ERK1 Regulates the Hematopoietic Stem Cell Niches

The mitogen-activated protein kinases (MAPK) ERK1 and ERK2 are among the major signal transduction molecules but little is known about their specific functions in vivo. ERK activity is provided by two isoforms, ERK1 and ERK2, which are ubiquitously expressed and share activators and substrates. However, there are not in vivo studies which have reported a role for ERK1 or ERK2 in HSCs and the bone marrow microenvironment. The present study shows that the ERK1-deficient mice present a mild osteopetrosis phenotype. The lodging and the homing abilities of the ERK1−/− HSC are impaired, suggesting that the ERK1−/−-defective environment may affect the engrafment of HSCs. Serial transplantations demonstrate that ERK1 is involved in the maintenance of an appropriate medullar microenvironment, but that the intrinsic properties of HSCs are not altered by the ERK1−/− defective microenvironment. Deletion of ERK1 impaired in vitro and in vivo osteoclastogenesis while osteoblasts were unaffected. As osteoclasts derive from precursors of the monocyte/macrophage lineage, investigation of the monocytic compartment was performed. In vivo analysis of the myeloid lineage progenitors revealed that the frequency of CMPs increased by approximately 1.3-fold, while the frequency of GMPs significantly decreased by almost 2-fold, compared with the respective WT compartments. The overall mononuclear-phagocyte lineage development was compromised in these mice due to a reduced expression of the M-CSF receptor on myeloid progenitors. These results show that the cellular targets of ERK1 are M-CSFR-responsive cells, upstream to osteoclasts. While ERK1 is well known to be activated by M-CSF, the present results are the first to point out an ERK1-dependent M-CSFR regulation on hematopoietic progenitors. This study reinforces the hypothesis of an active cross-talk between HSCs, their progeny and bone cells in the maintenance of the homeostasis of these compartments

Control of Bone Mass and Remodeling by PTH Receptor Signaling in Osteocytes

Osteocytes, former osteoblasts buried within bone, are thought to orchestrate skeletal adaptation to mechanical stimuli. However, it remains unknown whether hormones control skeletal homeostasis through actions on osteocytes. Parathyroid hormone (PTH) stimulates bone remodeling and may cause bone loss or bone gain depending on the balance between bone resorption and formation. Herein, we demonstrate that transgenic mice expressing a constitutively active PTH receptor exclusively in osteocytes exhibit increased bone mass and bone remodeling, as well as reduced expression of the osteocyte-derived Wnt antagonist sclerostin, increased Wnt signaling, increased osteoclast and osteoblast number, and decreased osteoblast apoptosis. Deletion of the Wnt co-receptor LDL related receptor 5 (LRP5) attenuates the high bone mass phenotype but not the increase in bone remodeling induced by the transgene. These findings demonstrate that PTH receptor signaling in osteocytes increases bone mass and the rate of bone remodeling through LRP5-dependent and -independent mechanisms, respectively

Preferential Re-Replication of Drosophila Heterochromatin in the Absence of Geminin

To ensure genomic integrity, the genome must be duplicated exactly once per cell cycle. Disruption of replication licensing mechanisms may lead to re-replication and genomic instability. Cdt1, also known as Double-parked (Dup) in Drosophila, is a key regulator of the assembly of the pre-replicative complex (pre-RC) and its activity is strictly limited to G1 by multiple mechanisms including Cul4-Ddb1 mediated proteolysis and inhibition by geminin. We assayed the genomic consequences of disregulating the replication licensing mechanisms by RNAi depletion of geminin. We found that not all origins of replication were sensitive to geminin depletion and that heterochromatic sequences were preferentially re-replicated in the absence of licensing mechanisms. The preferential re-activation of heterochromatic origins of replication was unexpected because these are typically the last sequences to be duplicated in a normal cell cycle. We found that the re-replication of heterochromatin was regulated not at the level of pre-RC activation, but rather by the formation of the pre-RC. Unlike the global assembly of the pre-RC that occurs throughout the genome in G1, in the absence of geminin, limited pre-RC assembly was restricted to the heterochromatin by elevated cyclin A-CDK activity. These results suggest that there are chromatin and cell cycle specific controls that regulate the re-assembly of the pre-RC outside of G1

Cell-specific proteome analyses of human bone marrow reveal molecular features of age-dependent functional decline

Diminishing potential to replace damaged tissues is a hallmark for ageing of somatic stem cells, but the mechanisms remain elusive. Here, we present proteome-wide atlases of age-associated alterations in human haematopoietic stem and progenitor cells (HPCs) and five other cell populations that constitute the bone marrow niche. For each, the abundance of a large fraction of the ~12,000 proteins identified is assessed in 59 human subjects from different ages. As the HPCs become older, pathways in central carbon metabolism exhibit features reminiscent of the Warburg effect, where glycolytic intermediates are rerouted towards anabolism. Simultaneously, altered abundance of early regulators of HPC differentiation reveals a reduced functionality and a bias towards myeloid differentiation. Ageing causes alterations in the bone marrow niche too, and diminishes the functionality of the pathways involved in HPC homing. The data represent a valuable resource for further analyses, and for validation of knowledge gained from animal models

Search for beautiful tetraquarks in the <i>ϒ</i>(1<i>S</i>)μ⁺μ⁻ invariant-mass spectrum

International audienceThe ϒ(1S)μ$^{+}$μ$^{−}$ invariant-mass distribution is investigated for a possible exotic meson state composed of two b quarks and two $\overline{b}$ quarks, ${X}_{b\overline{b}b\overline{b}}$ . The analysis is based on a data sample of pp collisions recorded with the LHCb detector at centre-of-mass energies $\sqrt{s}=7$ , 8 and 13 TeV, corresponding to an integrated luminosity of 6.3 fb$^{−1}$. No significant excess is found, and upper limits are set on the product of the production cross-section and the branching fraction as functions of the mass of the ${X}_{b\overline{b}b\overline{b}}$ state. The limits are set in the fiducial volume where all muons have pseudorapidity in the range [2.0, 5.0], and the ${X}_{b\overline{b}b\overline{b}}$ state has rapidity in the range [2.0, 4.5] and transverse momentum less than 15 GeV/c

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 B(B0→D ̄ ̄ ̄ ̄0μ+μ−)&lt;5.1×10−8, B(B+→D+sμ+μ−)&lt;3.2×10−8, B(B0s→D ̄ ̄ ̄ ̄0μ+μ−)&lt;1.6×10−7 and fc/fu⋅B(B+c→D+sμ+μ−)&lt;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 B+c→D+sJ/ψ multiplied by the fragmentation-fraction ratio is measured to be fc/fu⋅B(B+c→D+sJ/ψ)=(1.63±0.15±0.13)×10−5, where the first uncertainty is statistical and the second systematic

Observation of Two New Excited Ξb0 States Decaying to Λb0 K-π+

Two narrow resonant states are observed in the Λb0K-π+ mass spectrum using a data sample of proton-proton collisions at a center-of-mass energy of 13 TeV, collected by the LHCb experiment and corresponding to an integrated luminosity of 6 fb-1. The minimal quark content of the Λb0K-π+ system indicates that these are excited Ξb0 baryons. The masses of the Ξb(6327)0 and Ξb(6333)0 states are m[Ξb(6327)0]=6327.28-0.21+0.23±0.12±0.24 and m[Ξb(6333)0]=6332.69-0.18+0.17±0.03±0.22 MeV, respectively, with a mass splitting of Δm=5.41-0.27+0.26±0.12 MeV, where the uncertainties are statistical, systematic, and due to the Λb0 mass measurement. The measured natural widths of these states are consistent with zero, with upper limits of Γ[Ξb(6327)0]&lt;2.20(2.56) and Γ[Ξb(6333)0]&lt;1.60(1.92) MeV at a 90% (95%) credibility level. The significance of the two-peak hypothesis is larger than nine (five) Gaussian standard deviations compared to the no-peak (one-peak) hypothesis. The masses, widths, and resonant structure of the new states are in good agreement with the expectations for a doublet of 1D Ξb0 resonances

Applying Perceptual Treatments for Reducing Operating Speeds on Curves: A Driving Simulator Study for Investigating Driver’s Speed Behavior

The aim of this driving simulator study is to investigate the effectiveness of different speed-reducing measures on a sharp curve of an existing road. Specifically, three perceptual treatments (white peripheral transverse bars, red peripheral transverse bars and optical speed bars) and chevrons are tested by means of a driving simulator over a randomly selected sample of forty-four drivers. The observed driving speeds are finally compared to those recorded under a baseline condition (with no treatment). Results confirmed the enormous potential of driving simulators in assessing the viability and design of several speed-reducing measures, especially those related to drivers’ perceptions that are strongly based on human factors issues, thereby allowing the selection of the most effective one in terms of cost reduction and safety promotion, in view of its actual implementation on the field

Electroweak parameters of the z0 resonance and the standard model

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