Examine the effectiveness of specific modes of exercise training in non-specific chronic low back pain (NSCLBP).
Network meta-analysis (NMA).
MEDLINE, CINAHL, SPORTDiscus, EMBASE, CENTRAL.
Exercise ...training randomised controlled/clinical trials in adults with NSCLBP.
Among 9543 records, 89 studies (patients=5578) were eligible for qualitative synthesis and 70 (pain), 63 (physical function), 16 (mental health) and 4 (trunk muscle strength) for NMA. The NMA consistency model revealed that the following exercise training modalities had the highest probability (surface under the cumulative ranking (SUCRA)) of being best when compared with true control: Pilates for pain (SUCRA=100%; pooled standardised mean difference (95% CI): -1.86 (-2.54 to -1.19)), resistance (SUCRA=80%; -1.14 (-1.71 to -0.56)) and stabilisation/motor control (SUCRA=80%; -1.13 (-1.53 to -0.74)) for physical function and resistance (SUCRA=80%; -1.26 (-2.10 to -0.41)) and aerobic (SUCRA=80%; -1.18 (-2.20 to -0.15)) for mental health. True control was most likely (SUCRA≤10%) to be the worst treatment for all outcomes, followed by therapist hands-off control for pain (SUCRA=10%; 0.09 (-0.71 to 0.89)) and physical function (SUCRA=20%; -0.31 (-0.94 to 0.32)) and therapist hands-on control for mental health (SUCRA=20%; -0.31 (-1.31 to 0.70)). Stretching and McKenzie exercise effect sizes did not differ to true control for pain or function (p>0.095; SUCRA<40%). NMA was not possible for trunk muscle endurance or analgesic medication. The quality of the synthesised evidence was low according to Grading of Recommendations Assessment, Development and Evaluation criteria.
There is low quality evidence that Pilates, stabilisation/motor control, resistance training and aerobic exercise training are the most effective treatments, pending outcome of interest, for adults with NSCLBP. Exercise training may also be more effective than therapist hands-on treatment. Heterogeneity among studies and the fact that there are few studies with low risk of bias are both limitations.
Essentials
Three dominant variants for the autosomal recessive bleeding disorder type‐8 have been described.
To date, there has been no phenotype/genotype correlation explaining their dominant ...transmission.
Proline plays an important role in P2Y12R ligand binding and signaling defects.
P2Y12R homodimer formation is critical for the receptor function and signaling.
Summary
Background
Although inherited platelet disorders are still underdiagnosed worldwide, advances in molecular techniques are improving disease diagnosis and patient management.
Objective
To identify and characterize the mechanism underlying the bleeding phenotype in a Caucasian family with an autosomal dominant P2RY12 variant.
Methods
Full blood counts, platelet aggregometry, flow cytometry and western blotting were performed before next‐generation sequencing (NGS). Detailed molecular analysis of the identified variant of the P2Y12 receptor (P2Y12R) was subsequently performed in mammalian cells overexpressing receptor constructs.
Results
All three referred individuals had markedly impaired ADP‐induced platelet aggregation with primary wave only, despite normal total and surface P2Y12R expression. By NGS, a single P2RY12:c.G794C substitution (p.R265P) was identified in all affected individuals, and this was confirmed by Sanger sequencing. Mammalian cell experiments with the R265P‐P2Y12R variant showed normal receptor surface expression versus wild‐type (WT) P2Y12R. Agonist‐stimulated R265P‐P2Y12R function (both signaling and surface receptor loss) was reduced versus WT P2Y12R. Critically, R265P‐P2Y12R acted in a dominant negative manner, with agonist‐stimulated WT P2Y12R activity being reduced by variant coexpression, suggesting dramatic loss of WT homodimers. Importantly, platelet P2RY12 cDNA cloning and sequencing in two affected individuals also revealed three‐fold mutant mRNA overexpression, decreasing even further the likelihood of WT homodimer formation. R265 located within extracellular loop 3 (EL3) is one of four residues that are important for receptor functional integrity, maintaining the binding pocket conformation and allowing rotation following ligand binding.
Conclusion
This novel dominant negative variant confirms the important role of R265 in EL3 in the functional integrity of P2Y12R, and suggests that pathologic heterodimer formation may underlie this family bleeding phenotype.
Summary
Background
The study of patients with bleeding problems is a powerful approach in determining the function and regulation of important proteins in human platelets. We have identified a ...patient with a chronic bleeding disorder expressing a homozygous P2RY12 mutation, predicting an arginine to cysteine (R122C) substitution in the G‐protein‐coupled P2Y12 receptor. This mutation is found within the DRY motif, which is a highly conserved region in G‐protein‐coupled receptors (GPCRs) that is speculated to play a critical role in regulating receptor conformational states.
Objectives
To determine the functional consequences of the R122C substitution for P2Y12 function.
Patient/methods
We performed a detailed phenotypic analysis of an index case and affected family members. An analysis of the variant R122C P2Y12 stably expressed in cells was also performed.
Results
ADP‐stimulated platelet aggregation was reduced as a result of a significant impairment of P2Y12 activity in the patient and family members. Cell surface R122C P2Y12 expression was reduced both in cell lines and in platelets; in cell lines, this was as a consequence of agonist‐independent internalization followed by subsequent receptor trafficking to lysosomes. Strikingly, members of this family also showed reduced thrombin‐induced platelet activation, owing to an intronic polymorphism in the F2R gene, which encodes protease‐activated receptor 1 (PAR‐1), that has been shown to be associated with reduced PAR‐1 receptor activity.
Conclusions
Our study is the first to demonstrate a patient with deficits in two stimulatory GPCR pathways that regulate platelet activity, further indicating that bleeding disorders constitute a complex trait.
Summary
Background
Genetic variations that affect the structure of the thromboxane A2 receptor (TP receptor) provide insights into the function of this key platelet and vascular receptor, but are ...very rare in unselected populations.
Objectives
To determine the functional consequences of the TP receptor Trp29Cys (W29C) substitution.
Patients/Methods
We performed a detailed phenotypic analysis of an index case (P1) with reduced platelet aggregation and secretion responses to TP receptor pathway activators, and a heterozygous TP receptor W29C substitution. An analysis of the variant W29C TP receptor expressed in heterologous cells was performed.
Results
Total TP receptor expression in platelets from P1 was similar to that of controls, but there was reduced maximum binding and reduced affinity of binding to the TP receptor antagonist 3HSQ29548. HEK293 cells transfected with W29C TP receptor cDNA showed similar total TP receptor expression to wild‐type (WT) controls. However, the TP receptor agonist U46619 was less potent at inducing rises in cytosolic free Ca2+ in HEK293 cells expressing the W29C TP receptor than in WT controls, indicating reduced receptor function. Immunofluorescence microscopy and cell surface ELISA showed intracellular retention and reduced cell surface expression of the W29C TP receptor in HEK293 cells. Consistent with the platelet phenotype, both maximum binding and the affinity of binding of 3HSQ29548 to the W29C TP receptor were reduced compared to WT controls.
Conclusion
These findings extend the phenotypic description of the very rare disorder TP receptor deficiency, and show that the W29C substitution reduces TP receptor function by reducing surface receptor expression and by disrupting ligand binding.
Platelet‐expressed GPCRs are critical regulators of platelet function. Pharmacological blockade of these receptors forms a powerful therapeutic tool in the treatment and prevention of arterial ...thrombosis associated with coronary atherosclerosis and ischaemic stroke. However, anti‐thrombotic drug therapy is associated with high inter‐patient variability in therapeutic response and adverse bleeding side effects. In order to optimize the use of existing anti‐platelet drugs and to develop new therapies, more detailed knowledge is required relating to the molecular mechanisms that regulate GPCR and therefore platelet function. One approach has been to identify rare, function‐disrupting mutations within key platelet proteins in patients with bleeding disorders. In this review, we describe how an integrated functional genomics strategy has contributed important structure‐function information about platelet GPCRs with specific emphasis upon purinergic and thromboxane A2 receptors. We also discuss the potential implications these findings have for pharmacotherapy and for understanding the molecular basis of mild bleeding disorders.
Linked Articles
This article is part of a themed section on 5th BPS Focused Meeting on Cell Signalling. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue‐13
Oxytocin (OT) has long been used as an uterotonic during labor management in women, and yet responses to OT infusion remain variable and unpredictable among patients. The investigation of oxytocin ...receptor (OTR) regulation will benefit labor management, because the clinical practice of continuous iv infusion of OT is not optimal. As with other G protein-coupled receptors, it is likely that the OTR internalizes and/or desensitizes upon continuous agonist exposure. The mechanisms by which this might occur, however, are unclear. Here we explore OTR internalization and desensitization in human embryonic kidney cells by utilizing inhibitors of heterologous second messenger systems and recently available mutant cDNA constructs. We report rapid and extensive internalization and desensitization of the OTR upon agonist exposure. Internalization was unaffected by inhibitors of protein kinase C or Ca(2+) calmodulin-dependant kinase II but was significantly reduced after transfection with dominant-negative mutant cDNAs of G protein-coupled receptor kinase 2, beta-Arrestin2, Dynamin, and Eps15 (a component of clathrin-coated pits). Moreover, desensitization of the OTR, measured by a calcium mobilization assay, was also inhibited by the aforementioned cDNA constructs. Thus, our data demonstrate, for the first time, the importance of the classical clathrin-mediated pathway during agonist-induced OTR internalization and desensitization.
ABSTRACT
We present the second data release of high-resolution (≤0.2 arcsec) 1.5-GHz radio images of 177 nearby galaxies from the Palomar sample, observed with the e-MERLIN array, as part of the ...Legacy e-MERLIN Multi-band Imaging of Nearby Galaxies Sample (LeMMINGs) survey. Together with the 103 targets of the first LeMMINGs data release, this represents a complete sample of 280 local active (LINER and Seyfert) and inactive galaxies (H ii galaxies and absorption line galaxies, ALG). This large program is the deepest radio survey of the local Universe, ≳1017.6 W Hz−1, regardless of the host and nuclear type: we detect radio emission ≳0.25 mJy beam−1 for 125/280 galaxies (44.6 per cent) with sizes of typically ≲100 pc. Of those 125, 106 targets show a core which coincides within 1.2 arcsec with the optical nucleus. Although we observed mostly cores, around one third of the detected galaxies features jetted morphologies. The detected radio core luminosities of the sample range between ∼1034 and 1040 erg s−1. LINERs and Seyferts are the most luminous sources, whereas H ii galaxies are the least. LINERs show FR I-like core-brightened radio structures while Seyferts reveal the highest fraction of symmetric morphologies. The majority of H ii galaxies have single radio core or complex extended structures, which probably conceal a nuclear starburst and/or a weak active nucleus (seven of them show clear jets). ALGs, which are typically found in evolved ellipticals, although the least numerous, exhibit on average the most luminous radio structures, similar to LINERs.
Understanding the origin and diversity of emission processes responsible for gamma-ray bursts (GRBs) remains a pressing challenge. While prompt and contemporaneous panchromatic observations have the ...potential to test predictions of the internal-external shock model, extensive multiband imaging has been conducted for only a few GRBs. We present rich, early-time, multiband data sets for two Swift events, GRB 110205A and GRB 110213A. The former shows optical emission since the early stages of the prompt phase, followed by the steep rising in flux up to ~1000 s after the burst (t -- Delta *a with Delta *a = --6.13 ? 0.75). We discuss this feature in the context of the reverse-shock scenario and interpret the following single power-law decay as being forward-shock dominated. Polarization measurements, obtained with the RINGO2 instrument mounted on the Liverpool Telescope, also provide hints on the nature of the emitting ejecta. The latter event, instead, displays a very peculiar optical to near-infrared light curve, with two achromatic peaks. In this case, while the first peak is probably due to the onset of the afterglow, we interpret the second peak to be produced by newly injected material, signifying a late-time activity of the central engine.
LeMMINGs Dullo, B. T.; Knapen, J. H.; Beswick, R. J. ...
Astronomy and astrophysics (Berlin),
07/2023, Letnik:
675
Journal Article
Recenzirano
Odprti dostop
We used high-resolution HST imaging and
e
-MERLIN 1.5-GHz observations of galaxy cores from the LeMMINGs survey to investigate the relation between optical structural properties and nuclear radio ...emission for a large sample of galaxies. We performed accurate, multi-component decompositions of new surface brightness profiles extracted from HST images for 163 LeMMINGs galaxies and fitted up to six galaxy components (e.g. bulges, discs, AGN, bars, rings, spiral arms, and nuclear star clusters) simultaneously with Sérsic and/or core-Sérsic models. By adding such decomposition data for ten LeMMINGs galaxies from our past work, the final sample of 173 nearby galaxies (102 Ss, 42 S0s, 23 Es, plus six Irr) with a typical bulge stellar mass of
M
∗,bulge
∼ 10
6
− 10
12.5
M
⊙
encompasses all optical spectral classes: low-ionisation nuclear emission-line region (LINER), Seyfert, Absorption Line Galaxy (ALG), and H
II
. We show that the bulge mass can be significantly overestimated in many galaxies when components such as bars, rings, and spirals are not included in the fits. We additionally implemented a Monte Carlo method to determine errors on the bulge, disc, and other fitted structural parameters. Moving (in the opposite direction) across the Hubble sequence, that is from the irregular to elliptical galaxies, we confirm that bulges become larger, more prominent, and round. Such bulge dominance is associated with a brighter radio core luminosity. We also find that the radio detection fraction increases with bulge mass. At
M
∗,bulge
≥ 10
11
M
⊙
, the radio detection fraction is 77%, declining to 24% for
M
∗,bulge
< 10
10
M
⊙
. Furthermore, we observe that core-Sérsic bulges tend to be systematically round and to possess high radio core luminosities and boxy-distorted or pure elliptical isophotes. However, there is no evidence for the previously alleged strong tendency of galaxies’ central structures (i.e. a sharp Sérsic, core-Sérsic dichotomy) with their radio loudness, isophote shape, and flattening.
Background and Purpose
Naturally occurring single‐nucleotide polymorphisms (SNPs) within GPCRs can result in alterations in various pharmacological parameters. Understanding the regulation and ...function of endocytic trafficking of the μ‐opioid receptor (MOP receptor) is of great importance given its implication in the development of opioid tolerance. This study has compared the agonist‐dependent trafficking and signalling of L83I, the rat orthologue of a naturally occurring variant of the MOP receptor.
Experimental Approach
Cell surface elisa, confocal microscopy and immunoprecipitation assays were used to characterize the trafficking properties of the MOP‐L83I variant in comparison with the wild‐type receptor in HEK 293 cells. Functional assays were used to compare the ability of the L83I variant to signal to several downstream pathways.
Key Results
Morphine‐induced internalization of the L83I MOP receptor was markedly increased in comparison with the wild‐type receptor. The altered trafficking of this variant was found to be specific to morphine and was both G‐protein receptor kinase‐ and dynamin‐dependent. The enhanced internalization of L83I variant in response to morphine was not due to increased phosphorylation of serine 375, arrestin association or an increased ability to signal.
Conclusions and Implications
These results suggest that morphine promotes a specific conformation of the L83I variant that makes it more liable to internalize in response to morphine, unlike the wild‐type receptor that undergoes significantly less morphine‐stimulated internalization, providing an example of a ligand‐selective biased receptor. The presence of this SNP within an individual may consequently affect the development of tolerance and analgesic responses.
Linked ArticlesThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
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