The Role of the NHERF-1 and NHERF-2 Adapter Proteins in Intestinal Ion Transport Regulation

The chloride channel CFTR (cystic fibrosis transmembrane conductance regulator) and the sodium/proton exchanger NHE3 are key proteins involved in transepithelial ion and water transport in several epithelial tissues, including the intestine. In this thesis we mainly focus on the role of the NHERF (NHE3 Regulatory Factor) proteins as regulators of CFTR and NHE3 activity. In chapter 2 we show that cAMP- and cGMP-dependent activation of CFTR was moderately reduced in the duodenum and jejunum (but not in ileum) of NHERF-1 deficient mice. This reduced activation of CFTR in may be explained by the ~30% reduced local abundance of CFTR protein in the jejunal crypts of the NHERF-1 deficient mice. As shown in chapter 3, the basal NHE3 activity was decreased in the jejunum and colon of NHERF-1 null mice. In addition, NHERF-1 deficient mice displayed a reduced sodium absorption in the jejunum. These observations may be explained by the reduced NHE3 protein level in the brush border membrane fraction of jejunum and colon of these mice. The cAMP- and/or cGMP dependent inhibition of NHE3 was not appreciably affected in NHERF-1 deficient mice. As described in chapter 4, NHERF-1 and/or NHERF-2 gene knockdown in polarized epithelial cells indicated that NHERF-2 is required for cGKII-dependent regulation of NHE3, but not of CFTR. An overview of the proteome of the jejunal brush border of the mouse is presented in chapter 5. Finally, chapter 6 shows that the glial fibrillary acidic protein (GFAP) is a specific binding partner for cGKII. cGKII was able to phosphorylate GFAP in vitro and expression of active cGKII in cultured glioblastoma cells increased GFAP abundance. We propose that cGKII-mediated phosphorylation of GFAP results in a more stable configuration and a prolonged half-life of this protein

Recent Results on Lead-Ion Accumulation in LEAR for the LHC

To prepare dense bunches of lead ions for the LHC it has been proposed to accumulate the 4.2 MeV/u linac beam in a storage ring with electron cooling. A series of experiments is being performed in the low-energy ring LEAR to test this technique. First results were already reported at the Beam Crystallisation Workshop in Erice in November 1995. Two more recent runs to complement these investigations were concerned with: further study of the beam lifetime; the dependence of the cooling time on optical settings of the storage ring and on neutralization of the electron beam; tests in view of multiturn injection. New results obtained in these two runs in December 1995 and in April 1996 will be discussed in this contribution

To respond or not to respond - a personal perspective of intestinal tolerance

For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research

Status of Muon Collider Research and Development and Future Plans

The status of the research on muon colliders is discussed and plans are outlined for future theoretical and experimental studies. Besides continued work on the parameters of a 3-4 and 0.5 TeV center-of-mass (CoM) energy collider, many studies are now concentrating on a machine near 0.1 TeV (CoM) that could be a factory for the s-channel production of Higgs particles. We discuss the research on the various components in such muon colliders, starting from the proton accelerator needed to generate pions from a heavy-Z target and proceeding through the phase rotation and decay ($\pi \to \mu \nu_{\mu}$) channel, muon cooling, acceleration, storage in a collider ring and the collider detector. We also present theoretical and experimental R & D plans for the next several years that should lead to a better understanding of the design and feasibility issues for all of the components. This report is an update of the progress on the R & D since the Feasibility Study of Muon Colliders presented at the Snowmass'96 Workshop [R. B. Palmer, A. Sessler and A. Tollestrup, Proceedings of the 1996 DPF/DPB Summer Study on High-Energy Physics (Stanford Linear Accelerator Center, Menlo Park, CA, 1997)].Comment: 95 pages, 75 figures. Submitted to Physical Review Special Topics, Accelerators and Beam

‘Trust me I am a Football Agent’. The discursive practices of the players’ agents in (un)professional football

While the public and media attention is largely focused on the corruption scandals of high-ranking officials in international football, FIFA’s decision in April 2015 to deregulate football agents raises further concerns about its ability for self-regulation and governance. FIFA’s introduction (2006) and subsequent updating (2008, 2015) of its regulations and legal frameworks governing the activity of agents in professional football has important implications on the inner workings of international football. In this regard, FIFA’s decision to deregulate the industry is perhaps a reflection of the neoliberal influences surrounding the organisation to let the agents govern themselves and deal with the wrongdoings of the alleged bribery, exploitation and trafficking of young players. However, the deregulation of agents by FIFA can also be seen as the organisation’s inefficiency to maintain the primacy of self-regulation and self-governance in serious matters of the industry, such as agents’ global leadership and regulation of practices. This paper, using qualitative data collected from players, agents and managers from professional football leagues in the UK and Ireland, aims to uncover the unethical, extremely complex and deceptive sides of the agents’ industry. By doing so, it aims to emphasise the need for gold standards of practice and leadership in the regulation of international football, which desperately needs to restore its integrity. Two key issues are unpacked: (i) the alleged (un)ethical behaviour of football agents that provokes so much hostility in the football world; (ii) the power shift(s) from clubs and managers to agents and players and the implications these may have on the ethics of the business practices in football

Системный анализ процесса затвердевания литых заготовок разной массы и назначения

Выявлены особенности пространственно-временной эволюции температурных полей в процессе затвердевания разных заготовок (слитков и отливок) для повышения их качества.Виявлено особливості просторово-часової еволюції температурних полів в процесі тверднення різних заготовок (зливків та виливків) для підвищення їх якості.It is revealed the peculiarities of distance-time evolution of the temperature fields in solidification process different billets (ingots and casts) for raise them quality

Intranasal Delivery of E-Selectin Reduces Atherosclerosis in ApoE−/− Mice

Mucosal tolerance to E-selectin prevents stroke and protects against ischemic brain damage in experimental models of stroke studying healthy animals or spontaneously hypertensive stroke-prone rats. A reduction in inflammation and neural damage was associated with immunomodulatory or “tolerogenic” responses to E-selectin. The purpose of the current study on ApoE deficient mice is to assess the capacity of this stroke prevention innovation to influence atherosclerosis, a major underlying cause for ischemic strokes; human E-selectin is being translated as a potential clinical prevention strategy for secondary stroke. Female ApoE−/− mice received intranasal delivery of E-selectin prior to (pre-tolerization) or simultaneously with initiation of a high-fat diet. After 7 weeks on the high-fat diet, lipid lesions in the aorta, serum triglycerides, and total cholesterol were assessed as markers of atherosclerosis development. We also assessed E-selectin-specific antibodies and cytokine responses, in addition to inflammatory responses that included macrophage infiltration of the aorta and altered gene expression profiles of aortic mRNA. Intranasal delivery of E-selectin prior to initiation of high-fat chow decreased atherosclerosis, serum total cholesterol, and expression of the leucocyte chemoattractant CCL21 that is typically upregulated in atherosclerotic lesions of ApoE−/− mice. This response was associated with the induction of E-selectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes. Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke. These results provide additional preclinical support for the potential of induction of mucosal tolerance to E-selectin to prevent stroke

Gut mucosal DAMPs in IBD: From mechanisms to therapeutic implications

Endogenous damage-associated molecular patterns (DAMPs) are released during tissue damage and have increasingly recognized roles in the etiology of many human diseases. The inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn’s disease (CD), are immune-mediated conditions where high levels of DAMPs are observed. DAMPs such as calprotectin (S100A8/9) have an established clinical role as a biomarker in IBD. In this review, we use IBD as an archetypal common chronic inflammatory disease to focus on the conceptual and evidential importance of DAMPs in pathogenesis and why DAMPs represent an entirely new class of targets for clinical translation. </p