Activity

On the 5-HT2A receptor, bromo-dragonfly showed the highest potency (EC50 = 0.05 nM, 400 times more potent than LSD), followed by most NBOMe compounds with EC50 values ranging from 0.11 nM (for 25N-NBOMe) to 1.3 nM (for 25T4-NBOMe)). Off-target activation of the μ-opioid receptor was identified for piperazines, phenethylamines (in particular NBOMe and 2C compounds) and tryptamines. Moreover, the synthetic cannabinoid metabolite 3-carboxy indole PB-22 activated the 5-HT2A receptor. Bromo-dragonfly was the only compound that activated all four receptors. These results highlight the possible interplay of known and unknown NPS targets and unveil its complexity. Moreover, the detailed, quantitative information presented facilitates our further understanding of NPS toxicology.

Hepatic steatosis is a common chronic liver disease that can progress into more severe stages of NAFLD or promote the development of life-threatening secondary diseases for some of those affected. These include the liver itself (nonalcoholic steatohepatitis or NASH; fibrosis and cirrhosis, and hepatocellular carcinoma) or other organs such as the vessels and the heart (cardiovascular disease) or the islets of Langerhans (type 2 diabetes). In addition to elevated caloric intake and a sedentary lifestyle, genetic and epigenetic predisposition contribute to the development of NAFLD and the secondary diseases.

We present data from genome-wide association studies (GWAS) and functional studies in rodents which describe polymorphisms identified in genes relevant for the disease as well as changes caused by altered DNA methylation and gene regulation via specific miRNAs. The review also provides information on the current status of the use of genetic and epigenetic factors as risk markers.

With our overview we provide an insight into the genetic and epigenetic landscape of NAFLD and argue about the applicability of currently defined risk scores for risk stratification and conclude that further efforts are needed to make the scores more usable and meaningful.

With our overview we provide an insight into the genetic and epigenetic landscape of NAFLD and argue about the applicability of currently defined risk scores for risk stratification and conclude that further efforts are needed to make the scores more usable and meaningful.Centrioles are microtubule-based structures in eukaryotic cells. From organizing the microtubule cytoskeleton during interphase to focusing the mitotic spindle during mitosis, centrioles are busy at all stages of the cell cycle. One crucial interphase function of centrioles is to assemble cilia, microtubular projections that can either be motile or nonmotile. Motile cilia function in sperm locomotion and propulsion of extracellular fluids, as in mucus flow in the lung. Immotile primary cilia are critical for some forms of intercellular signaling. Here, we review how procentrioles mature into daughter and, then, mother centrioles. We highlight key steps in ciliogenesis, including the acquisition of appendages by the mother centriole, as well as the distal centriole, an understudied domain critical for ciliogenesis. Importantly, several genes mutated in ciliopathies encode distal centriolar components. We propose that understanding how centrioles are remodeled to support cilium assembly will provide insights into the molecular etiologies of ciliopathies.Luminescent hydrogels are emerging soft materials with applications in photoelectric, biomedicine, sensors and actuators, which are fabricated via covalently conjugation of luminophors to hydrogelators or physical loading of luminescent organic/inorganic materials into hydrogel matrices. Due to the intrinsic stimulus-responsiveness for hydrogels such as thermo-, pH, ionic strength, light and redox, luminescent hydrogels could respond to external physical or chemical stimuli through varying the luminescent properties such as colors, fluorescent intensity and so on, affording diverse application potential in addition to the pristine individual hydrogels or luminescent materials. Based on the rapid development of such area, here we systematically summarize and discuss the design protocols, properties as well as the applications of stimulus-responsive luminescent hydrogels. Because of the stimuli-responsiveness, biocompatibility, injectable and controllability of luminescent hydrogels, they are widely used as functional smart materials. We illustrate the applications of luminescent hydrogels. The future developments about luminescent hydrogels are also presented.N6-methyladenosine (m6A) is one of the most abundant modifications on mRNAs and plays important roles in various biological processes. The formation of m6A is catalyzed by a methyltransferase complex (MTC) containing a key factor methyltransferase-like 3 (Mettl3). However, the functions of Mettl3 and m6A modification in hepatic lipid and glucose metabolism remain unclear. Here, we showed that both Mettl3 expression and m6A level increased in the livers of mice with high fat diet (HFD)-induced metabolic disorders. Overexpression of Mettl3 aggravated HFD-induced liver metabolic disorders and insulin resistance. In contrast, hepatocyte-specific knockout of Mettl3 significantly alleviated HFD-induced metabolic disorders by slowing weight gain, reducing lipid accumulation, and improving insulin sensitivity. Mechanistically, Mettl3 depletion-mediated m6A loss caused extended RNA half-lives of metabolism-related genes, which consequently protected mice against HFD-induced metabolic syndrome. selleck kinase inhibitor Our findings reveal a critical role of Mettl3-mediated m6A in HFD-induced metabolic disorders and hepatogenous diabetes.Neurodevelopmental disorders (NDDs) show a wide range of overlapping clinical features. Intellectual disability (ID), developmental delay (DD), autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), language and communication disorders with or without motor abnormalities and/or epilepsy have been reported associated to single or multiple genes but in many cases the genetic basis remains unknown. The increasingly use of array-CGH has significantly improved the yield of diagnosing genomic disorders and led to the identification of several novel microdeletion and microduplication syndromes. TANC2 encodes a synaptic scaffold protein interacting with multiple neuropsychiatric disorder-related postsynaptic density (PSD) proteins in dendrites. Here, we describe a new case of TANC2 gene disruption in a 17q23.3 de novo microdeletion identified by array-CGH. The patient presented craniofacial dysmorphic features, hypotonia, and severe cognitive and motor impairment. In conclusion, our data add a further line of evidence supporting the role of TANC2 in NDDs and will help further researches to elucidate the regulatory mechanism of synaptic function and plasticity related to TANC2 haploinsufficiency.