In Vivo Evaluation of α7 Nicotinic Acetylcholine Receptor Agonists [11C]A-582941 and [11C]A-844606 in Mice and Conscious Monkeys

BACKGROUND: The alpha7 nicotinic acetylcholine receptors (nAChRs) play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. The goal of this study was to evaluate the two carbon-11-labeled alpha7 nAChR agonists [(11)C]A-582941 and [(11)C]A-844606 for their potential as novel positron emission tomography (PET) tracers. METHODOLOGY/PRINCIPAL FINDINGS: The two tracers were synthesized by methylation of the corresponding desmethyl precursors using [(11)C]methyl triflate. Effects of receptor blockade in mice were determined by coinjection of either tracer along with a carrier or an excess amount of a selective alpha7 nAChR agonist (SSR180711). Metabolic stability was investigated using radio-HPLC. Dynamic PET scans were performed in conscious monkeys with/without SSR180711-treatment. [(11)C]A-582941 and [(11)C]A-844606 showed high uptake in the mouse brain. Most radioactive compounds in the brain were detected as an unchanged form. However, regional selectivity and selective receptor blockade were not clearly observed for either compound in the mouse brain. On the other hand, the total distribution volume of [(11)C]A-582941 and [(11)C]A-844606 was high in the hippocampus and thalamus but low in the cerebellum in the conscious monkey brain, and reduced by pretreatment with SSR180711. CONCLUSIONS/SIGNIFICANCE: A nonhuman primate study suggests that [(11)C]A-582941 and [(11)C]A-844606 would be potential PET ligands for imaging alpha7 nAChRs in the human brain

Th22 Cells Promote Osteoclast Differentiation via Production of IL-22 in Rheumatoid Arthritis

T helper (Th) cells can differentiate into functionally distinct subsets and play a pivotal role in inflammatory and autoimmune diseases such as rheumatoid arthritis (RA). Th22 cells have been identified as a new subset secreting interleukin (IL)-22. Although elevated levels of IL-22 in the synovial fluids of RA patients were reported, its pathological roles remain unclear. Here, we demonstrated that IL-22 was characteristically produced from CD3+CD4+CC-chemokine receptor (CCR)4+CCR6+CCR10+ cells and their ability of the production of IL-22 markedly exceeded that of other Th subsets and the subset, thereby, designated Th22 cells. Th22 cells were efficiently induced by the stimulation with tumor necrosis factor-α, IL-6, and IL-1β. Th22 cells were markedly infiltrated in synovial tissue in patients with active RA, but not in patients with osteoarthritis (OA). CCL17, CCL20, and CCL28, which are chemokine ligands of CCR4, CCR6, and CCR10, respectively, were abundantly expressed in RA synovial tissue compared to OA. By in vitro Trans-well migration assay, Th22 cells efficiently migrated toward CCL28. Co-culture of Th22 cells, which were sorted from peripheral blood, with monocytes in the presence of macrophage colony-stimulating factor and receptor activator of nuclear factor (NF)-κB ligand induced osteoclasts formation more efficiently than that of either Th1 cells or Th17 cells. Furthermore, IL-22 markedly augmented osteoclast differentiation by promoting nuclear factor of activated T cells c1 expression in CD14+ monocytes. Contrarily, the addition of IFN-γ to the culture significantly decreased osteoclasts number, whereas IL-17 had marginal effects. IL-22 neutralizing antibody inhibited osteoclast formation in the co-culture of Th22 cells with CD14+ monocytes. Collectively, the results indicated that Th22 cells, which co-express chemokine receptors CCR4, CCR6, and CCR10, possess strong potency of tissue migration and accumulate into inflamed synovial tissues where the ligands such as CCL28 are highly expressed. Thus, Th22 cells have the capacity to promote osteoclast differentiation through production of IL-22 and thus play a pivotal role in bone destruction in patients with RA

Facile synthesis of graphene sheets intercalated by carbon spheres for high-performance supercapacitor electrodes

The composites consisting of graphene oxides (GOs) and carbon spheres (CSs), which were hydrothermally derived from the aqueous solution of glucose with average diameter of 200 nm, were mechanically mixed, and the GOs/CSs (GCSs) were thermally treated at high temperatures in the range of 700–900 °C. In the GCS composites, the CSs as spacers located between the GO sheets prevent the aggregation and restacking of graphene sheets. The GCS composites (GO/CS = 1) treated at 800 °C (GCS@800) have the high specific capacitances of 272.8 and 197.5 F g−1 in a three-electrode cell at the current density of 0.2 and 10 A g−1, respectively, in 6 M KOH aqueous solution, and demonstrated high rate capability and good cycling stability. The excellent electrochemical performance of the GCS@800 electrode is attributed to its structure with hierarchical porous structures including overwhelming micropores and a few of macropores. This work provides an effective and simple technique by integrating CSs and graphene sheets into composite structures for high-performance energy storage devices

Synthesis of submicron metastable phase of silicon using femtosecond laser-driven shock wave

We measured the grain size of metastable phase of Si synthesized by shock compression. We analyzed the crystalline structures of the femtosecond laser-driven shock compressed silicon with x-ray diffraction measurements. We found that submicron grains of metastable Si-VIII exist in the silicon. We suggest that the pressure loading time is too short for the nucleated high-pressure phases to grow in case of the femtosecond laser-driven shock compression, therefore Si-VIII grains of submicron size are obtained. We are expecting to discover other unique crystalline structures induced by the femtosecond laser-driven shock wave. © 2011 American Institute of Physics.Tsujino M., Sano T., Sakata O., et al, Journal of Applied Physics, 110, 12, 126103 (2011) https://doi.org/10.1063/1.3673591

Genetic evidence implies that primary and relapsed tumors arise from common precursor cells in primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare subtype of lymphoma that arises within the brain or the eyes. PCNSL recurs within the central nervous system (CNS) in most relapsed cases, whereas extra- CNS relapse is experienced in rare cases. The present study aimed at identifying the presence of common precur -sor cells (CPC) for primary intra- and relapsed extra- CNS tumors, and further assess -ing the initiating events in bone marrow (BM). Targeted deep sequencing was carried out for five paired primary intra- and relapsed extra- CNS tumors of PCNSL. Two to five mutations were shared by each pair of intra- and extra- CNS tumors. In particular, MYD88 mutations, L265P in three and P258L in one, were shared by four pairs. Unique somatic mutations were observed in all five intra- CNS tumors and in four out of five extra- CNS tumors. Remarkably, IgH clones in the intra- and the extra- CNS tumors in two pairs were distinct from each other, whereas one pair of tumors shared identical monoclonalIgH rearrangement. In a cohort of 23 PCNSL patients, L265P MYD88 mutations were examined in tumor- free BM mononuclear cells (MNC) in which the PCNSL tumors had L265P MYD88 mutations. L265P MYD88 mutationswere detected by a droplet digital PCR method in nine out of 23 bone marrow mono -nuclear cells. These results suggest that intra- and extra- tumors are derived from CPC with MYD88 mutations in most PCNSL, arising either before or after IgH rear-rangement. The initiatingMYD88 mutations may occur during B- cell differentiation in BM