Angelman syndrome is a complex neurodevelopmental disorder characterized by delayed development, intellectual disability, speech impairment, and ataxia. It results from the loss of UBE3A protein, an E3 ubiquitin ligase, in neurons of the brain.  https://www.selleckchem.com/products/BIBF1120.html  Despite the dynamic spatiotemporal expression of UBE3A observed in rodents and the potential clinical importance of when and where it is expressed, its expression pattern in humans remains unknown. This reflects a common challenge of studying human neurodevelopment prenatal periods are hard to access experimentally. In this work, human cerebral organoids reveal a change from weak to strong UBE3A in neuronal nuclei within 3 weeks of culture. Angelman syndrome human induced pluripotent stem cell-derived organoids also exhibit early silencing of paternal UBE3A, with topoisomerase inhibitors partially rescuing UBE3A levels and calcium transient phenotypes. This work establishes human cerebral organoids as an important model for studying UBE3A and motivates their broader use in understanding complex neurodevelopmental disorders.Most organs and tissues in the body, including bone, can repair after an injury due to the activation of endogenous adult stem/progenitor cells to replace the damaged tissue. Inherent dysfunctions of the endogenous stem/progenitor cells in skeletal repair disorders are still poorly understood. Here, we report that Fgfr3Y637C/+ over-activating mutation in Prx1-derived skeletal stem/progenitor cells leads to failure of fracture consolidation. We show that periosteal cells (PCs) carrying the Fgfr3Y637C/+ mutation can engage in osteogenic and chondrogenic lineages, but following transplantation do not undergo terminal chondrocyte hypertrophy and transformation into bone causing pseudarthrosis. Instead, Prx1Cre;Fgfr3Y637C/+ PCs give rise to fibrocartilage and fibrosis. Conversely, wild-type PCs transplanted at the fracture site of Prx1Cre;Fgfr3Y637C/+ mice allow hypertrophic cartilage transition to bone and permit fracture consolidation. The results thus highlight cartilage-to-bone transformation as a necessary step for bone repair and FGFR3 signaling within PCs as a key regulator of this transformation.Research shows a higher incidence of colorectal cancer in men. However, the molecular mechanisms for this gender disparity remain unknown. We report the roles of androgen in proliferation and differentiation of intestinal stem cells via targeting of the androgen receptor (AR) on intestinal stromal cells by negatively regulating BMP signaling. Orchidectomy (ORX) or the AR antagonist promotes expansion of intestinal epithelium but suppresses intestinal stem cell (ISC) proliferation. Conversely, the AR agonist inhibits ISC differentiation but augments proliferation in ovariectomized mice. Mechanistically, activation of the AR increases expression of BMP antagonists but lowers expression of BMP4 and Wnt antagonists in primary stromal cells, which promotes intestinal organoid growth. Interestingly, the BMP pathway inhibitor LDN-193189 reverses the ORX-induced effects. Our results highlight that stromal cells constitute the intestinal stem cell niche and provide a possible explanation for higher incidence rates of colorectal cancer in men.The hippocampal subfields perform distinct operations during acquisition, differentiation, and recollection of episodic memories, and deficits in pattern separation are among the first symptoms of Alzheimer's disease (AD). We investigated how hippocampal subfields contribute to pattern separation and how this is affected by Apolipoprotein-E (APOE), the strongest AD genetic risk factor. Using ultra-high-field (7T) functional magnetic resonance imaging (fMRI), APOE-ε3-ε3 carriers predominantly recruited cornu ammonis 3 (CA3) during a spatial mnemonic discrimination task, whereas APOE-ε3-ε4 and APOE-ε3-ε2 carriers engaged CA3 and dentate gyrus (DG) to the same degree. Specifically, APOE-ε3-ε4 carriers showed reduced pattern separation in CA3, whereas APOE-ε3-ε2 carriers exhibited increased effects in DG and pattern separation-related functional connectivity between DG and CA3. Collectively, these results demonstrate that AD genetic risk alters hemodynamic responses in young pre-symptomatic individuals, paving the way for development of biomarkers for preclinical AD.Octopuses are active predators with highly flexible bodies and rich behavioral repertoires [1-3]. They display advanced cognitive abilities, and the size of their large nervous system rivals that of many mammals. However, only one third of the neurons constitute the CNS, while the rest are located in an elaborate PNS, including eight arms, each containing myriad sensory receptors of various modalities [2-4]. This led early workers to question the extent to which the CNS is privy to non-visual sensory input from the periphery and to suggest that it has limited capacity to finely control arm movement [3-5]. This conclusion seemed reasonable considering the size of the PNS and the results of early behavioral tests [3, 6-8]. We recently demonstrated that octopuses use visual information to control goal-directed complex single arm movements [9]. However, that study did not establish whether animals use information from the arm itself [9-12]. We here report on development of two-choice, single-arm mazes that test the ability of octopuses to perform operant learning tasks that mimic normal tactile exploration behavior and require the non-peripheral neural circuitry to use focal sensory information originating in single arms [1, 10]. We show that the CNS of the octopus uses peripheral information about arm motion as well as tactile input to accomplish learning tasks that entail directed control of movement. We conclude that although octopus arms have a great capacity to act independently, they are also subject to central control, allowing well-organized, purposeful behavior of the organism as a whole.Glucosinolates (GSs) are sulfur-containing secondary metabolites characteristic of cruciferous plants [1, 2]. Their breakdown products, isothiocyanates (ITCs), are released following tissue disruption by insect feeding or other mechanical damages [3, 4]. ITCs repel and are toxic to generalist herbivores, while specialist herbivores utilize the volatile ITCs as key signals for localizing host plants [5, 6]. However, the molecular mechanisms underlying detection of ITCs remain open. Here, we report that in the diamondback moth Plutella xylostella, a crucifer specialist, ITCs indeed drive the host preference for Arabidopsis thaliana, and the two olfactory receptors Or35 and Or49 are essential for this behavior. By performing gene expression analyses, we identified 12 (out of 59 in total) female-biased Ors, suggesting their possible involvement in oviposition choice. By ectopically expressing these Ors in Xenopus oocytes and screening their responses with 49 odors (including 13 ITCs, 25 general plant volatiles, and 11 sex pheromone components), we found that Or35 and Or49 responded specifically to three ITCs (iberverin, 4-pentenyl ITC, and phenylethyl ITC).