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Search Results: 1 - 10 of 9133 matches for " Avraham Ben-Nun "
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DQB1*0602 rather than DRB1*1501 confers susceptibility to multiple sclerosis-like disease induced by proteolipid protein (PLP)
Nathali Kaushansky, Daniel M Altmann, Chella S David, Hans Lassmann, Avraham Ben-Nun
Journal of Neuroinflammation , 2012, DOI: 10.1186/1742-2094-9-29
Abstract: The HLA-DRB1*1501- and HLA-DQB1*0602-Tg mice (MHC-II-/-), and control non-HLA-DR15-relevant-Tg mice were immunized with a set of overlapping PLP peptides or with recombinant soluble PLP for induction of "humanized" MS-like disease, as well as for ex-vivo analysis of immunogenic/immunodominant HLA-restricted T-cell epitopes and associated cytokine secretion profile.PLP autoimmunity in both HLA-DR15-Tg mice was focused on 139-151 and 175-194 epitopes. Strikingly, however, the HLA-DRB1*1501-transgenics were refractory to disease induction by any of the overlapping PLP peptides, while HLA-DQB1*0602 transgenics were susceptible to disease induction by PLP139-151 and PLP175-194 peptides. Although both transgenics responded to both peptides, the PLP139-151- and PLP175-194-reactive T-cells were directed to Th1/Th17 phenotype in DQB1*0602-Tg mice and towards Th2 in DRB1*1501-Tg mice.While genome studies map a strong MS susceptibility effect to the region of DRB1*1501, our findings offer a rationale for potential involvement of pathogenic DQ6-associated autoimmunity in MS. Moreover, that DQB1*0602, but not DRB1*1501, determines disease-susceptibility to PLP in HLA-transgenics, suggests a potential differential, functional role for DQB1*0602 as a predisposing allele in MS. This, together with previously demonstrated disease-susceptibility to MBP and MOG in DRB1*1501-transgenics, also suggests a differential role for DRB1*1501 and DQB1*0602 depending on target antigen and imply a potential complex 'genotype/target antigen/phenotype' relationship in MS heterogeneity.Multiple sclerosis (MS) is a disease of the human central nervous system (CNS), characterized by perivascular inflammation, accompanied by primary demyelination and axonal damage. It is believed to result from autoimmune mechanisms leading to destruction of myelin, presumably initiated by abnormally activated T cells that recognize CNS components in MS patients. The pathogenic autoimmunity in MS appears to be associa
‘Multi-Epitope-Targeted’ Immune-Specific Therapy for a Multiple Sclerosis-Like Disease via Engineered Multi-Epitope Protein Is Superior to Peptides
Nathali Kaushansky, Nicole Kerlero de Rosbo, Rina Zilkha-Falb, Reut Yosef-Hemo, Lydia Cohen, Avraham Ben-Nun
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027860
Abstract: Antigen-induced peripheral tolerance is potentially one of the most efficient and specific therapeutic approaches for autoimmune diseases. Although highly effective in animal models, antigen-based strategies have not yet been translated into practicable human therapy, and several clinical trials using a single antigen or peptidic-epitope in multiple sclerosis (MS) yielded disappointing results. In these clinical trials, however, the apparent complexity and dynamics of the pathogenic autoimmunity associated with MS, which result from the multiplicity of potential target antigens and “epitope spread”, have not been sufficiently considered. Thus, targeting pathogenic T-cells reactive against a single antigen/epitope is unlikely to be sufficient; to be effective, immunospecific therapy to MS should logically neutralize concomitantly T-cells reactive against as many major target antigens/epitopes as possible. We investigated such “multi-epitope-targeting” approach in murine experimental autoimmune encephalomyelitis (EAE) associated with a single (“classical”) or multiple (“complex”) anti-myelin autoreactivities, using cocktail of different encephalitogenic peptides vis-a-vis artificial multi-epitope-protein (designated Y-MSPc) encompassing rationally selected MS-relevant epitopes of five major myelin antigens, as “multi-epitope-targeting” agents. Y-MSPc was superior to peptide(s) in concomitantly downregulating pathogenic T-cells reactive against multiple myelin antigens/epitopes, via inducing more effective, longer lasting peripheral regulatory mechanisms (cytokine shift, anergy, and Foxp3+ CTLA4+ regulatory T-cells). Y-MSPc was also consistently more effective than the disease-inducing single peptide or peptide cocktail, not only in suppressing the development of “classical” or “complex EAE” or ameliorating ongoing disease, but most importantly, in reversing chronic EAE. Overall, our data emphasize that a “multi-epitope-targeting” strategy is required for effective immune-specific therapy of organ-specific autoimmune diseases associated with complex and dynamic pathogenic autoimmunity, such as MS; our data further demonstrate that the “multi-epitope-targeting” approach to therapy is optimized through specifically designed multi-epitope-proteins, rather than myelin peptide cocktails, as “multi-epitope-targeting” agents. Such artificial multi-epitope proteins can be tailored to other organ-specific autoimmune diseases.
SV40 Assembly In Vivo and In Vitro
Ariella Oppenheim,O. Ben-nun-Shaul,S. Mukherjee,M. Abd-El-Latif
Computational and Mathematical Methods in Medicine , 2008, DOI: 10.1080/17486700802168312
Abstract: The Simian virus 40 (SV40) capsid is a T = 7d icosahedral lattice ∼45 nm in diameter surrounding the ∼5 kb circular minichromosome. The outer shell is composed of 360 monomers of the major capsid protein VP1, tightly bound in 72 pentamers. VP1 is a jellyroll β-barrel, with extending N- and C-terminal arms. The N-terminal arms bind DNA and face the interior of the capsid. The flexible C-arms tie together the 72 pentamers in three distinct kinds of interactions, thus facilitating the formation of a T = 7 icosahedron from identical pentameric building blocks. Assembly in vivo was shown to occur by addition of capsomers around the DNA. We apply a combination of biochemical and genetic approaches to study SV40 assembly. Our in vivo and in vitro studies suggest the following model: one or two capsomers bind at a high affinity to ses, the viral DNA encapsidation signal, forming the nucleation centre for assembly. Next, multiple capsomers attach concomitantly, at lower affinity, around the minichromosome. This increases their local concentration facilitating rapid, cooperative assembly reaction. Formation of the icosahedron proceeds either by gradual addition of single pentamers to the growing shell or by concerted assembly of pentamer clusters.
High Cooperativity of the SV40 Major Capsid Protein VP1 in Virus Assembly
Santanu Mukherjee, Mahmoud Abd-El-Latif, Michal Bronstein, Orly Ben-nun-Shaul, Stanislav Kler, Ariella Oppenheim
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0000765
Abstract: SV40 is a small, non enveloped DNA virus with an icosahedral capsid of 45 nm. The outer shell is composed of pentamers of the major capsid protein, VP1, linked via their flexible carboxy-terminal arms. Its morphogenesis occurs by assembly of capsomers around the viral minichromosome. However the steps leading to the formation of mature virus are poorly understood. Intermediates of the assembly reaction could not be isolated from cells infected with wt SV40. Here we have used recombinant VP1 produced in insect cells for in vitro assembly studies around supercoiled heterologous plasmid DNA carrying a reporter gene. This strategy yields infective nanoparticles, affording a simple quantitative transduction assay. We show that VP1 assembles under physiological conditions into uniform nanoparticles of the same shape, size and CsCl density as the wild type virus. The stoichiometry is one DNA molecule per capsid. VP1 deleted in the C-arm, which is unable to assemble but can bind DNA, was inactive indicating genuine assembly rather than non-specific DNA-binding. The reaction requires host enzymatic activities, consistent with the participation of chaperones, as recently shown. Our results demonstrate dramatic cooperativity of VP1, with a Hill coefficient of ~6. These findings suggest that assembly may be a concerted reaction. We propose that concerted assembly is facilitated by simultaneous binding of multiple capsomers to a single DNA molecule, as we have recently reported, thus increasing their local concentration. Emerging principles of SV40 assembly may help understanding assembly of other complex systems. In addition, the SV40-based nanoparticles described here are potential gene therapy vectors that combine efficient gene delivery with safety and flexibility.
Early Characterization of the Severity and Transmissibility of Pandemic Influenza Using Clinical Episode Data from Multiple Populations
Pete Riley?,Michal Ben-Nun,Jon A. Linker?,Angelia A. Cost?,Jose L. Sanchez?,Dylan George?,David P. Bacon?,Steven Riley
PLOS Computational Biology , 2015, DOI: 10.1371/journal.pcbi.1004392
Abstract: The potential rapid availability of large-scale clinical episode data during the next influenza pandemic suggests an opportunity for increasing the speed with which novel respiratory pathogens can be characterized. Key intervention decisions will be determined by both the transmissibility of the novel strain (measured by the basic reproductive number R0) and its individual-level severity. The 2009 pandemic illustrated that estimating individual-level severity, as described by the proportion pC of infections that result in clinical cases, can remain uncertain for a prolonged period of time. Here, we use 50 distinct US military populations during 2009 as a retrospective cohort to test the hypothesis that real-time encounter data combined with disease dynamic models can be used to bridge this uncertainty gap. Effectively, we estimated the total number of infections in multiple early-affected communities using the model and divided that number by the known number of clinical cases. Joint estimates of severity and transmissibility clustered within a relatively small region of parameter space, with 40 of the 50 populations bounded by: pC, 0.0133–0.150 and R0, 1.09–2.16. These fits were obtained despite widely varying incidence profiles: some with spring waves, some with fall waves and some with both. To illustrate the benefit of specific pairing of rapidly available data and infectious disease models, we simulated a future moderate pandemic strain with pC approximately ×10 that of 2009; the results demonstrating that even before the peak had passed in the first affected population, R0 and pC could be well estimated. This study provides a clear reference in this two-dimensional space against which future novel respiratory pathogens can be rapidly assessed and compared with previous pandemics.
Multiple Estimates of Transmissibility for the 2009 Influenza Pandemic Based on Influenza-like-Illness Data from Small US Military Populations
Pete Riley ,Michal Ben-Nun,Richard Armenta,Jon A. Linker,Angela A. Eick,Jose L. Sanchez,Dylan George,David P. Bacon,Steven Riley
PLOS Computational Biology , 2013, DOI: 10.1371/journal.pcbi.1003064
Abstract: Rapidly characterizing the amplitude and variability in transmissibility of novel human influenza strains as they emerge is a key public health priority. However, comparison of early estimates of the basic reproduction number during the 2009 pandemic were challenging because of inconsistent data sources and methods. Here, we define and analyze influenza-like-illness (ILI) case data from 2009–2010 for the 50 largest spatially distinct US military installations (military population defined by zip code, MPZ). We used publicly available data from non-military sources to show that patterns of ILI incidence in many of these MPZs closely followed the pattern of their enclosing civilian population. After characterizing the broad patterns of incidence (e.g. single-peak, double-peak), we defined a parsimonious SIR-like model with two possible values for intrinsic transmissibility across three epochs. We fitted the parameters of this model to data from all 50 MPZs, finding them to be reasonably well clustered with a median (mean) value of 1.39 (1.57) and standard deviation of 0.41. An increasing temporal trend in transmissibility (, p-value: 0.013) during the period of our study was robust to the removal of high transmissibility outliers and to the removal of the smaller 20 MPZs. Our results demonstrate the utility of rapidly available – and consistent – data from multiple populations.
Complete Exact Solution of Diffusion-Limited Coalescence, A + A -> A
Daniel ben-Avraham
Physics , 1998, DOI: 10.1103/PhysRevLett.81.4756
Abstract: Some models of diffusion-limited reaction processes in one dimension lend themselves to exact analysis. The known approaches yield exact expressions for a limited number of quantities of interest, such as the particle concentration, or the distribution of distances between nearest particles. However, a full characterization of a particle system is only provided by the infinite hierarchy of multiple-point density correlation functions. We derive an exact description of the full hierarchy of correlation functions for the diffusion-limited irreversible coalescence process A + A -> A.
Inhomogeneous Steady States of Diffusion-Limited Coalescence, A+A<-->A
Daniel ben-Avraham
Physics , 1998, DOI: 10.1016/S0375-9601(98)00695-1
Abstract: We study the steady state of diffusion-limited coalescence, A+A<-->A, in the presence of a trap and with a background drift. In one dimension this model can be analyzed exactly through the method of inter-particle distribution functions (IPDF). Because of the irreversible trap the steady state of the system is a non-equilibrium state. An interesting phase transition, controlled by the drift away from the trap, takes place: from a non-trivial steady state, when the drift is weak, to a trivial steady state (the vacuum), as the drift increases beyond some critical point. Surprisingly, regardless of the drift strength, the computed IPDF resembles that of an homogeneous equilibrium system, without the trap. We suggest that this is due to "shielding": the particle nearest to the trap shields the remaining particles from the effects of the trap. Finally, we compare the exact solution to that of a reaction-diffusion equation, and we determine the optimal values of the appropriate rate coefficients.
Fisher Waves in the Diffusion-Limited Coalescence Process A+A<-->A
Daniel ben-Avraham
Physics , 1998, DOI: 10.1016/S0375-9601(98)00569-6
Abstract: Fisher waves have been studied recently in the specific case of diffusion-limited reversible coalescence, A+A<-->A, on the line. An exact analysis of the particles concentration showed that waves propagate from a stable region to an unstable region at constant speed, just as in Fisher's "mean-field" theory; but also that the wave front fails to retain its initial shape and instead it broadens with time. Our present analysis encompasses the full hierarchy of multiple-point density correlation functions, and thus it provides a complete exact description of the same system. We find that as the wave propagates, the particles in the stable phase remain distributed exactly as in their initial (equilibrium) state. On the other hand, the leading particle---the one at the edge of the wave---advances as a biased random walk, rather than simply linearly with time. Thus the shape of the wave remains actually constant, but it is the "noisy" propagation of the wave's edge that causes its apparent broadening.
Diffusion-Limited Coalescence, A+A<-->A, with a Trap
Daniel ben-Avraham
Physics , 1998, DOI: 10.1103/PhysRevE.58.4351
Abstract: We study diffusion-limited coalescence, A+A<-->A$, in one dimension, and derive an exact solution for the steady state in the presence of a trap. Without the trap, the system arrives at an equilibrium state which satisfies detailed balance, and can therefore be analyzed by classical equilibrium methods. The trap introduces an irreversible element, and the stationary state is no longer an equilibrium state. The exact solution is compared to that of a reaction-diffusion equation --- the habitual approximation method of choice. The exact solution allows us to determine the rate coefficients in the reaction-diffusion equation, without appealing to renormalization group techniques.
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