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In selective autophagy, cargo recruitment is mediated by LC3-interacting regions (LIRs) / Atg8-interacting motifs (AIMs) in the cargo or cargo receptor proteins. The binding of these motifs to LC3/Atg8 proteins at the phagophore membrane is often modulated by post-translational modifications, especially phosphorylation. As a challenge for computational LIR predictions, sequences may contain the short canonical (W/F/Y)XX(L/I/V) motif without being functional. Conversely, LIRs may be formed by non-canonical but functional sequence motifs. AlphaFold2 has proven to be useful for LIR predictions, even if some LIRs are missed and proteins with thousands of residues reach the limits of computational feasibility. We present a fragment-based approach to address these limitations. We find that fragment length and phosphomimetic mutations modulate the interactions predicted by AlphaFold2. Systematic fragment screening for a range of target proteins yields structural models for interactions that AlphaFold2 and AlphaFold3 fail to predict for full-length targets. We provide guidance on fragment choice, sequence tuning, and LC3 isoform effects for optimal LIR screens. Finally, we also test the transferability of this general framework to SUMO-SIM interactions, another type of protein-protein interaction involving short linear motifs (SLiMs).
In selective autophagy, cargo recruitment is mediated by LC3-interacting regions (LIRs) / Atg8-interacting motifs (AIMs) in the cargo or cargo receptor proteins. The binding of these motifs to LC3/Atg8 proteins at the phagophore membrane is often modulated by post-translational modifications, especially phosphorylation. As a challenge for computational LIR predictions, sequences may contain the short canonical (W/F/Y)XX(L/I/V) motif without being functional. Conversely, LIRs may be formed by non-canonical but functional sequence motifs. AlphaFold2 has proven to be useful for LIR predictions, even if some LIRs are missed and proteins with thousands of residues reach the limits of computational feasibility. We present a fragment-based approach to address these limitations. We find that fragment length and phosphomimetic mutations modulate the interactions predicted by AlphaFold2. Systematic fragment screening for a range of target proteins yields structural models for interactions that AlphaFold2 and AlphaFold3 fail to predict for full-length targets. We provide guidance on fragment choice, sequence tuning, and LC3 isoform effects for optimal LIR screens. Finally, we also test the transferability of this general framework to SUMO-SIM interactions, another type of protein-protein interaction involving short linear motifs (SLiMs).
Abstract
Inhibition of midbrain dopamine neurons is thought to underlie the signaling of events that are less rewarding than expected and drive learning based on these negative prediction errors. It has recently been shown that Kv4.3 channels influence the integration of inhibitory inputs in specific subpopulations of dopamine neurons. The functional properties of Kv4.3 channels are themselves strongly determined by the binding of auxiliary β-subunits; among them KChIP4a stands-out for its unique combination of modulatory effects. These include decreasing surface membrane trafficking and slowing inactivation kinetics. Therefore, we hypothesized that KChIP4a expression in dopamine neurons could play a crucial role in behavior, in particular by affecting the computation of negative prediction errors. We developed a mouse line where the alternative exon that codes for the KChIP4a splice variant was selectively deleted in midbrain dopamine neurons. In a reward-based reinforcement learning task, we observed that dopamine neuron-specific KChIP4a deletion selectively accelerated the rate of extinction learning, without impacting the acquisition of conditioned responses. We further found that this effect was due to a faster decrease in the initiation rate of goal-directed behaviors, and not faster increases in action disengagement. Furthermore, computational fitting of the behavioral data with a Rescorla-Wagner model confirmed that the observed phenotype was attributable to a selective increase in the learning rate from negative prediction errors. Finally, KChIP4a deletion did not affect performance in other dopamine-sensitive behavioral tasks that did not involve learning from disappointing events, including an absence of effects on working memory, locomotion and novelty preference. Taken together, our results demonstrate that an exon- and midbrain dopamine neuron-specific deletion of an A-type K+ channel β-subunit leads to a selective gain of function in extinction learning.
One Sentence Summary
Exon- and midbrain dopamine neuron-specific deletion of the Kv4 channel β-subunit KChIP4a selectively accelerates extinction learning
Dopamine (DA) neurons in the substantia nigra (SN) control several essential functions, including the voluntary movement, learning and motivated behavior. Healthy DA SN neurons show diverse firing patterns in vivo, ranging from slow pacemaker-like activity (1-10 Hz) to transient high frequency bursts (<100 Hz), interspersed with pauses that can last hundreds of milliseconds. Recent in vivo patch experiments have started to reveal the subthreshold mechanisms underlying this physiological diversity, but the impact of challenges like cell loss on the in vivo activity of adult DA SN neurons, and how these may relate to behavioral disturbances, are still largely unknown. We investigated the in vivo electrophysiological properties of surviving SN DA neurons after partial unilateral 6-OHDA lesions, a single-hit, non-progressive model of neuronal cell loss. We show that mice subjected to this model have an initial motor impairment, measured by asymmetrical rotations in the open field test, which recovered over time. At 3 weeks post-lesion, when open field locomotion was strongly impaired, surviving DA SN neurons showed a compressed in vivo dynamic firing range, characterized by a 10-fold reduction of in vivo burst firing compared to controls. This in vivo phenotype was accompanied by pronounced in vitro pacemaker instability. In contrast, in the chronic post-lesion phase (>2 months), where turning symmetry in open field locomotion had recovered, surviving SN DA neurons displayed the full dynamic range of in vivo firing, including in vivo bursting, similar to controls. The normalized in vivo firing pattern was associated with a 2-fold acceleration of stable in vitro pacemaking, mediated by Kv4.3 potassium channel downregulation. Our findings demonstrate the existence of a homeostatic pacemaker plasticity mechanism in surviving DA SN neurons after pronounced cell loss.
The signaling lipid phosphatidylinositol-4,5-bisphosphate (PIP2) regulates many ion channels. It inhibits eukaryotic cyclic nucleotide-gated (CNG) channels while activating their relatives, the hyperpolarization-activated and cyclic nucleotide-modulated (HCN) channels. The prokaryotic SthK channel from Spirochaeta thermophila shares features with CNG and HCN channels and is an established model for this channel family. Here, we show SthK activity is inhibited by PIP2. A cryo-EM structure of SthK in nanodiscs reveals a PIP2-fitting density coordinated by arginine and lysine residues from the S4 helix and the C-linker, located between voltage-sensing and pore domains of adjacent subunits. Mutation of two arginine residues weakens PIP2 inhibition with the double mutant displaying insensitivity to PIP2. We propose that PIP2 inhibits SthK by gluing S4 and S6 together, stabilizing a resting channel conformation. The PIP2 binding site is partially conserved in CNG channels suggesting the possibility of a similar inhibition mechanism in the eukaryotic homologs.
The production of the ψ(2S) charmonium state was measured with ALICE in Pb-Pb collisions at sNN−−−√=5.02 TeV, in the dimuon decay channel. A significant signal was observed for the first time at LHC energies down to zero transverse momentum, at forward rapidity (2.5<y<4). The measurement of the ratio of the inclusive production cross sections of the ψ(2S) and J/ψ resonances is reported as a function of the centrality of the collisions and of transverse momentum, in the region pT<12 GeV/c. The results are compared with the corresponding measurements in pp collisions, by forming the double ratio [σψ(2S)/σJ/ψ]Pb−Pb/[σψ(2S)/σJ/ψ]pp. It is found that in Pb-Pb collisions the ψ(2S) is suppressed by a factor of ∼2 with respect to the J/ψ. The ψ(2S) nuclear modification factor RAA was also obtained as a function of both centrality and pT. The results show that the ψ(2S) resonance yield is strongly suppressed in Pb-Pb collisions, by a factor up to ∼3 with respect to pp. Comparisons of cross section ratios with previous SPS findings by the NA50 experiment and of RAA with higher-pT results at LHC energy are also reported. These results and the corresponding comparisons with calculations of transport and statistical models address questions on the presence and properties of charmonium states in the quark-gluon plasma formed in nuclear collisions at the LHC.
The production of the ψ(2S) charmonium state was measured with ALICE in Pb-Pb collisions at sNN−−−√=5.02 TeV, in the dimuon decay channel. A significant signal was observed for the first time at LHC energies down to zero transverse momentum, at forward rapidity (2.5<y<4). The measurement of the ratio of the inclusive production cross sections of the ψ(2S) and J/ψ resonances is reported as a function of the centrality of the collisions and of transverse momentum, in the region pT<12 GeV/c. The results are compared with the corresponding measurements in pp collisions, by forming the double ratio [σψ(2S)/σJ/ψ]Pb−Pb/[σψ(2S)/σJ/ψ]pp. The ψ(2S) nuclear modification factor RAA was also obtained as a function of both centrality and pT. The results show that the ψ(2S) resonance yield is strongly suppressed in Pb-Pb collisions, by a factor up to ∼3 with respect to pp. Furthermore, the ψ(2S) suppression in Pb-Pb collisions is stronger than the one observed for the J/ψ by a factor ∼2. Comparisons of cross section ratios with previous SPS findings by the NA50 experiment, and of RAA with higher-pT results at LHC energy are also reported. These results and the corresponding comparisons with calculations of transport and statistical models address questions on the existence and properties of charmonium states in the quark-gluon plasma formed in nuclear collisions at the LHC.
The production of the ψ(2S) charmonium state was measured with ALICE in Pb-Pb collisions at sNN−−−√=5.02 TeV, in the dimuon decay channel. A significant signal was observed for the first time at LHC energies down to zero transverse momentum, at forward rapidity (2.5<y<4). The measurement of the ratio of the inclusive production cross sections of the ψ(2S) and J/ψ resonances is reported as a function of the centrality of the collisions and of transverse momentum, in the region pT<12 GeV/c. The results are compared with the corresponding measurements in pp collisions, by forming the double ratio [σψ(2S)/σJ/ψ]Pb−Pb/[σψ(2S)/σJ/ψ]pp. The ψ(2S) nuclear modification factor RAA was also obtained as a function of both centrality and pT. The results show that the ψ(2S) resonance yield is strongly suppressed in Pb-Pb collisions, by a factor up to ∼3 with respect to pp. Furthermore, the ψ(2S) suppression in Pb-Pb collisions is stronger than the one observed for the J/ψ by a factor ∼2. Comparisons of cross section ratios with previous SPS findings by the NA50 experiment, and of RAA with higher-pT results at LHC energy are also reported. These results and the corresponding comparisons with calculations of transport and statistical models address questions on the existence and properties of charmonium states in the quark-gluon plasma formed in nuclear collisions at the LHC.
The first measurement of the cross section for incoherent photonuclear production of J/ψ vector mesons as a function of the Mandelstam |t| variable is presented. The measurement was carried out with the ALICE detector at midrapidity, |y|<0.8, using ultra-peripheral collisions of Pb nuclei at a centre-of-mass energy per nucleon pair of sNN−−−√=5.02 TeV. This rapidity interval corresponds to a Bjorken-x range (0.3−1.4)×10−3. Cross sections are given in five |t| intervals in the range 0.04<|t|<1 GeV2 and compared to the predictions by different models. Models that ignore quantum fluctuations of the gluon density in the colliding hadron predict a |t|-dependence of the cross section much steeper than in data. The inclusion of such fluctuations in the same models provides a better description of the data.
The ALICE experiment was proposed in 1993, to study strongly interacting matter at extreme energy densities via a comprehensive investigation of nuclear collisions at the LHC. Its physics programme initially focused on the determination of the properties of the Quark-Gluon Plasma (QGP), a deconfined state of quarks and gluons and was extended along the years, covering a diverse ensemble of observables related to Quantum Chromodynamics (QCD), the theory of strong interactions. The experiment has studied Pb-Pb, Xe-Xe, p-Pb and pp collisions in the multi-TeV energy range, during the Run 1 and Run 2 data taking periods at the LHC (2009-2018). The aim of this review article is to gather and summarise a selection of ALICE physics results and to discuss their implications on the current understanding of the macroscopic and microscopic properties of strongly interacting matter at the highest temperature reached in the laboratory. It will be shown that it is possible to have a quantitative description of the properties of the QGP produced in Pb--Pb collisions. We also show that various features, commonly ascribed to QGP formation, are detected for a wide range of interacting system sizes. Precision measurements of QCD-related observables not directly connected to the study of the QGP will also be discussed. Prospects for future measurements with the ALICE detector and its foreseen upgrades will also be briefly described.