A Pair of Dopamine Neurons Target the D1-Like Dopamine Receptor DopR in the Central Complex to Promote Ethanol-Stimulated Locomotion in Drosophila

Dopamine is a mediator of the stimulant properties of drugs of abuse, including ethanol, in mammals and in the fruit fly Drosophila. The neural substrates for the stimulant actions of ethanol in flies are not known. We show that a subset of dopamine neurons and their targets, through the action of the D1-like dopamine receptor DopR, promote locomotor activation in response to acute ethanol exposure. A bilateral pair of dopaminergic neurons in the fly brain mediates the enhanced locomotor activity induced by ethanol exposure, and promotes locomotion when directly activated. These neurons project to the central complex ellipsoid body, a structure implicated in regulating motor behaviors. Ellipsoid body neurons are required for ethanol-induced locomotor activity and they express DopR. Elimination of DopR blunts the locomotor activating effects of ethanol, and this behavior can be restored by selective expression of DopR in the ellipsoid body. These data tie the activity of defined dopamine neurons to D1-like DopR-expressing neurons to form a neural circuit that governs acute responding to ethanol

Search for B c + → π + μ + μ - decays and measurement of the branching fraction ratio B ( B c + → ψ ( 2 S ) π + ) / B ( B c + → J / ψ π + )

The first search for nonresonant Bc+→π+μ+μ- decays is reported. The analysis uses proton–proton collision data collected with the LHCb detector between 2011 and 2018, corresponding to an integrated luminosity of 9fb-1. No evidence for an excess of signal events over background is observed and an upper limit is set on the branching fraction ratio B(Bc+→π+μ+μ-)/B(Bc+→J/ψπ+)<2.1×10-4 at 90% confidence level. Additionally, an updated measurement of the ratio of the Bc+→ψ(2S)π+ and Bc+→J/ψπ+ branching fractions is reported. The ratio B(Bc+→ψ(2S)π+)/B(Bc+→J/ψπ+) is measured to be 0.254±0.018±0.003±0.005, where the first uncertainty is statistical, the second systematic, and the third is due to the uncertainties on the branching fractions of the leptonic J/ψ and ψ(2S) decays. This measurement is the most precise to date and is consistent with previous LHCb results

Search for the B s 0 → μ + μ − γ decay

A search for the fully reconstructed Bs0→ μ+μ−γ decay is performed at the LHCb experiment using proton-proton collisions at s = 13 TeV corresponding to an integrated luminosity of 5.4 fb−1. No significant signal is found and upper limits on the branching fraction in intervals of the dimuon mass are setBBs0→μ+μ−γ<4.2×10−8, mμ+μ−∈2mμ1.70GeV/c2, BBs0→μ+μ−γ<7.7×10−8, mμ+μ−∈1.70, 2.88GeV/c2, BBs0→μ+μ−γ<4.2×10−8, mμ+μ−∈3.92mBs0GeV/c2, at 95% confidence level. Additionally, upper limits are set on the branching fraction in the [2mμ, 1.70] GeV/c2 dimuon mass region excluding the contribution from the intermediate ϕ(1020) meson, and in the region combining all dimuon-mass intervals

A model-independent measurement of the CKM angle γ in partially reconstructed B ± → D * h ± decays with D → K S 0 h + h − ( h = π, K )

A measurement of CP-violating observables in B± → D*K± and B± → D*π± decays is made where the photon or neutral pion from the D*→ Dγ or D*→ Dπ0 decay is not reconstructed. The D meson is reconstructed in the self-conjugate decay modes, D → KS0π+π− or D → KS0K+K−. The distribution of signal yields in the D decay phase space is analysed in a model-independent way. The measurement uses a data sample collected in proton-proton collisions at centre-of-mass energies of 7, 8, and 13 TeV, corresponding to a total integrated luminosity of approximately 9 fb−1. The B± → D*K± and B± → D*π±CP-violating observables are interpreted in terms of hadronic parameters and the CKM angle γ, resulting in a measurement of γ = (92−17+21)°. The total uncertainty includes the statistical and systematic uncertainties, and the uncertainty due to external strong-phase inputs

Measurement of the Z boson production cross-section in pp collisions at s = 5. 02 TeV

The first measurement of the Z boson production cross-section at centre-of-mass energy s = 5.02 TeV in the forward region is reported, using pp collision data collected by the LHCb experiment in year 2017, corresponding to an integrated luminosity of 100 ± 2 pb−1. The production cross-section is measured for final-state muons in the pseudorapidity range 2.0 20 GeV/c. The integrated cross-section is determined to beσZ→μ+μ−=39.6±0.7stat±0.6syst±0.8lumipb for the di-muon invariant mass in the range 60 < Mμμ< 120 GeV/c2. This result and the differential cross-section results are in good agreement with theoretical predictions at next-to-next-to-leading order in the strong coupling constant. Based on a previous LHCb measurement of the Z boson production cross-section in pPb collisions at sNN = 5.02 TeV, the nuclear modification factor RpPb is measured for the first time at this energy. The measured values are 1.2−0.3+0.5 (stat) ± 0.1(syst) in the forward region (1.5

Study of B c + → χ c π + decays

A study of Bc+→χcπ+ decays is reported using proton-proton collision data, collected with the LHCb detector at centre-of-mass energies of 7, 8, and 13 TeV, corresponding to an integrated luminosity of 9 fb−1. The decay Bc+→χc2π+ is observed for the first time, with a significance exceeding seven standard deviations. The relative branching fraction with respect to the Bc+→J/ψπ+ decay is measured to beBBc+→χc2π+BBc+→J/ψπ+=0.37±0.06±0.02±0.01, where the first uncertainty is statistical, the second is systematic, and the third is due to the knowledge of the χc2→ J/ψγ branching fraction. No significant Bc+→χc1π+ signal is observed and an upper limit for the relative branching fraction for the Bc+→χc1π+ and Bc+→χc2π+ decays of BBc+→χc1π+BBc+→χc2π+=<0.49 is set at the 90% confidence level

Mass spectrometry-based absolute quantification of 20S proteasome status for controlled ex-vivo expansion of Human Adipose-derived Mesenchymal Stromal/Stem Cells

The proteasome controls a multitude of cellular processes through protein degradation and has been identified as a therapeutic target in oncology. However, our understanding of its function and the development of specific modulators are hampered by the lack of a straightforward method to determine the overall proteasome status in biological samples. Here, we present a method to determine the absolute quantity and stoichiometry of ubiquitous and tissue-specific human 20S proteasome subtypes based on a robust, absolute SILAC-based multiplexed LC-Selected Reaction Monitoring (SRM) quantitative mass spectrometry assay with high precision, accuracy, and sensitivity. The method was initially optimized and validated by comparison with a reference ELISA assay and by analyzing the dynamics of catalytic subunits in HeLa cells following IFNγ-treatment and in range of human tissues. It was then successfully applied to reveal IFNγ- and O2-dependent variations of proteasome status during primary culture of Adipose-derived-mesenchymal Stromal/Stem Cells (ADSCs). The results show the critical importance of controlling the culture conditions during cell expansion for future therapeutic use in humans. We hypothesize that a shift from the standard proteasome to the immunoproteasome could serve as a predictor of immunosuppressive and differentiation capacities of ADSCs and, consequently, that quality control should include proteasomal quantification in addition to examining other essential cell parameters. The method presented also provides a new powerful tool to conduct more individualized protocols in cancer or inflammatory diseases where selective inhibition of the immunoproteasome has been shown to reduce side effects

A search for rare B → Dμ + μ − decays

A search for rare B → Dμ+μ− decays is performed using proton-proton collision data collected by the LHCb experiment, corresponding to an integrated luminosity of 9 fb−1. No significant signals are observed in the non-resonant μ+μ− modes, and upper limits of BB0→D¯0μ+μ−<5.1×10−8, BB+→Ds+μ+μ−<3.2×10−8, BBs0→D¯0μ+μ−<1.6×10−7 and fc/fu·BBc+→Ds+μ+μ−<9.6×10−8 are set at the 95 % confidence level, where fc and fu are the fragmentation fractions of a B meson with a c and u quark respectively in proton-proton collisions. Each result is either the first such measurement or an improvement by three orders of magnitude on an existing limit. Separate upper limits are calculated when the muon pair originates from a J/ψ → μ+μ− decay. The branching fraction of Bc+→Ds+J/ψ multiplied by the fragmentation-fraction ratio is measured to befcfu·BBc+→Ds+J/ψ=1.63±0.15±0.13×10−5, where the first uncertainty is statistical and the second systematic

The Homeodomain Derived Peptide Penetratin Induces Curvature of Fluid Membrane Domains

BACKGROUND:Protein membrane transduction domains that are able to cross the plasma membrane are present in several transcription factors, such as the homeodomain proteins and the viral proteins such as Tat of HIV-1. Their discovery resulted in both new concepts on the cell communication during development, and the conception of cell penetrating peptide vectors for internalisation of active molecules into cells. A promising cell penetrating peptide is Penetratin, which crosses the cell membranes by a receptor and metabolic energy-independent mechanism. Recent works have claimed that Penetratin and similar peptides are internalized by endocytosis, but other endocytosis-independent mechanisms have been proposed. Endosomes or plasma membranes crossing mechanisms are not well understood. Previously, we have shown that basic peptides induce membrane invaginations suggesting a new mechanism for uptake, "physical endocytosis". METHODOLOGY/PRINCIPAL FINDINGS:Herein, we investigate the role of membrane lipid phases on Penetratin induced membrane deformations (liquid ordered such as in "raft" microdomains versus disordered fluid "non-raft" domains) in membrane models. Experimental data show that zwitterionic lipid headgroups take part in the interaction with Penetratin suggesting that the external leaflet lipids of cells plasma membrane are competent for peptide interaction in the absence of net negative charges. NMR and X-ray diffraction data show that the membrane perturbations (tubulation and vesiculation) are associated with an increase in membrane negative curvature. These effects on curvature were observed in the liquid disordered but not in the liquid ordered (raft-like) membrane domains. CONCLUSIONS/SIGNIFICANCE:The better understanding of the internalisation mechanisms of protein transduction domains will help both the understanding of the mechanisms of cell communication and the development of potential therapeutic molecular vectors. Here we showed that the membrane targets for these molecules are preferentially the fluid membrane domains and that the mechanism involves the induction of membrane negative curvature. Consequences on cellular uptake are discussed