Discovery of Homobivalent Bitopic Ligands of the Cannabinoid CB2 Receptor**

Single chemical entities with potential to simultaneously interact with two binding sites are emerging strategies in medicinal chemistry. We have designed, synthesized and functionally characterized the first bitopic ligands for the CB2 receptor. These compounds selectively target CB2 versus CB1 receptors. Their binding mode was studied by molecular dynamic simulations and site-directed mutagenesis

Brain pyrimidine nucleotide synthesis and Alzheimer disease

Many patients suffering late-onset Alzheimer disease show a deficit in respiratory complex IV activity. The de novo pyrimidine biosynthesis pathway connects with the mitochondrial respiratory chain upstream from respiratory complex IV. We hypothesized that these patients would have decreased pyrimidine nucleotide levels. Then, different cell processes for which these compounds are essential, such as neuronal membrane generation and maintenance and synapses production, would be compromised. Using a cell model, we show that inhibiting oxidative phosphorylation function reduces neuronal differentiation. Linking these processes to pyrimidine nucleotides, uridine treatment recovers neuronal differentiation. To unmask the importance of these pathways in Alzheimer disease, we firstly confirm the existence of the de novo pyrimidine biosynthesis pathway in adult human brain. Then, we report altered mRNA levels for genes from both de novo pyrimidine biosynthesis and pyrimidine salvage pathways in brain from patients with Alzheimer disease. Thus, uridine supplementation might be used as a therapy for those Alzheimer disease patients with low respiratory complex IV activity

Cholangiocarcinoma progression depends on the uptake and metabolization of extracellular lipids

[Background and Aims] Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with a dismal prognosis. We investigated if lipid metabolism is disrupted in CCA and its role in tumor proliferation.[Approach and Results] The in vitro and in vivo tumorigenic capacity of five human CCA cell lines was analyzed. Proteome, lipid content, and metabolic fluxes were evaluated in CCA cells and compared with normal human cholangiocytes (NHC). The Akt1/NOTCH1 intracellular cytoplasmic domain (Nicd1)-driven CCA mouse model was also evaluated. The proteome of CCA cells was enriched in pathways involved in lipid and lipoprotein metabolism. The EGI1 CCA cell line presented the highest tumorigenic capacity. Metabolic studies in high (EGI1) versus low (HUCCT1) proliferative CCA cells in vitro showed that both EGI1 and HUCCT1 incorporated more fatty acids (FA) than NHC, leading to increased triglyceride storage, also observed in Akt1/Nicd1-driven CCA mouse model. The highly proliferative EGI1 CCA cells showed greater uptake of very-low-density and HDLs than NHC and HUCCT1 CCA cells and increased cholesteryl ester content. The FA oxidation (FAO) and related proteome enrichment were specifically up-regulated in EGI1, and consequently, pharmacological blockade of FAO induced more pronounced inhibition of their tumorigenic capacity compared with HUCCT1. The expression of acyl-CoA dehydrogenase ACADM, the first enzyme involved in FAO, was increased in human CCA tissues and correlated with the proliferation marker PCNA.[Conclusions] Highly proliferative human CCA cells rely on lipid and lipoprotein uptake to fuel FA catabolism, suggesting that inhibition of FAO and/or lipid uptake could represent a therapeutic strategy for this CCA subclass.This work was supported by “Ayudas para apoyar grupos de investigación del sistema Universitario Vasco” (IT971‐16 to PA), MCIU/AEI/FEDER, UE (2018‐095134‐B‐100 to PA and by the University of Basque Country COLAB20/01 to PA; Spanish Carlos III Health Institute (ISCIII) (FIS PI15/01132, PI18/01075, PI21/00922, and Miguel Servet Program CON14/00129 and CPII19/00008 to JMB; FIS PI14/00399, PI17/00022 and PI20/00186 to MJP; Sara Borrell [CD19/00254 to PMR]) cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER); CIBERehd (ISCIII) to JMB, MJP, PMR, PA and LB); “Diputación Foral Gipuzkoa” (DFG15/010, DFG16/004 to JMB and 2020‐CIEN‐000067‐01 to PMR), Department of Health of the Basque Country (2019111024 to MJP, 2017111010 to JMB, and 2020111077 to JMB and PA), “Euskadi RIS3” (2016222001, 2017222014, 2018222029, 2019222054, 2020333010 to JMB), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD to JMB) and Department of Industry of the Basque Country (Elkartek: KK‐2020/00008 to JMB); La Caixa Scientific Foundation (HR17‐00601 to JMB). “Fundación Científica de la Asociación Española Contra el Cáncer” (AECC Scientific Foundation, to JMB). AMMF‐The Cholangiocarcinoma Charity (EU/2019/AMMFt/001, to JMB and PMR). MRDG was funded by “Fundación Científica de la Asociación Española Contra el Cáncer” (AECC de Bizkaia), MJP was funded by the Spanish Ministry of Economy and Competitiveness (MINECO: “Ramón y Cajal” Program RYC‐2015‐17755), IL, AL and FG‐R by the Basque Government (PRE_2016_1_0152, PRE_2018_2_0195 and PRE 2020 2 02500, respectively), AN‐Z and BG‐S by the UPV/EHU, AB‐V by “Programa de especialización de Personal Investigador Doctor” at the UPV/EHU (2019‐2020) and MA by the MCIU/AEI/FEDER

Modes of functional biodiversity control on tree productivity across the European continent

The relative contribution of community functional diversity and composition to ecosystem functioning is a critical question in ecology in order to enable better predictions of how ecosystems may respond to a changing climate. However, there is little consensus about which modes of functional biodiversity are most important for tree growth at large spatial scales. Here we assessed the relative importance of climate, functional diversity and functional identity (i.e. the community mean values of four key functional traits) for tree growth across the European continent, spanning the northern boreal to the southern Mediterranean forests. Using data from five European national forest inventories we applied a hierarchical linear model to estimate the sensitivity of tree growth to changes in climate, functional diversity and functional identity along a latitudinal gradient. Functional diversity was weakly related to tree growth in the temperate and boreal regions and more strongly in the Mediterranean region. In the temperate region, where climate was the most important predictor, functional diversity and identity had a similar importance for tree growth. Functional identity was strongest at the latitudinal extremes of the continent, largely driven by strong changes in the importance of maximum height along the latitudinal gradient

Observation of two new Ξb−\Xi_b^- baryon resonances

Two structures are observed close to the kinematic threshold in the $\Xi_b^0 \pi^-$ mass spectrum in a sample of proton-proton collision data, corresponding to an integrated luminosity of 3.0 fb$^{-1}$ recorded by the LHCb experiment. In the quark model, two baryonic resonances with quark content $bds$ are expected in this mass region: the spin-parity $J^P = \frac{1}{2}^+$ and $J^P=\frac{3}{2}^+$ states, denoted $\Xi_b^{\prime -}$ and $\Xi_b^{*-}$. Interpreting the structures as these resonances, we measure the mass differences and the width of the heavier state to be $m(\Xi_b^{\prime -}) - m(\Xi_b^0) - m(\pi^{-}) = 3.653 \pm 0.018 \pm 0.006$ MeV$/c^2$, $m(\Xi_b^{*-}) - m(\Xi_b^0) - m(\pi^{-}) = 23.96 \pm 0.12 \pm 0.06$ MeV$/c^2$, $\Gamma(\Xi_b^{*-}) = 1.65 \pm 0.31 \pm 0.10$ MeV, where the first and second uncertainties are statistical and systematic, respectively. The width of the lighter state is consistent with zero, and we place an upper limit of $\Gamma(\Xi_b^{\prime -}) < 0.08$ MeV at 95% confidence level. Relative production rates of these states are also reported.Comment: 17 pages, 2 figure

Study of B−→DK−π+π−B^{-}\to DK^-\pi^+\pi^- and B−→Dπ−π+π−B^-\to D\pi^-\pi^+\pi^- decays and determination of the CKM angle γ\gamma

We report a study of the suppressed $B^-\to DK^-\pi^+\pi^-$ and favored $B^-\to D\pi^-\pi^+\pi^-$ decays, where the neutral $D$ meson is detected through its decays to the $K^{\mp}\pi^{\pm}$ and CP-even $K^+K^-$ and $\pi^+\pi^-$ final states. The measurement is carried out using a proton-proton collision data sample collected by the LHCb experiment, corresponding to an integrated luminosity of 3.0~fb$^{-1}$. We observe the first significant signals in the CP-even final states of the $D$ meson for both the suppressed $B^-\to DK^-\pi^+\pi^-$ and favored $B^-\to D\pi^-\pi^+\pi^-$ modes, as well as in the doubly Cabibbo-suppressed $D\to K^+\pi^-$ final state of the $B^-\to D\pi^-\pi^+\pi^-$ decay. Evidence for the ADS suppressed decay $B^{-}\to DK^-\pi^+\pi^-$, with $D\to K^+\pi^-$, is also presented. From the observed yields in the $B^-\to DK^-\pi^+\pi^-$, $B^-\to D\pi^-\pi^+\pi^-$ and their charge conjugate decay modes, we measure the value of the weak phase to be $\gamma=(74^{+20}_{-19})^{\rm o}$. This is one of the most precise single-measurement determinations of $\gamma$ to date.Comment: 22 pages, 9 figures; All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2015-020.htm

Measurement of the branching fraction ratio B(Bc+→ψ(2S)π+)/B(Bc+→J/ψπ+)\mathcal{B}(B_c^+ \rightarrow \psi(2S)\pi^+)/\mathcal{B}(B_c^+ \rightarrow J/\psi \pi^+)

Using $pp$ collision data collected by LHCb at center-of-mass energies $\sqrt{s}$ = 7 TeV and 8 TeV, corresponding to an integrated luminosity of 3 fb$^{-1}$, the ratio of the branching fraction of the $B_c^+ \rightarrow \psi(2S)\pi^+$ decay relative to that of the $B_c^+ \rightarrow J/\psi\pi^+$ decay is measured to be 0.268 $\pm$ 0.032 (stat) $\pm$ 0.007 (syst) $\pm$ 0.006 (BF). The first uncertainty is statistical, the second is systematic, and the third is due to the uncertainties on the branching fractions of the $J/\psi \rightarrow \mu^+\mu^-$ and $\psi(2S) \rightarrow \mu^+\mu^-$ decays. This measurement is consistent with the previous LHCb result, and the statistical uncertainty is halved.Comment: 17 pages including author list, 2 figure

Study of WW boson production in association with beauty and charm

The associated production of a $W$ boson with a jet originating from either a light parton or heavy-flavor quark is studied in the forward region using proton-proton collisions. The analysis uses data corresponding to integrated luminosities of 1.0 and $2.0\,{\rm fb}^{-1}$ collected with the LHCb detector at center-of-mass energies of 7 and 8 TeV, respectively. The $W$ bosons are reconstructed using the $W\to\mu\nu$ decay and muons with a transverse momentum, $p_{\rm T}$, larger than 20 GeV in the pseudorapidity range $2.0 20$ GeV and $2.2 < \eta < 4.2$. The sum of the muon and jet momenta must satisfy $p_{\rm T} > 20$ GeV. The fraction of $W+$jet events that originate from beauty and charm quarks is measured, along with the charge asymmetries of the $W\!+\!b$ and $W\!+\!c$ production cross-sections. The ratio of the $W+$jet to $Z+$jet production cross-sections is also measured using the $Z\to\mu\mu$ decay. All results are in agreement with Standard Model predictions

First observation and amplitude analysis of the B−→D+K−π−B^{-}\to D^{+}K^{-}\pi^{-} decay

The $B^{-}\to D^{+}K^{-}\pi^{-}$ decay is observed in a data sample corresponding to $3.0~\rm{fb}^{-1}$ of $pp$ collision data recorded by the LHCb experiment during 2011 and 2012. Its branching fraction is measured to be ${\cal B}(B^{-}\to D^{+}K^{-}\pi^{-}) = (7.31 \pm 0.19 \pm 0.22 \pm 0.39) \times 10^{-5}$ where the uncertainties are statistical, systematic and from the branching fraction of the normalisation channel $B^{-}\to D^{+}\pi^{-}\pi^{-}$, respectively. An amplitude analysis of the resonant structure of the $B^{-}\to D^{+}K^{-}\pi^{-}$ decay is used to measure the contributions from quasi-two-body $B^{-}\to D_{0}^{*}(2400)^{0}K^{-}$, $B^{-}\to D_{2}^{*}(2460)^{0}K^{-}$, and $B^{-}\to D_{J}^{*}(2760)^{0}K^{-}$ decays, as well as from nonresonant sources. The $D_{J}^{*}(2760)^{0}$ resonance is determined to have spin~1.Comment: 39 pages, 10 figures, submitted to Phys. Rev. D. Updated following erratum 10.1103/PhysRevD.93.11990