IgM memory B cells: a mouse/human paradox

Humoral memory is maintained by two types of persistent cells, memory B cells and plasma cells, which have different phenotypes and functions. Long-lived plasma cells can survive for a lifespan within a complex niche in the bone marrow and provide continuous protective serum antibody levels. Memory B cells reside in secondary lymphoid organs, where they can be rapidly mobilized upon a new antigenic encounter. Surface IgG has long been taken as a surrogate marker for memory in the mouse. Recently, however, we have brought evidence for a long-lived IgM memory B cell population in the mouse, while we have also argued that, in humans, these same cells are not classical memory B cells but marginal zone (MZ) B cells which, as opposed to their mouse MZ counterpart, recirculate and carry a mutated B cell receptor. In this review, we will discuss these apparently paradoxical results

Uptake Mechanism of ApoE-Modified Nanoparticles on Brain Capillary Endothelial Cells as a Blood-Brain Barrier Model

Background: The blood-brain barrier (BBB) represents an insurmountable obstacle for most drugs thus obstructing an effective treatment of many brain diseases. One solution for overcoming this barrier is a transport by binding of these drugs to surface-modified nanoparticles. Especially apolipoprotein E (ApoE) appears to play a major role in the nanoparticle-mediated drug transport across the BBB. However, at present the underlying mechanism is incompletely understood. Methodology/Principal Findings: In this study, the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells was investigated to differentiate between active and passive uptake mechanism by flow cytometry and confocal laser scanning microscopy. Furthermore, different in vitro co-incubation experiments were performed with competing ligands of the respective receptor. Conclusions/Significance: This study confirms an active endocytotic uptake mechanism and shows the involvement of low density lipoprotein receptor family members, notably the low density lipoprotein receptor related protein, on the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells. This knowledge of the uptake mechanism of ApoE-modified nanoparticles enables future developments to rationally create very specific and effective carriers to overcome the blood-brain barrier

Energy conservation in the gut microbe Methanomassiliicoccus luminyensis is based on membrane-bound ferredoxin oxidation coupled to heterodisulfide reduction.

Item does not contain fulltextMethanomassiliicoccus luminyensis was originally isolated from human feces and belongs to the seventh order of methanogens, the Methanomassiliicoccales, which are only distantly related to other methanogenic archaea. The organism forms methane from the reduction of methylamines or methanol using molecular hydrogen as reductant. The energy-conserving system in M. luminyensis is unique and the enzymes involved in this process are not found in this combination in members of the other methanogenic orders. In this context our central question was how the organism is able to generate ATP. Energy transduction was dependent on a membrane-bound ferredoxin: heterodisulfide oxidoreductase composed of reduced ferredoxin as an electron donor, at least one protein in the membrane fraction and the heterodisulfide reductase HdrD, which reduced the electron acceptor CoM-S-S-CoB. Electron transfer of this respiratory chain proceeded with a rate of 145 nmol reduced heterodisulfide min(-1) .mg(-1) membrane protein. Methanomassiliicoccus luminyensis is the first example of a methanogenic archaeon that does not require Na(+) ions for energy conservation. Only protons were used as coupling ions for the generation of the electrochemical ion gradient. The membrane-bound F420 H2 :phenazine oxidoreductase complex (without the electron input module FpoF) probably catalyzed the oxidation of reduced ferredoxin and potentially acted as primary proton pump in this electron transport system. In summary, the energy-conserving system of M. luminyensis possesses features found in the pathways of hydrogenotrophic and methylotrophic/aceticlastic methanogenesis. Consequently, the composition of the enzymes involved in ion translocation across the cytoplasmic membrane is different from all other methanogenic archaea.13 p

Circumventing the Dephasing and Depletion Limits of Laser-Wakefield Acceleration

Compact electron accelerators are paramount to next-generation synchrotron light sources and free-electron lasers, as well as for advanced accelerators at the TeV energy frontier. Recent progress in laser-plasma driven accelerators (LPA) has extended their electron energies to the multi-GeV range and improved beam stability for insertion devices. However, the subluminal group velocity of plasma waves limits the final electron energy that can be achieved in a single LPA accelerator stage, also known as the dephasing limit. Here, we present the first laser-plasma driven electron accelerator concept providing constant acceleration without electrons outrunning the wakefield. The laser driver is provided by an overlap region of two obliquely incident, ultrashort laser pulses with tilted pulse fronts in the line foci of two cylindrical mirrors, aligned to coincide with the trajectory of the accelerated electrons. Such a geometry of laterally coupling the laser into a plasma allows for the overlap region to move with the vacuum speed of light, while the laser fields in the plasma are continuously being replenished by the successive parts of the laser pulses. Our scheme is robust against parasitic self-injection and self-phase modulation as well as drive-laser depletion and defocusing along the accelerated electron beam. It works for a broad range of plasma densities in gas targets. This method opens the way for scaling up electron energies beyond 10 GeV, possibly towards TeV-scale electron beams, without the need for multiple laser-accelerator stages

Circumventing the Dephasing and Depletion Limits of Laser-Wakefield Acceleration

Compact electron accelerators are paramount to next-generation synchrotron light sources and free-electron lasers, as well as for advanced accelerators at the TeV energy frontier. Recent progress in laser-plasma driven accelerators (LPA) has extended their electron energies to the multi-GeV range and improved beam stability for insertion devices. However, the subluminal group velocity of plasma waves limits the final electron energy that can be achieved in a single LPA accelerator stage, also known as the dephasing limit. Here, we present the first laser-plasma driven electron accelerator concept providing constant acceleration without electrons outrunning the wakefield. The laser driver is provided by an overlap region of two obliquely incident, ultrashort laser pulses with tilted pulse fronts in the line foci of two cylindrical mirrors, aligned to coincide with the trajectory of the accelerated electrons. Such a geometry of laterally coupling the laser into a plasma allows for the overlap region to move with the vacuum speed of light, while the laser fields in the plasma are continuously being replenished by the successive parts of the laser pulses. Our scheme is robust against parasitic self-injection and self-phase modulation as well as drive-laser depletion and defocusing along the accelerated electron beam. It works for a broad range of plasma densities in gas targets. This method opens the way for scaling up electron energies beyond 10 GeV, possibly towards TeV-scale electron beams, without the need for multiple laser-accelerator stages