3,125 research outputs found
Conditional immortalization of human B cells by CD40 ligation
No full textIt is generally assumed that human differentiated cells have a limited life-span and proliferation capacity in vivo, and that genetic modifications are a prerequisite for their immortalization in vitro. Here we readdress this issue, studying the long-term proliferation potential of human B cells. It was shown earlier that human B cells from peripheral blood of healthy donors can be efficiently induced to proliferate for up to ten weeks in vitro by stimulating their receptor CD40 in the presence of interleukin-4. When we applied the same stimuli under conditions of modified cell number and culture size, we were surprised to find that our treatment induced B cells to proliferate throughout an observation period of presently up to 1650 days, representing more than 370 population doublings, which suggested that these B cells were immortalized in vitro. Long-term CD40-stimulated B cell cultures could be established from most healthy adult human donors. These B cells had a constant phenotype, were free from Epstein-Barr virus, and remained dependent on CD40 ligation. They had constitutive telomerase activity and stabilized telomere length. Moreover, they were susceptible to activation by Toll-like receptor 9 ligands, and could be used to expand antigen-specific cytotoxic T cells in vitro. Our results indicate that human somatic cells can evade senescence and be conditionally immortalized by external stimulation only, without a requirement for genetic manipulation or oncoviral infection. Conditionally immortalized human B cells are a new tool for immunotherapy and studies of B cell oncogenesis, activation, and function
Application of the IS-MP-IA model to the German economy and policy implications
No full textExtending the IS-MP-IA model developed by Romer (2000) and applying the GARCH (Engle, 1982, 2001) methodology, the author finds that equilibrium GDP in Germany is positively affected by stock market performance and real exchange rate appreciation, and negatively influenced by the expected inflation rate, the government deficit/GDP ratio, and the U.S. federal funds rate. The relatively low deficit/GDP ratio of 1.83% in 2003 indicates that its fiscal condition was healthy. However, some other EU members may need to exercise fiscal discipline. Because real appreciation has a positive impact on output, a stronger euro may not be a concern for Germany but may be worried by those EU member nations which depend upon exports to stimulate their economies.
Immune response to different sequences of the EBNA I molecule in Epstein-Barr virus-related disorders and in autoimmune diseases
No full textEpstein-Barr virus (EBV) infection is associated with production of autoantibodies. The N-terminal 35-58 sequence of EBNA I, one of the nuclear antigens encoded by EBV, is highly homologous to the C-terminal 95-119 region of the ribonucleoprotein SmD. Autoantibodies specific for SmD are present only in systemic lupus (SLE) sera and are therefore considered a serological marker of SLE. We measured antibodies to the EBNA I 35-58 sequence in EBV-related diseases and in autoimmune disorders. Antibodies to the EBNA I 35-58 peptide were present in 30% of normal sera, 12% Burkitt lymphoma, 22% infectious mononucleosis, 25% rheumatoid arthritis, 38% SLE and 33% Sjogren's syndrome. Antibodies to the SmD 95-119 peptide were detectable in 32% of SLE sera, 17% infectious mononucleosis and 12% Burkitt lymphoma. The specificity of anti-EBNA I 35-58 antibodies affinity-purified from nine sera was analysed by means of an inhibition assay. Only anti-EBNA I 35-58 antibodies affinity-purified from SLE sera have a similar affinity for the viral peptide and the SmD C-terminal one; they also bind the recombinant SmD in western blot. The results indicate that antibodies to EBNA I 35-58 are produced in normals, in EBV-related diseases and in autoimmune disorder, but only SLE sera contain anti-viral antibodies cross-reactive with an autoantigen
Winning redefined, a new brand positioning for MP Motorsport
No full textMP Motorsport is a talent educating race team participating in the classes below the Formula 1. The problem with the lower classes and therefore MP Motorsport as well is that these classes don’t get much attention and exposure. As a company run by people with passion the branding and positioning is more something that naturally emerged from this passion rather than a series of conscious decisions. This makes it fragile. A more conscious strategy and vision on how MP Motorsport needs to be branded and positioned against their competition that is more than “look how cool racing is” is needed to become more attractive for sponsoring. This report describes the process from analysis to finding the right positioning and an advise for a new brand identity and an implementation plan to help becoming more attractive for sponsoring goals. The analysis done with employees showed a unique characteristic that will help the team to position themselves against the competition; the family atmosphere. This atmosphere is what also characterises their contradictory personality. This personality is on one hand leading and ambitious and on the other hand modest and involved. Competition and stakeholder analysis have been performed to find the right combination of being unique to the competition, desirable for the stakeholders (the fans and sponsors) and builds upon the core strengths of the company. Then using the brand key model, a positioning is made with the essence: Be your best self. The belief, “in everyone hides a talent” and values like “everyone is equal” and “together we succeed” combined with the essence and the positioning resulted in a brand story that describes the feeling MP Motorsport wants to communicate. To manifestate the brand, an advise has been set up for a tone of voice and tone of image. Wrapped in a concept called “winning redefined” this advise is part of the whole implementation plan that should lead the way for the team to implement the newly created brand in short and long term actions. In 3 phases MP Motorsport is advised to start with a clear brand introduction to the target groups Gen Z and potential sponsors. The next phase revolves around creating a community to attract both Gen Z talents and subsequently sponsors to interact with the team and each other. Finally the last phase is long term focused and aims for sustainable growth. In this phase the community is established and can expect various opportunities to discover and develop a whole range of talents, sponsors and gen z are connected to each other via MP Motorsport and the team is able to finance the lower classes without the pressure of the money drivers bring along.Strategic Product Desig
Derivations (MP) and Evaluations (OT)
No full textThe main claim of this paper is that the minimalist framework and optimality theory adopt more or less the same architecture of grammar: both assume that a generator defines a set S of potentially well-formed expressions that can be generated on the basis of a given input, and that there is an evaluator that selects the expressions from S that are actually grammatical in a given language L. The paper therefore proposes a model of grammar in which the strengths of the two frameworks are combined: more specifically, it is argued that the computational system of human language CHL from MP creates a set S of potentially well-formed expressions, and that these are subsequently evaluated in an optimality theoretic fashion.The definitive version of this paper is published in Linguistics in Potsdam 25 (2006).Broekhuis, H. (2006). Derivations (MP) and Evaluations (OT)*. In H. Broekhuis & R. Vogel (Eds), Linguistics in Potsdam 25. Optimality Theory and Minimalism: A possible Convergence? Potsdam : Universitätsverlag PotsdamISBN: 9783939469544 (published book)This research is supported by the Netherlands Organisation of Scientific Research (NWO), grant 276-70-00
Epstein-Barr virus and multiple sclerosis
No full textThis review of the considerable evidence linking EpsteineBarr virus (EBV) infection to risk and disease progression in multiple sclerosis (MS) builds on the background to the virus and its interactions with the human host available in the online supplement (see supplement, available online only). The evidence for a similarity in the geographic patterns of occurrence of MS and EBV infection (with infectious mononucleosis or EBV specific serology used as surrogate markers), when reviewed critically, is very limited. There is strong evidence however that people with MS are more likely to report a past history of infectious mononucleosis (thought to represent initial EBV infection at an older age), and higher titres of EBV specific antibodies are associated with an increased risk of developing MS. Elevated levels of the latter are apparent many years before MS onset (compared with non-MS controls) and there is a doseeresponse relationship between MS risk and antibody titre, with antibodies to the EBV nuclear antigen-1 particularly important. The evidence in relation to EBV DNA load in blood or CSF is conflicting, as is that in relation to T cell responses to EBV. Several hypotheses that have been proposed to explain the links between EBV and MS risk are reviewed and gaps requiring further research are identified
Stroom- en sedimentmeting Roompot-Veerse Dam (mp.8), 15 en 22 januari 1996
No full textStroom- en sedimentmeting Roompot-Veerse Dam (mp.8) 15 en 22 januari 1996.Deltawerken, Oosterscheld
Utilising proteomic approaches to understand oncogenic human herpesviruses
No full textThe γ‑herpesviruses Epstein-Barr virus and Kaposi's sarcoma‑associated herpesvirus are successful pathogens, each infecting a large proportion of the human population. These viruses persist for the life of the host and may each contribute to a number of malignancies, for which there are currently no cures. Large‑scale proteomic-based approaches provide an excellent means of increasing the collective understanding of the proteomes of these complex viruses and elucidating their numerous interactions within the infected host cell. These large‑scale studies are important for the identification of the intricacies of viral infection and the development of novel therapeutics against these two important pathogens
A novel approach to MP-PIC: Continuum particle model for dense particle flows in fluidized beds
No full textA novel approach to Multiphase-Particle-in-Cell (MP-PIC), called Continuum Particle Model (CPM), is developed for dense gas-particle flows. CPM has high computational speed, comparable to that of MP-PIC, but a robustness and accuracy closer to that of a Discrete Element Model (DEM). The gas phase is treated as a continuum phase and particles are tracked discretely, but particle collisions are modelled by considering the divergence of the continuum particle stress tensor. Details on efficient solution to the model are presented. For comparison, a parametric study is performed for quasi-2D fluidized beds. Comparison of CFD-CPM is made with MP-PIC and CFD-DEM. The particle stress models by Harris and Crighton, and by Srivastava and Sundaresan are tested in our CFD-CPM. Results from CFD-CPM based on the Srivastava and Sundaresan particle stress model show good agreement with CFD-DEM results. We validate our model by comparison with experimental benchmark results from Gopalan et. al. (2016).Complex Fluid Processin
Updated open-label extension clinical data and new magnetization transfer ratio imaging data from a Phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive multiple sclerosis
No full textIntroduction: Mounting evidence suggests Epstein-Barr virus (EBV) is a necessary risk factor for development of multiple sclerosis (MS) [Abrahamyan et al. JNNP 2020]. Early experience with autologous EBV-specific T-cell therapy proved safe and may offer clinical benefit [Pender MP et al. JCI Insight 2018; Ioannides ZA et al. Front Neurol 2021].
Objectives/Aims: Evaluate the safety and potential efficacy of ATA188 in adults with progressive MS in an ongoing open-label extension (OLE) study, including an imaging biomarker: magnetization transfer ratio (MTR).
Methods: In part 1 of this 2-part Phase I/II study, 4 cohorts received escalating doses of ATA188. Patients (pts) were followed for 1 year and could participate in a 4-year OLE. Sustained disability improvement (SDI; including expanded disability status scale [EDSS] and timed 25-foot walk), as well as safety, were measured [Pender MP et al. EAN 2020]. As a biomarker of improvement, change from baseline in MTR, an exploratory endpoint, was assessed.
Results: 25 pts received ⩾1 dose of ATA188 and were followed for up to 33 mos (m). No grade >3 adverse events (AE), dose-limiting toxicities, cytokine release syndrome, graft vs host disease, or infusion-related reactions were observed. 2 treatment-emergent serious AEs were previously reported (muscle spasticity [grade 2; not treatment related]; MS relapse [grade 3; possibly treatment related]) and, as of April 2021, 1 was reported in the OLE (fall; grade 2; not treatment related). Efficacy was evaluated in 24 pts in the initial 12m period and, as of April 2021, in 18 pts in the OLE followed for up to 33m. 9 pts met SDI criteria either in the initial 12m period (n=7) or in the OLE (n=2); of these, 7 had sustained EDSS improvement. Of the 8 pts that achieved SDI and entered the OLE, 7 maintained SDI at all subsequent timepoints. Pts with sustained EDSS improvement (vs those without) had greater increases in MTR signal (in unenhancing T2 lesions and normal-appearing brain tissue) at 12m.
Conclusions: Preliminary data indicate ATA188 is well tolerated. Sustained EDSS improvement drove SDI in most pts, and in all but 1 pt, SDI was maintained at all subsequent timepoints. As a biomarker associated with disability, pts with sustained EDSS improvement (vs those without) showed greater increases in MTR signal at 12m, which may be suggestive of remyelination. The Phase 2 portion of this study, EMBOLD (NCT03283826), is ongoing and currently enrolling.No Full Tex
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