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Release of neuropeptides from dense core vesicles (DCVs) is essential for neuromodulation. Compared to the release of small neurotransmitters, much less is known about the mechanisms and proteins contributing to neuropeptide release. By optogenetics, behavioral analysis, electrophysiology, electron microscopy, and live imaging, we show that synapsin SNN-1 is required for cAMP-dependent neuropeptide release in Caenorhabditis elegans hermaphrodite cholinergic motor neurons. In synapsin mutants, behaviors induced by the photoactivated adenylyl cyclase bPAC, which we previously showed to depend on acetylcholine and neuropeptides (Steuer Costa et al., 2017), are altered like in animals with reduced cAMP. Synapsin mutants have slight alterations in synaptic vesicle (SV) distribution, however, a defect in SV mobilization was apparent after channelrhodopsin-based photostimulation. DCVs were largely affected in snn-1 mutants: DCVs were ∼30% reduced in synaptic terminals, and not released following bPAC stimulation. Imaging axonal DCV trafficking, also in genome-engineered mutants in the serine-9 protein kinase A phosphorylation site, showed that synapsin captures DCVs at synapses, making them available for release. SNN-1 co-localized with immobile, captured DCVs. In synapsin deletion mutants, DCVs were more mobile and less likely to be caught at release sites, and in non-phosphorylatable SNN-1B(S9A) mutants, DCVs traffic less and accumulate, likely by enhanced SNN-1 dependent tethering. Our work establishes synapsin as a key mediator of neuropeptide release.
Kinase fusions are considered oncogenic drivers in numerous types of cancer. In lung adenocarcinoma 5–10% of patients harbor kinase fusions. The most frequently detected kinase fusion involves the Anaplastic Lymphoma Kinase (ALK) and Echinoderm Microtubule-associated protein-Like 4 (EML4). In addition, oncogenic kinase fusions involving the tyrosine kinases RET and ROS1 are found in smaller subsets of patients. In this study, we employed quantitative mass spectrometry-based phosphoproteomics to define the cellular tyrosine phosphorylation patterns induced by different oncogenic kinase fusions identified in patients with lung adenocarcinoma. We show that exogenous expression of the kinase fusions in HEK 293T cells leads to widespread tyrosine phosphorylation. Direct comparison of different kinase fusions demonstrates that the kinase part and not the fusion partner primarily defines the phosphorylation pattern. The tyrosine phosphorylation patterns differed between ALK, ROS1, and RET fusions, suggesting that oncogenic signaling induced by these kinases involves the modulation of different cellular processes.
TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.
Extant research shows that CEO characteristics affect earnings management. This paper studies how investors infer a specific characteristic of CEOs, namely moral commitment to honesty, from earnings management and how this perception – in conjunction with their own social and moral preferences – shapes their investment choices. We conduct two laboratory experiments simulating investment choices. Our results show that participants perceive a CEO to be more committed to honesty when they infer that the CEO engaged less in earnings management. For investment decisions, a one standard deviation increase in a CEO's perceived commitment to honesty compared to another CEO reduces the relevance of differences in the CEOs’ claimed future returns by 40%. This effect is most prominent among investors with a proself value orientation. To prosocial investors, their own honesty values and those attributed to the CEO matter directly, while returns play a secondary role. Overall, perceived CEO honesty matters to different investors for distinct reasons.
At particle collider experiments, elementary particle interactions with large momentum transfer produce quarks and gluons (known as partons) whose evolution is governed by the strong force, as described by the theory of quantum chromodynamics (QCD). The vacuum is not transparent to the partons and induces gluon radiation and quark pair production in a process that can be described as a parton shower. Studying the pattern of the parton shower is one of the key experimental tools in understanding the properties of QCD. This pattern is expected to depend on the mass of the initiating parton, through a phenomenon known as the dead-cone effect, which predicts a suppression of the gluon spectrum emitted by a heavy quark of mass m and energy E, within a cone of angular size m/E around the emitter. A direct observation of the dead-cone effect in QCD has not been possible until now, due to the challenge of reconstructing the cascading quarks and gluons from the experimentally accessible bound hadronic states. We report the first direct observation of the QCD dead-cone by using new iterative declustering techniques to reconstruct the parton shower of charm quarks. This result confirms a fundamental feature of QCD, which is derived more generally from its origin as a gauge quantum field theory. Furthermore, the measurement of a dead-cone angle constitutes a direct experimental observation of the non-zero mass of the charm quark, which is a fundamental constant in the standard model of particle physics.
The pT-differential production cross sections of prompt and non-prompt (produced in beauty-hadron decays) D mesons were measured by the ALICE experiment at midrapidity (|y|<0.5) in proton--proton collisions at s√=5.02 TeV. The data sample used in the analysis corresponds to an integrated luminosity of (19.3±0.4) nb−1. D mesons were reconstructed from their decays D0→K−π+, D+→K−π+π+, and D+s→ϕπ+→K−K+π+ and their charge conjugates. Compared to previous measurements in the same rapidity region, the cross sections of prompt D+ and D+s mesons have an extended pT coverage and total uncertainties reduced by a factor ranging from 1.05 to 1.6, depending on pT, allowing for a more precise determination of their pT-integrated cross sections. The results are well described by perturbative QCD calculations. The fragmentation fraction of heavy quarks to strange mesons divided by the one to non-strange mesons, fs/(fu+fd), is compatible for charm and beauty quarks and with previous measurements at different centre-of-mass energies and collision systems. The bb¯¯¯ production cross section per rapidity unit at midrapidity, estimated from non-prompt D-meson measurements, is dσbb¯¯¯/dy||y|<0.5=34.5±2.4(stat.)+4.7−2.9(tot.syst.) μb. It is compatible with previous measurements at the same centre-of-mass energy and with the cross section predicted by perturbative QCD calculations.
The pT-differential production cross sections of prompt and non-prompt (produced in beauty-hadron decays) D mesons were measured by the ALICE experiment at midrapidity (|y|<0.5) in proton--proton collisions at s√=5.02 TeV. The data sample used in the analysis corresponds to an integrated luminosity of (19.3±0.4) nb−1. D mesons were reconstructed from their decays D0→K−π+, D+→K−π+π+, and D+s→ϕπ+→K−K+π+ and their charge conjugates. Compared to previous measurements in the same rapidity region, the cross sections of prompt D+ and D+s mesons have an extended pT coverage and total uncertainties reduced by a factor ranging from 1.05 to 1.6, depending on pT, allowing for a more precise determination of their pT-integrated cross sections. The results are well described by perturbative QCD calculations. The fragmentation fraction of heavy quarks to strange mesons divided by the one to non-strange mesons, fs/(fu+fd), is compatible for charm and beauty quarks and with previous measurements at different centre-of-mass energies and collision systems. The bb¯¯¯ production cross section per rapidity unit at midrapidity, estimated from non-prompt D-meson measurements, is dσbb¯¯¯/dy||y|<0.5=34.5±2.4(stat.)+4.7−2.9(tot.syst.) μb. It is compatible with previous measurements at the same centre-of-mass energy and with the cross section predicted by perturbative QCD calculations.
J/ψ production as a function of charged-particle multiplicity in p–Pb
collisions at √sNN = 8.16 TeV
(2021)
Inclusive J/ψ yields and average transverse momenta in p-Pb collisions at a center-of-mass energy per nucleon pair sNN−−−√ = 8.16 TeV are measured as a function of the charged-particle pseudorapidity density with ALICE. The J/ψ mesons are reconstructed at forward (2.03<ycms<3.53) and backward (−4.46<ycms<−2.96) center-of-mass rapidity in their dimuon decay channel while the charged-particle pseudorapidity density is measured around midrapidity. The J/ψ yields at forward and backward rapidity normalized to their respective average values increase with the normalized charged-particle pseudorapidity density, the former showing a weaker increase than the latter. The normalized average transverse momenta at forward and backward rapidity manifest a steady increase from low to high charged-particle pseudorapidity density with a saturation beyond the average value.