Sleep loss drives acetylcholine- and somatostatin interneuron-mediated gating of hippocampal activity to inhibit memory consolidation

Sleep loss disrupts consolidation of hippocampus-dependent memory. To characterize effects of learning and sleep loss, we quantified activity-dependent phosphorylation of ribosomal protein S6 (pS6) across the dorsal hippocampus of mice. We find that pS6 is enhanced in dentate gyrus (DG) following single-trial contextual fear conditioning (CFC) but is reduced throughout the hippocampus after brief sleep deprivation (SD; which disrupts contextual fear memory [CFM] consolidation). To characterize neuronal populations affected by SD, we used translating ribosome affinity purification sequencing to identify cell type-specific transcripts on pS6 ribosomes (pS6-TRAP). Cell type-specific enrichment analysis revealed that SD selectively activated hippocampal somatostatin-expressing (Sst+) interneurons and cholinergic and orexinergic hippocampal inputs. To understand the functional consequences of SD-elevated Sst+ interneuron activity, we used pharmacogenetics to activate or inhibit hippocampal Sst+ interneurons or cholinergic input from the medial septum. The activation of either cell population was sufficient to disrupt sleep-dependent CFM consolidation by gating activity in granule cells. The inhibition of either cell population during sleep promoted CFM consolidation and increased S6 phosphorylation among DG granule cells, suggesting their disinhibition by these manipulations. The inhibition of either population across post-CFC SD was insufficient to fully rescue CFM deficits, suggesting that additional features of sleeping brain activity are required for consolidation. Together, our data suggest that state-dependent gating of DG activity may be mediated by cholinergic input and local Sst+ interneurons. This mechanism could act as a sleep loss-driven inhibitory gate on hippocampal information processing.</p

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Causal role for sleep-dependent reactivation of learning-activated sensory ensembles for fear memory consolidation

Learning-activated engram neurons play a critical role in memory recall. An untested hypothesis is that these same neurons play an instructive role in offline memory consolidation. Here we show that a visually-cued fear memory is consolidated during post-conditioning sleep in mice. We then use TRAP (targeted recombination in active populations) to genetically label or optogenetically manipulate primary visual cortex (V1) neurons responsive to the visual cue. Following fear conditioning, mice respond to activation of this visual engram population in a manner similar to visual presentation of fear cues. Cue-responsive neurons are selectively reactivated in V1 during post-conditioning sleep. Mimicking visual engram reactivation optogenetically leads to increased representation of the visual cue in V1. Optogenetic inhibition of the engram population during post-conditioning sleep disrupts consolidation of fear memory. We conclude that selective sleep-associated reactivation of learning-activated sensory populations serves as a necessary instructive mechanism for memory consolidation

A study of C ⁣PC\!P violation in the decays B±→[K+K−π+π−]Dh±B^\pm\to[K^+K^-\pi^+\pi^-]_D h^{\pm} (h=K,πh = K, \pi) and B±→[π+π−π+π−]Dh±B^\pm\to[\pi^+\pi^-\pi^+\pi^-]_D h^{\pm}

The first study of $C\!P$ violation in the decay mode $B^\pm\to[K^+K^-\pi^+\pi^-]_D h^{\pm}$, with $h=K,\pi$, is presented, exploiting a data sample of proton-proton collisions collected by the LHCb experiment that corresponds to an integrated luminosity of $9$ fb$^{-1}$. The analysis is performed in bins of phase space, which are optimised for sensitivity to local $C\!P$ asymmetries. $C\!P$-violating observables that are sensitive to the angle $\gamma$ of the Unitarity Triangle are determined. The analysis requires external information on charm-decay parameters, which are currently taken from an amplitude analysis of LHCb data, but can be updated in the future when direct measurements become available. Measurements are also performed of phase-space integrated observables for $B^\pm\to[K^+K^-\pi^+\pi^-]_D h^{\pm}$ and $B^\pm\to[\pi^+\pi^-\pi^+\pi^-]_D h^{\pm}$ decays.The first study of $C\!P$ violation in the decay mode {{B} ^\pm } \rightarrow [{{K} ^+} {{K} ^-} {{\uppi } ^+} {{\uppi } ^-} ]_{D} h^\pm , with $h=K,\pi$, is presented, exploiting a data sample of proton–proton collisions collected by the LHCb experiment that corresponds to an integrated luminosity of $9\text {\,fb} ^{-1}$. The analysis is performed in bins of phase space, which are optimised for sensitivity to local $C\!P$ asymmetries. $C\!P$-violating observables that are sensitive to the angle $\gamma$ of the Unitarity Triangle are determined. The analysis requires external information on charm-decay parameters, which are currently taken from an amplitude analysis of LHCb data, but can be updated in the future when direct measurements become available. Measurements are also performed of phase-space integrated observables for {{B} ^\pm } \rightarrow [{{K} ^+} {{K} ^-} {{\uppi } ^+} {{\uppi } ^-} ]_{D} h^\pm and {{B} ^\pm } \rightarrow [{{\uppi } ^+} {{\uppi } ^-} {{\uppi } ^+} {{\uppi } ^-} ]_{D} h^\pm decays.The first study of $C\!P$ violation in the decay mode $B^\pm\to[K^+K^-\pi^+\pi^-]_D h^\pm$, with $h=K,\pi$, is presented, exploiting a data sample of proton-proton collisions collected by the LHCb experiment that corresponds to an integrated luminosity of $9$ fb$^{-1}$. The analysis is performed in bins of phase space, which are optimised for sensitivity to local $C\!P$ asymmetries. $C\!P$-violating observables that are sensitive to the angle $\gamma$ of the Unitarity Triangle are determined. The analysis requires external information on charm-decay parameters, which are currently taken from an amplitude analysis of LHCb data, but can be updated in the future when direct measurements become available. Measurements are also performed of phase-space integrated observables for $B^\pm\to[K^+K^-\pi^+\pi^-]_D h^\pm$ and $B^\pm\to[\pi^+\pi^-\pi^+\pi^-]_D h^\pm$ decays

Observation of the Bs0 ⁣→D∗+D∗−B^0_s\!\to D^{*+}D^{*-} decay

International audienceThe first observation of the ${B}_s^0$→ D$^{∗+}$D$^{∗−}$ decay and the measurement of its branching ratio relative to the B$^{0}$→ D$^{∗+}$D$^{∗−}$ decay are presented. The data sample used corresponds to an integrated luminosity of 9 fb$^{−1}$ of proton-proton collisions recorded by the LHCb experiment at centre-of-mass energies of 7, 8 and 13 TeV between 2011 and 2018. The decay is observed with more than 10 standard deviations and the time-integrated ratio of branching fractions is determined to be$\frac{\mathcal{B}\left({B}_s^0\to {D}^{\ast +}{D}^{\ast -}\right)}{\mathcal{B}\left({B}^0\to {D}^{\ast +}{D}^{\ast -}\right)}=0.269\pm 0.032\pm 0.011\pm 0.008,$where the first uncertainty is statistical, the second systematic and the third due to the uncertainty of the fragmentation fraction ratio f$_{s}$/f$_{d}$. The ${B}_s^0$→ D$^{*+}$D$^{*−}$ branching fraction is calculated to be$\mathcal{B}\left({B}_s^0\to {D}^{\ast +}{D}^{\ast -}\right)=\left(2.15\pm 0.26\pm 0.09\pm 0.06\pm 0.16\right)\times {10}^{-4},$where the fourth uncertainty is due to the B$^{0}$→ D$^{*+}$D$^{*−}$ branching fraction. These results are calculated using the average ${B}_s^0$ meson lifetime in simulation. Correction factors are reported for scenarios where either a purely heavy or a purely light ${B}_s^0$ eigenstate is considered.[graphic not available: see fulltext

First observation of the <math display="inline"><msup><mi>B</mi><mo>+</mo></msup><mo stretchy="false">→</mo><msubsup><mi>D</mi><mi>s</mi><mo>+</mo></msubsup><msubsup><mi>D</mi><mi>s</mi><mo>-</mo></msubsup><msup><mi>K</mi><mo>+</mo></msup></math> decay

International audienceThe B+→Ds+Ds-K+ decay is observed for the first time using proton-proton collision data collected by the LHCb detector at center-of-mass energies of 7, 8, and 13 TeV, corresponding to an integrated luminosity of 9  fb-1. Its branching fraction relative to that of the B+→D+D-K+ decay is measured to be B(B+→Ds+Ds-K+)B(B+→D+D-K+)=0.525±0.033±0.027±0.034, where the first uncertainty is statistical, the second systematic, and the third is due to the uncertainties on the branching fractions of the Ds±→K∓K±π± and D±→K∓π±π± decays. This measurement fills an experimental gap in the knowledge of the family of Cabibbo-favored b¯→c¯cs¯ transitions and opens the path for unique studies of spectroscopy in future

Measurement of the <math display="inline"><mrow><msubsup><mrow><mi mathvariant="normal">Λ</mi></mrow><mrow><mi>b</mi></mrow><mrow><mn>0</mn></mrow></msubsup><mo stretchy="false">→</mo><mi mathvariant="normal">Λ</mi><mo stretchy="false">(</mo><mn>1520</mn><mo stretchy="false">)</mo><msup><mrow><mi>μ</mi></mrow><mrow><mo>+</mo></mrow></msup><msup><mrow><mi>μ</mi></mrow><mrow><mo>-</mo></mrow></msup></mrow></math> Differential Branching Fraction

The branching fraction of the rare decay $\Lambda_{b}^{0}\to \Lambda(1520) \mu^{+}\mu^{-}$ is measured for the first time, in the squared dimuon mass intervals, $q^2$, excluding the $J/\psi$ and $\psi(2S)$ regions. The data sample analyzed was collected by the LHCb experiment at center-of-mass energies of 7, 8, and 13 TeV, corresponding to a total integrated luminosity of $9\,\mathrm{fb}^{-1}$. The result in the highest $q^{2}$ interval, $q^{2} > 15.0\,\mathrm{GeV}^2/c^4$, where theoretical predictions have the smallest model dependence, agrees with the predictions.The branching fraction of the rare decay Λb0→Λ(1520)μ+μ- is measured for the first time, in the squared dimuon mass intervals q2, excluding the J/ψ and ψ(2S) regions. The data sample analyzed was collected by the LHCb experiment at center-of-mass energies of 7, 8, and 13 TeV, corresponding to a total integrated luminosity of 9  fb-1. The result in the highest q2 interval, q2&gt;15.0  GeV2/c4, where theoretical predictions have the smallest model dependence, agrees with the predictions.The branching fraction of the rare decay $\Lambda_{b}^{0}\to \Lambda(1520) \mu^{+}\mu^{-}$ is measured for the first time, in the squared dimuon mass intervals, $q^2$, excluding the $J/\psi$ and $\psi(2S)$ regions. The data sample analyzed was collected by the LHCb experiment at center-of-mass energies of 7, 8, and 13 TeV, corresponding to a total integrated luminosity of $9\ \mathrm{fb}^{-1}$. The result in the highest $q^{2}$ interval, $q^{2} >15.0\ \mathrm{GeV}^2/c^4$, where theoretical predictions have the smallest model dependence, agrees with the predictions

First observation and branching fraction measurement of the Λb0→Ds−p {\Lambda}_b^0\to {D}_s^{-}p decay

International audienceThe first observation of the ${\Lambda}_b^0\to {D}_s^{-}p$ decay is presented using proton-proton collision data collected by the LHCb experiment at a centre-of-mass energy of $\sqrt{s}$ = 13 TeV, corresponding to a total integrated luminosity of 6 fb$^{−1}$. Using the ${\Lambda}_b^0\to {\Lambda}_c^{+}{\pi}^{-}$ decay as the normalisation mode, the branching fraction of the ${\Lambda}_b^0\to {D}_s^{-}p$ decay is measured to be $\mathcal{B}\left({\Lambda}_b^0\to {D}_s^{-}p\right)=\left(12.6\pm 0.5\pm 0.3\pm 1.2\right)\times {10}^{-6}$, where the first uncertainty is statistical, the second systematic and the third due to uncertainties in the branching fractions of the ${\Lambda}_b^0\to {\Lambda}_c^{+}{\pi}^{-}$, ${D}_s^{-}\to {K}^{-}{K}^{+}{\pi}^{-}$ and ${\Lambda}_c^{+}\to p{K}^{-}{\pi}^{+}$ decays.[graphic not available: see fulltext

Observation of a resonant structure near the Ds+Ds−D_s^+ D_s^- threshold in the B+→Ds+Ds−K+B^+\to D_s^+ D_s^- K^+ decay

An amplitude analysis of the $B^+\to D_s^+ D_s^- K^+$ decay is carried out to study for the first time its intermediate resonant contributions, using proton-proton collision data collected with the LHCb detector at centre-of-mass energies of 7, 8 and 13 TeV. A near-threshold peaking structure, referred to as $X(3960)$, is observed in the $D_s^+ D_s^-$ invariant-mass spectrum with significance greater than 12 standard deviations. The mass, width and the quantum numbers of the structure are measured to be $3956\pm5\pm10$ MeV, $43\pm13\pm8$ MeV and $J^{PC}=0^{++}$, respectively, where the first uncertainties are statistical and the second systematic. The properties of the new structure are consistent with recent theoretical predictions for a state composed of $c\bar{c} s\bar{s}$ quarks. Evidence for an additional structure is found around 4140 MeV in the $D_s^+ D_s^-$ invariant mass, which might be caused either by a new resonance with the $0^{++}$ assignment or by a $J/\psi \phi\leftrightarrow D_s^+ D_s^-$ coupled-channel effect.An amplitude analysis of the B+→Ds+Ds-K+ decay is carried out to study for the first time its intermediate resonant contributions, using proton-proton collision data collected with the LHCb detector at center-of-mass energies of 7, 8, and 13 TeV. A near-threshold peaking structure, referred to as X(3960), is observed in the Ds+Ds- invariant-mass spectrum with significance greater than 12 standard deviations. The mass, width, and the quantum numbers of the structure are measured to be 3956±5±10  MeV, 43±13±8  MeV, and JPC=0++, respectively, where the first uncertainties are statistical and the second systematic. The properties of the new structure are consistent with recent theoretical predictions for a state composed of cc¯ss¯ quarks. Evidence for an additional structure is found around 4140 MeV in the Ds+Ds- invariant mass, which might be caused either by a new resonance with the 0++ assignment or by a J/ψϕ↔Ds+Ds- coupled-channel effect.An amplitude analysis of the $B^+\to D_s^+ D_s^- K^+$ decay is carried out to study for the first time its intermediate resonant contributions, using proton-proton collision data collected with the LHCb detector at centre-of-mass energies of 7, 8 and 13 TeV. A near-threshold peaking structure, referred to as $X(3960)$, is observed in the $D_s^+ D_s^-$ invariant-mass spectrum with significance greater than 12 standard deviations. The mass, width and the quantum numbers of the structure are measured to be $3956\pm5\pm10$ MeV, $43\pm13\pm8$ MeV and $J^{PC}=0^{++}$, respectively, where the first uncertainties are statistical and the second systematic. The properties of the new structure are consistent with recent theoretical predictions for a state composed of $c\bar{c}s\bar{s}$ quarks. Evidence for an additional structure is found around 4140 MeV in the $D_s^+ D_s^-$ invariant mass, which might be caused either by a new resonance with the $0^{++}$ assignment or by a $J/\psi \phi\leftrightarrow D_s^+ D_s^-$ coupled-channel effect