2,571 research outputs found
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 baryon resonances
Two structures are observed close to the kinematic threshold in the mass spectrum in a sample of proton-proton collision data, corresponding
to an integrated luminosity of 3.0 fb recorded by the LHCb experiment.
In the quark model, two baryonic resonances with quark content are
expected in this mass region: the spin-parity and
states, denoted and .
Interpreting the structures as these resonances, we measure the mass
differences and the width of the heavier state to be
MeV,
MeV,
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
MeV at 95% confidence level. Relative
production rates of these states are also reported.Comment: 17 pages, 2 figure
Study of and decays and determination of the CKM angle
We report a study of the suppressed and favored
decays, where the neutral meson is detected
through its decays to the and CP-even and
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. We observe the first significant
signals in the CP-even final states of the meson for both the suppressed
and favored modes, as well as
in the doubly Cabibbo-suppressed final state of the decay. Evidence for the ADS suppressed decay , with , is also presented. From the observed
yields in the , and their
charge conjugate decay modes, we measure the value of the weak phase to be
. This is one of the most precise
single-measurement determinations of 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
Using collision data collected by LHCb at center-of-mass energies
= 7 TeV and 8 TeV, corresponding to an integrated luminosity of 3
fb, the ratio of the branching fraction of the decay relative to that of the
decay is measured to be 0.268 0.032 (stat) 0.007 (syst) 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 and 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 boson production in association with beauty and charm
The associated production of a 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 collected with the LHCb detector
at center-of-mass energies of 7 and 8 TeV, respectively. The bosons are
reconstructed using the decay and muons with a transverse
momentum, , larger than 20 GeV in the pseudorapidity range
GeV
and . The sum of the muon and jet momenta must satisfy
GeV. The fraction of jet events that originate from beauty
and charm quarks is measured, along with the charge asymmetries of the
and production cross-sections. The ratio of the jet to
jet production cross-sections is also measured using the
decay. All results are in agreement with Standard Model predictions
First observation and amplitude analysis of the decay
The decay is observed in a data sample
corresponding to of collision data recorded by the LHCb
experiment during 2011 and 2012. Its branching fraction is measured to be
where the uncertainties are statistical, systematic and from
the branching fraction of the normalisation channel , respectively. An amplitude analysis of the resonant
structure of the decay is used to measure the
contributions from quasi-two-body ,
, and
decays, as well as from nonresonant sources. The
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
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