Hansaleh3190

Adaptation to changes in ambient light intensity, in retinal cells and circuits, optimizes visual functions. In the retina, light-adaptation results in changes in light-sensitivity and spatiotemporal tuning of ganglion cells. Under light-adapted conditions, contrast sensitivity (CS) of ganglion cells is a bandpass function of spatial frequency; in contrast, dark-adaptation reduces CS, especially at higher spatial frequencies. In this work, we aimed to understand intrinsic neuromodulatory mechanisms that underlie retinal adaptation to changes in ambient light level. Specifically, we investigated how CS is affected by dopamine (DA), nitric oxide (NO), and modifiers of electrical coupling through gap junctions, under different conditions of adapting illumination. Using the optokinetic response as a behavioral readout of direction-selective ganglion cell activity, we characterized the spatial CS of chicks under high- and low-photopic conditions and how it was regulated by DA, NO, and gap-junction uncouplers. We oe vitreous humor. Finally, the chick's large eyes, and the many similarities between their adaptational circuit functions and those in mammals such as the mouse, make them a promising model for future retinal research. Compelling evidence has implicated role of microRNAs (miRNAs) in neurogenesis. Methyl-CpG Binding Protein 2 (MeCP2) was a key contributor to neurological disease. This study investigated whether miR-212-3p affects early neurogenesis associated with MeCP2. Microarray-based gene expression profiling of neurogenesis was employed to identify differentially expressed genes. Next, miR-212-3p expression in neural progenitor cells (NPCs) was detected using in situ hybridization and immunofluorescence. Effect of miR-212-3p and MeCP2 on cell viability, β-tubulin III expression and the AKT/mammalian target of rapamycin (mTOR) pathway activity was examined with gain- and loss-of-function experiments. In vivo experiments were also performed to verify effects of miR-212-3p on nerve tube development. MiR-212-3p expression was decreased while MeCP2 expression was increased during differentiation of NPCs. MiR-212-3p targets MeCP2 and down-regulates its expression, which resulted in repressed cell differentiation, proliferation as well as blocked AKT/mTOR pathway activation, subsequently early neurogenesis was prevented. Furthermore, overexpression of miR-212-3p inhibited nerve tube development in vivo. Taken together, miR-212-3p could restrain early neurogenesis through the blockade of AKT/mTOR pathway activation by targeting MeCP2, suggesting a promising therapeutic target for neurogenic disorders. GPCR antagonist Phosphodiesterase 7B (PDE7B) inhibition has been considered as a therapeutic target for the treatment of several neurological disorders. Currently, there are no radio-labeled tracers available to determine receptor occupancy (RO) of this target. Developing such a tracer could greatly facilitate the identification of viable PDE7B inhibitors. In the current study, a liquid chromatography tandem mass spectrometry (LC─MS/MS) method was utilized to evaluate the brain distribution of unlabeled tracer candidates following intravenous micro-dosing. This novel approach resulted in an accelerated identification of a potential novel RO tracer for PDE7B. The identified molecule, Compound 30, showed reasonable target-tissue specificity (striatum/cerebellum ratio of 2.2) and suitable uptake (0.25% of the injected dose/g brain tissue) as demonstrated in rats dosed with the unlabeled compound. Compound 30 was subsequently labeled with tritium (3H). In vitro characterization of 3H-Compound 30 demonstrated that this compound possessed a high target affinity with a subnanomolar Kd (0.8 nM) and a Bmax of 58 fmol/mg of protein using rat brain homogenate. Intravenous microdosing of 3H-Compound 30 showed preferential binding in the rat striatum, consistent with the mRNA distribution of PDE7B. In vitro displacement study with other structurally distinct PDE7B target-specific inhibitors using rat brain homogenate indicated that 3H-Compound 30 is an ideal tracer for Ki analysis. This is the first report of a preclinical tracer for PDE7B. With further characterization, Compound 30 may ultimately show the appropriate properties required to be further developed as a PDE7B PET ligand for clinical studies. Cyclodextrins (CDs) form complex crystals with drugs and improve physicochemical properties of drugs. However, only few reports have summarized relationships between crystal structures of drug/CD and dissolution behavior. In this study, we developed cimetidine (CIM)/CD complex crystals to achieve sustained drug release and investigated the relationship between the dissolution behavior of CIM/CD complexes and their crystal structures. CIM and three types of CDs (α-, β-, and γ-CD) formed a complex crystal when subjected to solvent mixing. The CIM/CD complexes had a highly reduced dissolution rate compared to that of the physical mixture of CIM and CD. β-CD improved the solubility of CIM, whereas γ-CD decreased its solubility. Based on the phase solubility diagram, CIM and α-, β-, and γ-CD indicated A-type positive (AP) and AL deviation, and B-type limited solubility (BS) profiles, respectively. In γ-CD, the saturated concentration of CIM decreased owing to the formation of a low-solubility complex with CIM. CIM/α-CD formed cage-type crystals, and CIM/β-CD and CIM/γ-CD formed channel-type crystals. The dissolution rate constant (k) of CIM/α-CD and CIM/β-CD were 0.045 and 0.04 h-1, respectively. CIM/γ-CD and CIM/β-CD displayed channel-type crystals; however, the channel-type crystals of CIM/γ-CD were stabilized by the presence of additional water molecules. Nuclear medicine is a routine but essential clinical option for diagnostic imaging and disease treatment. Encapsulating radioisotopes in injectable biodegradable hydrogels is ideal for localizing radiation sources to target tissues or organs to achieve long-term, low-dose radiotherapy. However, difficulties in the on-site production of radioactive gels upon treatment and the unpredictable radiation level at the target region are major obstacles to their clinical use. In this study, we bypassed these limitations by developing locally injectable hydrogel microparticles based on 131I-labeled photo-crosslinkable hyaluronic acid (HA) and a microfluidic high-throughput droplet generator. This approach enabled rapid on-site production of injectable, radioactive, biodegradable (IRB) HA microgels, thus allowing their immediate therapeutic application with improved local retention and predictable radioactivity. We demonstrated the clinical utility of this comprehensive approach by preparing IRB HA microgels within 15 min and localizing them to the target tissue (rat muscle) with minimal off-target biodistribution and in vivo radioactivity that extended beyond 3 weeks.