364 research outputs found
Carbamoylphosphonates inhibit autotaxin and metastasis formation in vivo
Autotaxin is an extracellular, two zinc-centered enzyme that hydrolyzes lysophosphatidyl choline to lysophosphatidic acid, involved in various cancerous processes, e.g. migration, proliferation and tumor progression. We examined the autotaxin inhibitory properties of extended structure carbamoylphosphonates (CPOs) PhOC(6)H(4)SO(2)NH(CH(2))nNHCOPO(3)H(2), with increasing lengths of methylene chains, (CH(2))(n), nâ=â4-8. Carbamoylphosphonates having nâ=â6, 7, 8 inhibited autotaxin in vitro with IC(50)âââ1.5â”M. Using an imaging probe we demonstrated that compound nâ=â6 inhibits recombinant autotaxin activity in vitro and in vivo, following oral CPO administration. Additionally, daily oral administration of compound nâ=â7 inhibited over 90% of lung metastases in a murine melanoma metastasis model. Both the carbamoylphosphonates and the enzymes reside and interact in the extracellular space expecting minimal toxic side effects, and presenting a novel approach for inhibiting tumor proliferation and metastasis dissemination
The global contribution of soil mosses to ecosystem services
Soil mosses are among the most widely distributed organisms on land. Experiments and observations suggest that they contribute to terrestrial soil biodiversity and function, yet their ecological contribution to soil has never been assessed globally under natural conditions. Here we conducted the most comprehensive global standardized field study to quantify how soil mosses influence 8 ecosystem services associated with 24 soil biodiversity and functional attributes across wide environmental gradients from all continents. We found that soil mosses are associated with greater carbon sequestration, pool sizes for key nutrients and organic matter decomposition rates but a lower proportion of soil-borne plant pathogens than unvegetated soils. Mosses are especially important for supporting multiple ecosystem services where vascular-plant cover is low. Globally, soil mosses potentially support 6.43âGt more carbon in the soil layer than do bare soils. The amount of soil carbon associated with mosses is up to six times the annual global carbon emissions from any altered land use globally. The largest positive contribution of mosses to soils occurs under a high cover of mat and turf mosses, in less-productive ecosystems and on sandy and salty soils. Our results highlight the contribution of mosses to soil life and functions and the need to conserve these important organisms to support healthy soils.The study work associated with this paper was funded by a Large Research Grant from the British Ecological Society (no. LRB17\1019; MUSGONET). D.J.E. is supported by the Hermon Slade Foundation. M.D.-B. was supported by a RamĂłn y Cajal grant from the Spanish Ministry of Science and Innovation (RYC2018-025483-I), a project from the Spanish Ministry of Science and Innovation for the Iâ+âDâ+âi (PID2020-115813RA-I00 funded by MCIN/AEI/10.13039/501100011033a) and a project PAIDI 2020 from the Junta de AndalucĂa (P20_00879). E.G. is supported by the European Research Council grant agreement 647038 (BIODESERT). M.B. is supported by a RamĂłn y Cajal grant from Spanish Ministry of Science (RYC2021-031797-I). A.d.l.R is supported by the AEI project PID2019-105469RB-C22. L.W. and Jianyong Wang are supported by the Program for Introducing Talents to Universities (B16011) and the Ministry of Education Innovation Team Development Plan (2013-373). The contributions of T.G. and T.U.N. were supported by the Research Program in Forest Biology, Ecology and Technology (P4-0107) and the research projects J4-3098 and J4-4547 of the Slovenian Research Agency. The contribution of P.B.R. was supported by the NSF Biological Integration Institutes grant DBI-2021898. J. DurĂĄn and A. RodrĂguez acknowledge support from the FCT (2020.03670.CEECIND and SFRH/BDP/108913/2015, respectively), as well as from the MCTES, FSE, UE and the CFE (UIDB/04004/2021) research unit financed by FCT/MCTES through national funds (PIDDAC)
Characterisation of age and polarity at onset in bipolar disorder
Background
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
Aims
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Method
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Results
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (ÎČ = â0.34 years, s.e. = 0.08), major depression (ÎČ = â0.34 years, s.e. = 0.08), schizophrenia (ÎČ = â0.39 years, s.e. = 0.08), and educational attainment (ÎČ = â0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
Conclusions
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses
Study of the decay
The decay is studied
in proton-proton collisions at a center-of-mass energy of TeV
using data corresponding to an integrated luminosity of 5
collected by the LHCb experiment. In the system, the
state observed at the BaBar and Belle experiments is
resolved into two narrower states, and ,
whose masses and widths are measured to be where the first uncertainties are statistical and the second
systematic. The results are consistent with a previous LHCb measurement using a
prompt sample. Evidence of a new
state is found with a local significance of , whose mass and width
are measured to be and , respectively. In addition, evidence of a new decay mode
is found with a significance of
. The relative branching fraction of with respect to the
decay is measured to be , where the first
uncertainty is statistical, the second systematic and the third originates from
the branching fractions of charm hadron decays.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-028.html (LHCb
public pages
Measurement of the ratios of branching fractions and
The ratios of branching fractions
and are measured, assuming isospin symmetry, using a
sample of proton-proton collision data corresponding to 3.0 fb of
integrated luminosity recorded by the LHCb experiment during 2011 and 2012. The
tau lepton is identified in the decay mode
. The measured values are
and
, where the first uncertainty is
statistical and the second is systematic. The correlation between these
measurements is . Results are consistent with the current average
of these quantities and are at a combined 1.9 standard deviations from the
predictions based on lepton flavor universality in the Standard Model.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-039.html (LHCb
public pages
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