A Complementary Scale of Biased Agonism for Agonists with Differing Maximal Responses

Compelling data in the literature from the recent years leave no doubt about the pluridimensional nature of G protein-coupled receptor function and the fact that some ligands can couple with different efficacies to the multiple pathways that a receptor can signal through, a phenomenon most commonly known as functional selectivity or biased agonism. Nowadays, transduction coefficients (log(τ/K)), based on the Black and Leff operational model of agonism, are widely used to calculate bias. Nevertheless, combining both affinity and efficacy in a single parameter can result in compounds showing a defined calculated bias of one pathway over other though displaying varying experimental bias preferences. In this paper, we present a novel scale (log(τ)), that attempts to give extra substance to different compound profiles in order to better classify compounds and quantify their bias. The efficacy-driven log(τ) scale is not proposed as an alternative to the affinity&efficacy-driven log(τ/K) scale but as a complement in those situations where partial agonism is present. Both theoretical and practical approaches using μ-opioid receptor agonists are presented

Allosteric control of an asymmetric transduction in a G protein-coupled receptor heterodimer

GPCRs play critical roles in cell communication. Although GPCRs can form heteromers, their role in signaling remains elusive. Here we used rat metabotropic glutamate (mGlu) receptors as prototypical dimers to study the functional interaction between each subunit. mGluRs can form both constitutive homo- and heterodimers. Whereas both mGlu2 and mGlu4 couple to G proteins, G protein activation is mediated by mGlu4 heptahelical domain (HD) exclusively in mGlu2-4 heterodimers. Such asymmetric transduction results from the action of both the dimeric extracellular domain, and an allosteric activation by the partially-activated non-functional mGlu2 HD. G proteins activation by mGlu2 HD occurs if either the mGlu2 HD is occupied by a positive allosteric modulator or if mGlu4 HD is inhibited by a negative modulator. These data revealed an oriented asymmetry in mGlu heterodimers that can be controlled with allosteric modulators. They provide new insight on the allosteric interaction between subunits in a GPCR dimer

Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program

Background Epigenetic programming during development is essential for determining cell lineages, and alterations in this programming contribute to the initiation of embryonal tumour development. In neuroblastoma, neural crest progenitors block their course of natural differentiation into sympathoadrenergic cells, leading to the development of aggressive and metastatic paediatric cancer. Research of the epigenetic regulators responsible for oncogenic epigenomic networks is crucial for developing new epigenetic-based therapies against these tumours. Mammalian switch/sucrose non-fermenting (mSWI/SNF) ATP-dependent chromatin remodelling complexes act genome-wide translating epigenetic signals into open chromatin states. The present study aimed to understand the contribution of mSWI/SNF to the oncogenic epigenomes of neuroblastoma and its potential as a therapeutic target. Methods Functional characterisation of the mSWI/SNF complexes was performed in neuroblastoma cells using proteomic approaches, loss-of-function experiments, transcriptome and chromatin accessibility analyses, and in vitro and in vivo assays. Results Neuroblastoma cells contain three main mSWI/SNF subtypes, but only BRG1-associated factor (BAF) complex disruption through silencing of its key structural subunits, ARID1A and ARID1B, impairs cell proliferation by promoting cell cycle blockade. Genome-wide chromatin remodelling and transcriptomic analyses revealed that BAF disruption results in the epigenetic repression of an extensive invasiveness-related expression program involving integrins, cadherins, and key mesenchymal regulators, thereby reducing adhesion to the extracellular matrix and the subsequent invasion in vitro and drastically inhibiting the initiation and growth of neuroblastoma metastasis in vivo. Conclusions We report a novel ATPase-independent role for the BAF complex in maintaining an epigenomic program that allows neuroblastoma invasiveness and metastasis, urging for the development of new BAF pharmacological structural disruptors for therapeutic exploitation in metastatic neuroblastoma

Polypropylene and polyvinylidene fluoride transobturator slings for the treatment of female stress urinary incontinence : 1-Year outcomes from a multicentre randomized trial

Finançament de: Fundación Dexeus Salud de la Mujer; CardiolinkTo compare the effectiveness and safety of polypropylene (PP) and polyvinylidene fluoride (PVDF) transobturator tapes (TOT) for the treatment of female stress urinary incontinence (SUI). This is a multicentre randomized trial. Women with SUI or stress-predominant mixed urinary incontinence and scheduled for a TOT procedure were randomized to PP or PVDF slings. The primary outcome was 1-year cure or improvement rate using composite criteria. Complications were also compared. Relationships with outcomes were analyzed using multivariable logistic regressions models. From April 2016 to January 2018 285 participants were randomized. PP and PVDF slings showed similar high cure or improvement rate (91.0% vs. 95.6%, p = .138). Improvement in validated questionnaires was also similar. PVDF slings were associated with a lower rate of de novo urgency incontinence (adjusted odds ratio = 0.35; 95% confidence interval = 0.15-0.80). We found no statistical differences in complications rates, although a higher incidence of long-term pain events were observed in the PP group. The study is underpowered to find differences in specific complications owing to the low number of events. PP and PVDF TOTs are equally effective, although PVDF is associated with fewer cases of de novo urgency incontinence. Further studies are needed to give robust conclusions on safety profiles

A 10-Year-Old Boy with Short Stature and Microcephaly, Diagnosed with Moyamoya Syndrome and Microcephalic Osteodysplastic Primordial Dwarfism Type II (MOPD II)

Rare disease Moyamoya syndrome is a rare cerebrovascular condition caused by blockage of the arteries of the basal ganglia. The Japanese word "moyamoya" means "a puff of smoke" which describes the appearance of the collateral compensatory vessels that develop over time. Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is a rare genetic syndrome characterized by microcephaly and short stature. In up to 25% of patients with MOPD II, there is an association with moyamoya syndrome. This report is of a Syrian boy diagnosed with moyamoya syndrome and MOPD II. A 10-year-old boy was referred to our pediatric endocrinology unit for short stature (-11.1 standard deviations). Exploration of the oral cavity showed dental malposition. Laboratory tests revealed mild thrombocytosis and hypernatremia. Glucagon-based growth hormone-stimulation testing revealed pathology, with growth hormone levels peaked at 30 minutes below 1 ng/ml. No abnormalities of carbohydrate metabolism or heart function were identified. Neuropsychological assessment found moderate to severe intellectual disability. Imaging studies showed osteoporosis, bilateral coxa vara, diffuse platyspondyly without scoliosis, malrotation of the left kidney, severe microcephaly with simplified convolution pattern, and moyamoya features with secondary brain atrophy. A genetic study identified a mutation in both alleles of the pericentrin (PCNT) gene, enabling the diagnosis of microcephalic osteodysplastic primordial dwarfism type II. This case highlights the importance of identifying the cause of short stature in children and genetic syndromes that may be linked with other abnormalities. MOPDII associated with moyamoya syndrome was diagnosed by cerebrovascular imaging, which led to a multidisciplinary approach to management

Fetal Left Ventricle Function Evaluated by Two-Dimensional Speckle-Tracking Echocardiography across Clinical Stages of Severity in Growth-Restricted Fetuses

Fetal growth restriction (FGR) can result in adverse perinatal outcomes due to cardiac dysfunction. This study used 2D speckle-tracking echocardiography to assess left ventricle (LV) longitudinal strain across FGR severity stages. A prospective longitudinal cohort study measured global (GLS) and segmental LV longitudinal strain in FGR fetuses, with evaluations conducted at various time points. FGR was classified into subtypes based on published criteria using fetal weight centile and Doppler parameters. A linear mixed model was employed to analyze repeated measures and compare Z-score measurements between groups throughout gestational age. The study included 40 FGR fetuses and a total of 107 evaluations were performed: 21 from small for gestational age (SGA), 74 from the FGR stage I, and 12 from the FGR stage ≥ II. The results indicate that SGA and stage I FGR fetuses exhibit higher LV GLS than stages ≥ II. Throughout gestation, SGA and FGR stage I fetuses showed similar behavior with consistently better LV GLS values when compared to FGR stages ≥ II. No significant differences were observed in LV GLS strain behavior between SGA and FGR stage I. In conclusion, all FGRs show signs of early cardiac dysfunction, with severe cases demonstrating significantly a lower LV GLS when compared to mild cases, suggesting deterioration of cardiac dysfunction with progression of fetal compromise

Structural disruption of BAF chromatin remodeller impairs neuroblastoma metastasis by reverting an invasiveness epigenomic program

Altres ajuts: Asociación Española Contra el Cáncer (LABAE18009SEGU to MFS, LABAE19004LLOB to DL-N, PROYE18010POSA to FP); Generalitat de Catalunya (2017FI_B_00095 to CJ, 2017SGR799 to FP and EdN; institutional funding through CERCA Programme); State Research Agency (institutional funding through Unidad de Excelencia María de Maeztu, CEX2018-000792-M)Epigenetic programming during development is essential for determining cell lineages, and alterations in this programming contribute to the initiation of embryonal tumour development. In neuroblastoma, neural crest progenitors block their course of natural differentiation into sympathoadrenergic cells, leading to the development of aggressive and metastatic paediatric cancer. Research of the epigenetic regulators responsible for oncogenic epigenomic networks is crucial for developing new epigenetic-based therapies against these tumours. Mammalian switch/sucrose non-fermenting (mSWI/SNF) ATP-dependent chromatin remodelling complexes act genome-wide translating epigenetic signals into open chromatin states. The present study aimed to understand the contribution of mSWI/SNF to the oncogenic epigenomes of neuroblastoma and its potential as a therapeutic target. Functional characterisation of the mSWI/SNF complexes was performed in neuroblastoma cells using proteomic approaches, loss-of-function experiments, transcriptome and chromatin accessibility analyses, and in vitro and in vivo assays. Neuroblastoma cells contain three main mSWI/SNF subtypes, but only BRG1-associated factor (BAF) complex disruption through silencing of its key structural subunits, ARID1A and ARID1B, impairs cell proliferation by promoting cell cycle blockade. Genome-wide chromatin remodelling and transcriptomic analyses revealed that BAF disruption results in the epigenetic repression of an extensive invasiveness-related expression program involving integrins, cadherins, and key mesenchymal regulators, thereby reducing adhesion to the extracellular matrix and the subsequent invasion in vitro and drastically inhibiting the initiation and growth of neuroblastoma metastasis in vivo. We report a novel ATPase-independent role for the BAF complex in maintaining an epigenomic program that allows neuroblastoma invasiveness and metastasis, urging for the development of new BAF pharmacological structural disruptors for therapeutic exploitation in metastatic neuroblastoma