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ß-Hydroxybutyrate (BHB) is a ketone body formed in high amounts during lipolysis and fasting. Ketone bodies and the ketogenic diet were suggested as neuroprotective agents in neurodegenerative disease. In the present work, we induced transient ischemia in mouse brain by unilaterally occluding the middle cerebral artery for 90 min. BHB (30 mg/kg), given immediately after reperfusion, significantly improved the neurological score determined after 24 h. In isolated mitochondria from mouse brain, oxygen consumption by the complexes I, II and IV was reduced immediately after ischemia but recovered slowly over 1 week. The single acute BHB administration after reperfusion improved complex I and II activity after 24 h while no significant effects were seen at later time points. After 24 h, plasma and brain BHB concentrations were strongly increased while mitochondrial intermediates (citrate, succinate) were unchanged in brain tissue. Our data suggest that a single administration of BHB may improve mitochondrial respiration for 1–2 days but not for later time points. Endogenous BHB formation seems to complement the effects of exogenous BHB administration.
Glucose hypometabolism, mitochondrial dysfunction, and cholinergic deficits have been reported in early stages of Alzheimer’s disease (AD). Here, we examine these parameters in TgF344-AD rats, an Alzheimer model that carries amyloid precursor protein and presenilin-1 mutations, and of wild type F344 rats. In mitochondria isolated from rat hippocampi, we found reductions of complex I and oxidative phosphorylation in transgenic rats. Further impairments, also of complex II, were observed in aged (wild-type and transgenic) rats. Treatment with a “cocktail” containing magnesium orotate, benfotiamine, folic acid, cyanocobalamin, and cholecalciferol did not affect mitochondrial activities in wild-type rats but restored diminished activities in transgenic rats to wild-type levels. Glucose, lactate, and pyruvate levels were unchanged by age, genetic background, or treatment. Using microdialysis, we also investigated extracellular concentrations of acetylcholine that were strongly reduced in transgenic animals. Again, ACh levels in wild-type rats did not change upon treatment with nutrients, whereas the cocktail increased hippocampal acetylcholine levels under physiological stimulation. We conclude that TgF344-AD rats display a distinct mitochondrial and cholinergic dysfunction not unlike the findings in patients suffering from AD. This dysfunction can be partially corrected by the application of the “cocktail” which is particularly active in aged rats. We suggest that the TgF344-AD rat is a promising model to further investigate mitochondrial and cholinergic dysfunction and potential treatment approaches for AD.
When a visual stimulus is repeated, average neuronal responses typically decrease, yet they might maintain or even increase their impact through increased synchronization. Previous work has found that many repetitions of a grating lead to increasing gamma-band synchronization. Here, we show in awake macaque area V1 that both repetition-related reductions in firing rate and increases in gamma are specific to the repeated stimulus. These effects show some persistence on the timescale of minutes. Gamma increases are specific to the presented stimulus location. Further, repetition effects on gamma and on firing rates generalize to images of natural objects. These findings support the notion that gamma-band synchronization subserves the adaptive processing of repeated stimulus encounters.
When a visual stimulus is repeated, average neuronal responses typically decrease, yet they might maintain or even increase their impact through increased synchronization. Previous work has found that many repetitions of a grating lead to increasing gamma-band synchronization. Here we show in awake macaque area V1 that both, repetition-related reductions in firing rate and increases in gamma are specific to the repeated stimulus. These effects showed some persistence on the timescale of minutes. Further, gamma increases were specific to the presented stimulus location. Importantly, repetition effects on gamma and on firing rates generalized to natural images. These findings suggest that gamma-band synchronization subserves the adaptive processing of repeated stimulus encounters, both for generating efficient stimulus responses and possibly for memory formation.
Enhanced labeling density and whole-cell 3D dSTORM imaging by repetitive labeling of target proteins
(2018)
With continuing advances in the resolving power of super-resolution microscopy, the inefficient labeling of proteins with suitable fluorophores becomes a limiting factor. For example, the low labeling density achieved with antibodies or small molecule tags limits attempts to reveal local protein nano-architecture of cellular compartments. On the other hand, high laser intensities cause photobleaching within and nearby an imaged region, thereby further reducing labeling density and impairing multi-plane whole-cell 3D super-resolution imaging. Here, we show that both labeling density and photobleaching can be addressed by repetitive application of trisNTA-fluorophore conjugates reversibly binding to a histidine-tagged protein by a novel approach called single-epitope repetitive imaging (SERI). For single-plane super-resolution microscopy, we demonstrate that, after multiple rounds of labeling and imaging, the signal density is increased. Using the same approach of repetitive imaging, washing and re-labeling, we demonstrate whole-cell 3D super-resolution imaging compensated for photobleaching above or below the imaging plane. This proof-of-principle study demonstrates that repetitive labeling of histidine-tagged proteins provides a versatile solution to break the "labeling barrier" and to bypass photobleaching in multi-plane, whole-cell 3D experiments.
Accurate labeling of endogenous proteins for advanced light microscopy in living cells remains challenging. Nanobodies have been widely used for antigen labeling, visualization of subcellular protein localization and interactions. To facilitate an expanded application, we present a scalable and high-throughput strategy to simultaneously target multiple endogenous proteins in living cells with micro- to nanometer resolution. For intracellular protein labeling, we advanced nanobodies by site-specific and stoichiometric attachment of bright organic fluorophores. Their fast and fine-tuned intracellular transfer by microfluidic cell squeezing enabled high-throughput delivery with less than 10% dead cells. This strategy allowed for the dual-color imaging of distinct endogenous cellular structures, and culminated in super-resolution imaging of native protein networks in genetically non-modified living cells. The simultaneous delivery of multiple engineered nanobodies does not only offer exciting prospects for multiplexed imaging of endogenous protein, but also holds potential for visualizing native cellular structures with unprecedented accuracy.
The azimuthal correlations of D mesons with charged particles were measured with the ALICE apparatus in pp collisions at s√=7 TeV and p–Pb collisions at sNN−−−√=5.02 TeV at the Large Hadron Collider. D0, D+, and D∗+ mesons and their charge conjugates with transverse momentum 3<pT<16 GeV/c and rapidity in the nucleon-nucleon centre-of-mass system |ycms|<0.5 (pp collisions) and −0.96<ycms<0.04 (p–Pb collisions) were correlated to charged particles with pT>0.3 GeV/c. The yield of charged particles in the correlation peak induced by the jet containing the D meson and the peak width are compatible within uncertainties in the two collision systems. The data are described within uncertainties by Monte-Carlo simulations based on PYTHIA, POWHEG, and EPOS 3 event generators.
The azimuthal correlations of D mesons and charged particles were measured with the ALICE detector in pp collisions at s√=7 TeV and p-Pb collisions at sNN−−−√=5.02 TeV at the Large Hadron Collider. D0, D+, and D∗+ mesons and their charge conjugates with transverse momentum 3<pT<16 GeV/c and rapidity in the nucleon-nucleon centre-of-mass system |ycms|<0.5 (pp collisions) and −0.96<ycms<0.04 (p-Pb collisions) were correlated to charged particles with pT>0.3 Gev/c. The properties of the correlation peak induced by the jet containing the D meson, described in terms of the yield of charged particles in the peak and peak width, are compatible within uncertainties between the two collision systems, and described by Monte-Carlo simulations based on the PYTHIA, POWHEG and EPOS 3 event generators.
At sufficiently high temperature and energy density, nuclear matter undergoes a transition to a phase in which quarks and gluons are not confined: the Quark-Gluon Plasma (QGP) [1]. Such an extreme state of strongly-interacting QCD (Quantum Chromo-Dynamics) matter is produced in the laboratory with high-energy collisions of heavy nuclei, where an enhanced production of strange hadrons is observed [2-6]. Strangeness enhancement, originally proposed as a signature of QGP formation in nuclear collisions [7], is more pronounced for multi-strange baryons. Several effects typical of heavy-ion phenomenology have been observed in high-multiplicity proton-proton (pp) collisions [8,9]. Yet, enhanced production of multi-strange particles has not been reported so far. Here we present the first observation of strangeness enhancement in high-multiplicity pp collisions. We find that the integrated yields of strange and multi-strange particles relative to pions increases significantly with the event charged-particle multiplicity. The measurements are in remarkable agreement with p-Pb collision results [10,11] indicating that the phenomenon is related to the final system created in the collision. In high-multiplicity events strangeness production reaches values similar to those observed in Pb-Pb collisions, where a QGP is formed.