The structured reactivation of hippocampal neuronal ensembles during fast synchronous oscillatory events, termed sharp-wave ripples (SWRs), has been suggested to play a crucial role in the storage ...and use of memory. Activity in both the CA2 and CA3 subregions can precede this population activity in CA1, and chronic inhibition of either region alters SWR oscillations. However, the precise contribution of CA2 to the oscillation, as well as to the reactivation of CA1 neurons within it, remains unclear. Here, we employ chemogenetics to transiently silence CA2 pyramidal cells in mice, and we observe that although SWRs still occur, the reactivation of CA1 pyramidal cell ensembles within the events lose both temporal and informational precision. These observations suggest that CA2 activity contributes to the fidelity of experience-dependent hippocampal replay.
•Silencing of CA2 decreases the temporal precision of SWRs and neuronal spiking•Assemblies from distinct experiences are co-activate following CA2 inhibition•CA1 spiking is more synchronous during replay in the absence of CA2•CA2 influences the informational and temporal precision of neuronal reactivation
He et al. find that DREADD-mediated silencing of CA2 decreases the temporal and informational precision of hippocampal replay. Ripples are less coordinated across CA1 and CA3, and cell assemblies show increased co-activity, both in and out of SWRs. CA2 plays a role in filtering information to be reactivated during replay.
► Calcineurin/NFAT inhibitors FK506 and VIVIT treated human PBMC derived osteoclasts in vitro. ► Differential regulation of ITAM receptors and adaptor molecules by calcineurin/NFAT inhibitors. ► ...FK506 and VIVIT suppress ITAM factors during late phase osteoclast differentiation.
Osteoclasts are specialised bone resorptive cells responsible for both physiological and pathological bone loss. Osteoclast differentiation and activity is dependent upon receptor activator NF-kappa-B ligand (RANKL) interacting with its receptor RANK to induce the transcription factor, nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1). The immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway has been identified as a co-stimulatory pathway in osteoclasts. Osteoclast-associated receptor (OSCAR) and triggering receptor expressed in myeloid cells (TREM2) are essential receptors that pair with adaptor molecules Fc receptor common gamma chain (FcRγ) and DNAX-activating protein 12kDa (DAP12) respectively to induce calcium signalling. Treatment with calcineurin-NFAT inhibitors, Tacrolimus (FK506) and the 11R-VIVIT (VIVIT) peptide, reduces NFATc1 expression consistent with a reduction in osteoclast differentiation and activity. This study aimed to investigate the effects of inhibiting calcineurin-NFAT signalling on the expression of ITAM factors and late stage osteoclast genes including cathepsin K (CathK), Beta 3 integrin (β3) and Annexin VIII (AnnVIII). Human peripheral blood mononuclear cells (PBMCs) were differentiated with RANKL and macrophage-colony stimulating factor (M-CSF) over 10days in the presence or absence of FK506 or VIVIT. Osteoclast formation (as assessed by tartrate resistant acid phosphatase (TRAP)) and activity (assessed by dentine pit resorption) were significantly reduced with treatment. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis demonstrated that FK506 treatment significantly (p<0.05) reduced the expression of NFATc1, CathK, OSCAR, FcRγ, TREM2 and DAP12 during the terminal stage of osteoclast formation. VIVIT treatment significantly (p<0.05) decreased CathK, OSCAR, FcRγ, and AnnVIII, gene expression. This data suggest FK506 and VIVIT act differently in targeting the calcineurin-NFAT signalling cascade to suppress key mediators of the ITAM pathway during late stage osteoclast differentiation and this is associated with a reduction in both osteoclast differentiation and activity.
Analysis of tissues retrieved from the bone-pannus interface from patients with rheumatoid arthritis (RA) and studies in animal models of inflammatory arthritis provide strong evidence that ...osteoclasts, the cells that are essential for physiological bone resorption, are responsible for articular bone destruction in RA. However, current treatments that specifically target osteoclast-mediated bone resorption in RA have not been successful in preventing bone erosions, and new therapeutic strategies are needed. It has been noted that, although osteoclast precursors are present within the bone microenvironment at sites of pathological bone resorption, cells expressing the full morphological and functional properties of mature osteoclasts are restricted to the immediate bone surface and adjacent calcified cartilage. These findings provide evidence that, in addition to requirements for specific cytokines, interaction of osteoclast precursors with these mineralised matrices results in activation of specific signal pathways and the induction of unique gene products that are essential for terminal osteoclast differentiation and activation. These studies are designed to define the gene products and signalling pathways regulated by bone and calcified cartilage, to identify new molecular targets and novel therapeutic approaches for preventing osteoclast-mediated joint destruction in RA and related forms of pathological bone loss.
The branching fraction of the rare decay Lambda(0 )(b)-> 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 fb(-1). The result in the highest q(2) interval, q(2) > 15.0 GeV2/c(4), where theoretical predictions have the smallest model dependence, agrees with the predictions.
A measurement of charm mixing and CP-violating parameters is reported, using B over bar -> D0(-> K0S pi+pi-)x mu- nu over bar mu X decays reconstructed in proton-proton collisions collected by ...the LHCb experiment during the years 2016 to 2018, corresponding to an integrated luminosity of 5.4 fb-1. The measured mixing and CP-violating parameters are xCP = 4.29 1 1.48(stat) 1 0.26(syst) x 10-3, yCP = 12.61 1 3.12(stat) 1 0.83(syst) x 10-3, Ax = -0.77 1 0.93(stat) 1 0.28(syst) x 10-3, Ay = 3.01 1 1.92(stat) 1 0.26(syst) x 10-3. The results are complementary to and consistent with previous measurements. A combination with the recent LHCb analysis of D*+ -> D0(-> K0S pi+ pi-)pi+ decays is reported.
The decay B- -> Lambda(+)(c)(Lambda) over bar K--(c)- is studied in proton-proton collisions at a center-of-mass energy of root s = 13 TeV using data corresponding to an integrated luminosity of 5 ...fb(-1) collected by the LHCb experiment. In the Lambda K-+(c)- system, the Xi(c)(2930)(0) state observed at the BABAR and Belle experiments is resolved into two narrower states, Xi(c)(2923)(0) and Xi(c)(2939)(0), whose masses and widths are measured to be m(Xi(c)(2930)(0) = 2924.5 +/- 0.4 +/- 1.1 Mev, m Xi(c)(2930)(0)) = 2938.5 +/- 0.9 +/- 2.3 Mev, Gamma(Xi(c)(2930)(0)) = 4.8 +/- 0.9 +/- 1.5 MeV, Gamma(Xi(c)(2930)(0) - 11.0 +/- 1.9 +/- 7.5 MeV, where the first uncertainties are statistical and the second systematic. The results are consistent with a previous LHCb measurement using a prompt Lambda K-+(c)- sample. Evidence of a new Xi(c)(2930)(0) state is found with a local significance of 3.8 sigma, whose mass and width are measured to be 2881.8 +/- 3.1 +/- 8.5 MeV and 12.4 +/- 5.3 +/- 5.8 MeV, respectively. In addition, evidence of a new decay mode Xi(c)(2930)(0) -> Lambda K-+(c) is found with a significance of 3.7 sigma. The relative branching fraction of B- -> Lambda(+)(c)(Lambda) over bar K--(c)- with respect to the B- -> D+D-K- decay is measured to be 2.36 +/- 0.11 +/- 0.22 +/- 0.25, where the first uncertainty is statistical, the second systematic and the third originates from the branching fractions of charm hadron decays.
A study of the B+ -> (KSK+)-K-0 K-pi(+) and B+ -> (KSK+K+)-K-0 pi(-) decays is performed using proton-proton collisions at center-of-mass energies of 7, 8 and 13 TeV at the LHCb experiment. The ...(KSK)-K-0 pi invariant mass spectra from both decay modes reveal a rich content of charmonium resonances. New precise measurements of the eta(c) and eta(c)(2S) resonance parameters are performed and branching fraction measurements are obtained for B+ decays to eta(c), J/psi, eta(c)(2S) and chi(c1) resonances. In particular, the first observation and branching fraction measurement of B+ -> chi K-c0(0)pi(+) is reported as well as first measurements of the B+ -> (KK+K-)-K-0 pi(+) and B+ -> (KK+K+)-K-0 pi(-) branching fractions. Dalitz plot analyses of eta(c) -> (KSK)-K-0 pi and eta(c)(2S) -> (KSK)-K-0 pi decays are performed. A new measurement of the amplitude and phase of the K pi S-wave as functions of the K pi mass is performed, together with measurements of the K-0*(1430), K-0*(1950) and a(0)(1700) parameters. Finally, the branching fractions of chi(c1) decays to K* resonances are also measured.
The interpretation of cosmic antiproton flux measurements from space-borne experiments is currently limited by the knowledge of the antiproton production cross-section in collisions between primary ...cosmic rays and the interstellar medium. Using collisions of protons with an energy of 6.5 TeV incident on helium nuclei at rest in the proximity of the interaction region of the LHCb experiment, the ratio of antiprotons originating from antihyperon decays to prompt production is measured for antiproton momenta between 12 and 110 GeV/c. The dominant antihyperon contribution, namely (Lambda) over bar -> (p) over bar pi(+) decays from promptly produced (Lambda) over bar particles, is also exclusively measured. The results complement the measurement of prompt antiproton production obtained from the same data sample. At the energy scale of this measurement, the antihyperon contributions to antiproton production are observed to be significantly larger than predictions of commonly used hadronic production models.
The treatment of tuberculosis is based on combinations of drugs that directly target Mycobacterium tuberculosis. A new global initiative is now focusing on a complementary approach of developing ...adjunct host-directed therapies.
Osteoclast and their mononuclear cell precursors are present within the bone microenvironment at sites of physiologic and pathologic bone resorption. Analysis of tissues from sites of bone resorption ...reveal that cells expressing the full morphological and functional properties of mature osteoclasts are restricted to the immediate bone surface. We hypothesize that in addition to cytokines, components of the bone matrix and specific cell surface receptors on osteoclasts and their precursors play an essential role in determining the genetic profile and functional properties of fully differentiated resorbing osteoclasts. We have employed expression profiling, with an in vitro model of matrix-dependent osteoclast differentiation, to identify the molecular pathways by which bone matrix-interactions induce terminal osteoclast differentiation and activation. In preliminary studies, we have identified unique genes and transcriptional pathways that are induced by interaction of osteoclast precursors with specific components of the mineralized bone matrix. The authenticity of the gene profiles, as markers of osteoclast differentiation and activation, have been provisionally validated using an in vivo animal bone implantation model and by examination of tissues from patients with specific forms of pathologic osteoclast-mediated bone resorption. The ultimate goal of our studies is to identify new molecular targets for inhibiting osteoclast-mediated bone loss in disorders of pathologic bone loss.
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