1,165 research outputs found
Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes
Currently, biased agonism is at the center stage of drug development approaches. We analyzed effects of a battery of cannabinoids plus/minus cannabidiol (CBD) in four functional parameters (cAMP levels, phosphorylation of extracellular signal–regulated kinases (ERK1/2), β-arrestin recruitment and label-free/DMR) in HEK-293T cells expressing cannabinoid receptors, CB or CB, or CB-CB heteroreceptor complexes. In all cases two natural agonists plus two selective synthetic agonists were used. Furthermore, the effect of cannabidiol, at a dose (100 nM) that does not allow significant binding to the orthosteric center of either receptor, was measured. From the huge amount of generated data, we would like to highlight that the two psychotropic molecules (Δ-tetrahydrocannabinol/THC and CP-55940) showed similar bias in CBR and that the bias of THC was particularly relevant toward MAPK pathway. Furthermore, THC did not activate the G protein coupled to CBR. Interestingly, the biased agonism was reduced when assays were performed in cells expressing the two receptors, thus suggesting that the heteromer allows less functional selectivity. In terms of cannabidiol action, the phytocannabinoid altered the functional responses, likely by allosteric means, and modified potency, agonist IC/EC values and biased agonism in qualitative and/or quantitative different ways depending on the agonist. The effect of cannabidiol on anandamide actions on both cannabinoid receptors was particularly noteworthy as was significantly different from that of other compounds. Results are a compendium of data on biased agonism on cannabinoid receptors in the absence and presence of cannabidiol. In addition, for the first time, GPCR biased agonism is characterized in an heteromeric context.This work was partially supported by grants from the Spanish
Ministry of Economy and Competitiveness (Ref. no. BFU2015-64405-R
and SAF2017-84117-R; they may include FEDER funds) and by grant
201413-30 from: Fundació la Marató de TV3Peer Reviewe
Renormalization Group Analysis of a Quivering String Model of Posture Control
Scaling concepts and renormalization group (RG) methods are applied to a
simple linear model of human posture control consisting of a trembling or
quivering string subject to damping and restoring forces. The string is driven
by uncorrelated white Gaussian noise intended to model the corrections of the
physiological control system. We find that adding a weak quadratic nonlinearity
to the posture control model opens up a rich and complicated phase space
(representing the dynamics) with various non-trivial fixed points and basins of
attraction. The transition from diffusive to saturated regimes of the linear
model is understood as a crossover phenomenon, and the robustness of the linear
model with respect to weak non-linearities is confirmed. Correlations in
posture fluctuations are obtained in both the time and space domain. There is
an attractive fixed point identified with falling. The scaling of the
correlations in the front-back displacement, which can be measured in the
laboratory, is predicted for both the large-separation (along the string) and
long-time regimes of posture control.Comment: 20 pages, 13 figures, RevTeX, accepted for publication in PR
Maximum in the Middle: Nonlinear Response of Microbial Plankton to Ultraviolet Radiation and Phosphorus
The responses of heterotrophic microbial food webs (HMFW) to the joint action of abiotic stressors related to global change have been studied in an oligotrophic high-mountain lake. A 2×5 factorial design field experiment performed with large mesocosms for >2 months was used to quantify the dynamics of the entire HMFW (bacteria, heterotrophic nanoflagellates, ciliates, and viruses) after an experimental P-enrichment gradient which approximated or surpassed current atmospheric P pulses in the presence vs. absence of ultraviolet radiation. HMFW underwent a mid-term (<20 days) acute development following a noticeable unimodal response to P enrichment, which peaked at intermediate P-enrichment levels and, unexpectedly, was more accentuated under ultraviolet radiation. However, after depletion of dissolved inorganic P, the HMFW collapsed and was outcompeted by a low-diversity autotrophic compartment, which constrained the development of HMFW and caused a significant loss of functional biodiversity. The dynamics and relationships among variables, and the response patterns found, suggest the importance of biotic interactions (predation/parasitism and competition) in restricting HMFW development, in contrast to the role of abiotic factors as main drivers of autotrophic compartment. The response of HMFW may contribute to ecosystem resilience by favoring the maintenance of the peculiar paths of energy and nutrient-mobilization in these pristine ecosystems, which are vulnerable to threats by the joint action of abiotic stressors related to global change.This research was supported by Junta de Andalucía (Excelencia P07-CVI-02598 to PC, and P09-RNM-5376 to JMMS), the Spanish Ministries of Medio Ambiente, Rural y Marino (PN2009/067 to PC) and Ciencia e Innovación (GLC2008-01127/BOS and CGL2011-23681 to PC), the ERC Advanced Grant project number 250254 “MINOS” (to GB), and two Spanish government grants (to JADM and FJB)
Implementation of a multidisciplinary psychoeducational intervention for Parkinson's disease patients and carers in the community: study protocol
Background: Parkinson’s disease progressively limits patients at different levels and as a result family members play
a key role in their care. However, studies show lack of an integrative approach in Primary Care to respond to the
difficulties and psychosocial changes experienced by them. The aim of this study is to evaluate the effects of a
multidisciplinary psychoeducational intervention focusing on improving coping skills, the psychosocial adjustment
to Parkinson’s disease and the quality of life in patients and family carers in a Primary Care setting.
Methods: This quasi-experimental study with control group and mixed methods was designed to evaluate a
multidisciplinary psychoeducational intervention. Based on the study power calculations, 100 people with
Parkinson’s disease and 100 family carers will be recruited and assigned to two groups. The intervention group will
receive the ReNACE psychoeducational intervention. The control group will be given a general educational
programme. The study will be carried out in six community-based health centres. The results obtained from the
two groups will be collected for evaluation at three time points: at baseline, immediately after the intervention and
at 6 months post-intervention. The results will be measured with these instruments: the Quality of Life Scale PDQ39 for patients and the Scale of Quality of Life of Care-givers SQLC for family carers, and for all participants the
Psychosocial Adjustment to Illness scale and the Brief COPE Inventory. Focus groups will be organised with some
patients and family carers who will have received the ReNACE psychoeducational intervention and also with the
healthcare professionals involved in its development.
Discussion: An important gap exists in the knowledge and application of interventions with a psychosocial
approach for people with PD and family carers as a whole. This study will promote this comprehensive approach in
Primary Care, which will clearly contribute in the existing knowledge and could reduce the burden of PD for
patients and family carers, and also in other long-term conditions
Anisotropy studies around the galactic centre at EeV energies with the Auger Observatory
Data from the Pierre Auger Observatory are analyzed to search for
anisotropies near the direction of the Galactic Centre at EeV energies. The
exposure of the surface array in this part of the sky is already significantly
larger than that of the fore-runner experiments. Our results do not support
previous findings of localized excesses in the AGASA and SUGAR data. We set an
upper bound on a point-like flux of cosmic rays arriving from the Galactic
Centre which excludes several scenarios predicting sources of EeV neutrons from
Sagittarius . Also the events detected simultaneously by the surface and
fluorescence detectors (the `hybrid' data set), which have better pointing
accuracy but are less numerous than those of the surface array alone, do not
show any significant localized excess from this direction.Comment: Matches published versio
Measurement of the Depth of Maximum of Extensive Air Showers above 10^18 eV
We describe the measurement of the depth of maximum, Xmax, of the
longitudinal development of air showers induced by cosmic rays. Almost four
thousand events above 10^18 eV observed by the fluorescence detector of the
Pierre Auger Observatory in coincidence with at least one surface detector
station are selected for the analysis. The average shower maximum was found to
evolve with energy at a rate of (106 +35/-21) g/cm^2/decade below 10^(18.24 +/-
0.05) eV and (24 +/- 3) g/cm^2/decade above this energy. The measured
shower-to-shower fluctuations decrease from about 55 to 26 g/cm^2. The
interpretation of these results in terms of the cosmic ray mass composition is
briefly discussed.Comment: Accepted for publication by PR
Azimuthal asymmetry in the risetime of the surface detector signals of the Pierre Auger Observatory
The azimuthal asymmetry in the risetime of signals in Auger surface detector
stations is a source of information on shower development. The azimuthal
asymmetry is due to a combination of the longitudinal evolution of the shower
and geometrical effects related to the angles of incidence of the particles
into the detectors. The magnitude of the effect depends upon the zenith angle
and state of development of the shower and thus provides a novel observable,
, sensitive to the mass composition of cosmic rays
above eV. By comparing measurements with predictions from
shower simulations, we find for both of our adopted models of hadronic physics
(QGSJETII-04 and EPOS-LHC) an indication that the mean cosmic-ray mass
increases slowly with energy, as has been inferred from other studies. However,
the mass estimates are dependent on the shower model and on the range of
distance from the shower core selected. Thus the method has uncovered further
deficiencies in our understanding of shower modelling that must be resolved
before the mass composition can be inferred from .Comment: Replaced with published version. Added journal reference and DO
Operations of and Future Plans for the Pierre Auger Observatory
Technical reports on operations and features of the Pierre Auger Observatory,
including ongoing and planned enhancements and the status of the future
northern hemisphere portion of the Observatory. Contributions to the 31st
International Cosmic Ray Conference, Lodz, Poland, July 2009.Comment: Contributions to the 31st ICRC, Lodz, Poland, July 200
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