👤 Paul Bassett

BACKGROUNDHypoactive sexual desire disorder (HSDD) is characterized by a persistent deficiency of sexual fantasies and desire for sexual activity, causing marked distress and interpersonal difficulty. It is the most prevalent female sexual health problem globally, affecting approximately 10% of women, but has limited treatment options. Melanocortin 4 receptor (MC4R) agonists have emerged as a promising therapy for women with HSDD, through unknown mechanisms. Studying the pathways involved is crucial for our understanding of normal and abnormal sexual behavior.METHODSUsing psychometric, functional neuroimaging, and hormonal analyses, we conducted a randomized, double-blinded, placebo-controlled, crossover clinical study to assess the effects of MC4R agonism compared with placebo on sexual brain processing in 31 premenopausal heterosexual women with HSDD.RESULTSMC4R agonism significantly increased sexual desire for up to 24 hours after administration compared with placebo. During functional neuroimaging, MC4R agonism enhanced cerebellar and supplementary motor area activity and deactivated the secondary somatosensory cortex, specifically in response to visual erotic stimuli, compared with placebo. In addition, MC4R agonism enhanced functional connectivity between the amygdala and the insula during visual erotic stimuli compared with placebo.CONCLUSIONThese data suggest that MC4R agonism enhanced sexual brain processing by reducing self-consciousness, increasing sexual imagery, and sensitizing women with HSDD to erotic stimuli. These findings provide mechanistic insight into the action of MC4R agonism in sexual behavior and are relevant to the ongoing development of HSDD therapies and MC4R agonist development more widely.TRIAL REGISTRATIONClinicalTrials.gov NCT04179734.FUNDINGThis is an investigator-sponsored study funded by AMAG Pharmaceuticals Inc., the Medical Research Council (MRC) (MR/T006242/1), and the National Institute for Health Research (NIHR) (CS-2018-18-ST2-002 and RP-2014-05-001). Show less

Endothelial-to-mesenchymal transition (EndMT) is a cellular transdifferentiation program in which endothelial cells partially lose their endothelial identity and acquire mesenchymal-like features. Renal capillary endothelial cells can undergo EndMT in association with persistent damage of the renal parenchyma. The functional consequence(s) of EndMT in kidney fibrosis remains unexplored. Here, we studied the effect of Twist or Snail deficiency in endothelial cells on EndMT in kidney fibrosis. Conditional deletion of Show less

Hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomeric proteins, the commonest being MYBPC3 encoding myosin-binding protein C. It is characterised by left ventricular hypertrophy but there is an important pre-hypertrophic phenotype with features including crypts, abnormal mitral leaflets and trabeculae. We investigated these during mouse cardiac development using high-resolution episcopic microscopy. In embryonic hearts from wildtype, homozygous (HO) and heterozygous (HET) Mybpc3-targeted knock-out (KO) mice we show that crypts (one or two) are a normal part of wildtype development but they almost all resolve by birth. By contrast, HO and HET embryos had increased crypt presence, abnormal mitral valve formation and alterations in the compaction process. In scarce normal human embryos, crypts were sometimes present. This study shows that features of the human pre-hypertrophic HCM phenotype occur in the mouse. In an animal model we demonstrate that there is an embryological HCM phenotype. Crypts are a normal part of cardiac development but, along with the mitral valve and trabeculae, their developmental trajectory is altered by the presence of HCM truncating Mybpc3 gene mutation. Show less

The GPHN gene codes for gephyrin, a key scaffolding protein in the neuronal postsynaptic membrane, responsible for the clustering and localization of glycine and GABA receptors at inhibitory synapses. Gephyrin has well-established functional links with several synaptic proteins that have been implicated in genetic risk for neurodevelopmental disorders such as autism spectrum disorder (ASD), schizophrenia and epilepsy including the neuroligins (NLGN2, NLGN4), the neurexins (NRXN1, NRXN2, NRXN3) and collybistin (ARHGEF9). Moreover, temporal lobe epilepsy has been linked to abnormally spliced GPHN mRNA lacking exons encoding the G-domain of the gephyrin protein, potentially arising due to cellular stress associated with epileptogenesis such as temperature and alkalosis. Here, we present clinical and genomic characterization of six unrelated subjects, with a range of neurodevelopmental diagnoses including ASD, schizophrenia or seizures, who possess rare de novo or inherited hemizygous microdeletions overlapping exons of GPHN at chromosome 14q23.3. The region of common overlap across the deletions encompasses exons 3-5, corresponding to the G-domain of the gephyrin protein. These findings, together with previous reports of homozygous GPHN mutations in connection with autosomal recessive molybdenum cofactor deficiency, will aid in clinical genetic interpretation of the GPHN mutation spectrum. Our data also add to the accumulating evidence implicating neuronal synaptic gene products as key molecular factors underlying the etiologies of a diverse range of neurodevelopmental conditions. Show less

Thyroid hormone is essential for normal skeletal development. Hypothyroidism is associated with growth arrest, failure of chondrocyte differentiation, and abnormal matrix synthesis. Thyroid hormone modulates the Indian hedgehog/PTHrP feedback loop and regulates fibroblast growth factor (FGF)/FGF receptor signaling. Because heparan sulfate (HS) proteoglycans (Prgs) (HSPGs) are absolutely required by these signaling pathways, we have investigated whether thyroid status affects HSPG expression within the growth plate. Tibial growth plate sections were obtained from 12-wk-old rats rendered euthyroid, thyrotoxic, or hypothyroid at 6 wk of age, 14-d-old congenitally hypothyroid Pax8-null mice, and TRalpha/TRbeta double-null mice lacking all thyroid hormone receptors. HS and chondroitin sulfate Prg expression was determined by immunohistochemistry using three monoclonal antibodies. There was increased HS staining in growth plates from hypothyroid animals predominantly within the extracellular matrix of reserve and proliferative zones. Cellular HS staining was also increased particularly in prehypertrophic chondrocytes. T3 regulation of HSPG core protein and HS synthetic and modification enzyme expression was studied in ATDC5 cells using semiquantitative RT-PCR. Thyroid hormone negatively regulated expression of the core protein Gpc6, the polymerase Ext1, and the modification enzyme Hs6st2. These studies demonstrate that the expression and distribution of growth plate Prgs are regulated by thyroid hormone, and the regulation of HSPG expression provides an important additional link between FGF and Indian hedgehog signaling and T3. These novel observations suggest that the cartilage matrix and especially HSPGs are critical mediators of the skeletal response to thyroid hormone. Show less