα, also acutely evoked GR translocation. The latter response was potentiated by combined exposure of cells to GR ligand and cytokine. Similarly, treatment with either DEX or IL-13 alone induced GR phosphorylation at its serine-211 residue (GRSer211), denoting its activated state, and combined treatment with DEX+IL-13 elicited heightened and sustained GRSer211phosphorylation. Interestingly, the above ligand-independent GR responses to IL-13 alone were not associated with downstream GR binding to its consensus DNA sequence or GR transactivation, whereas both DEX-induced GR:DNA binding and transcriptional activity were significantly heightened in the presence of IL-13, coupled to increased recruitment of the transcriptional co-factor, MED14. The stimulated GR signaling responses to DEX were prevented in IL-13-exposed cells wherein GRSer211 phosphorylation was suppressed either by transfection with specific serine phosphorylation-deficient mutant GRs or treatment with inhibitors of the MAPKs, ERK1/2 and JNK. Collectively, these novel data highlight a heretofore-unidentified homeostatic mechanism in HASM cells that involves pro-asthmatic cytokine-driven, MAPK-mediated, non-ligand-dependent GR activation that confers heightened glucocorticoid ligand-stimulated GR signaling. These findings raise the consideration that perturbations in this homeostatic cytokine-driven GR signaling mechanism may be responsible, at least in part, for the insensirtivity to glucocorticoid therapy that is commonly seen in individuals with severe asthma