Pleiotropic Control of Secondary Metabolism and Morphological Development by KsbC,a Butyrolactone Autoregulator Receptor Homologue in Kitasatospora setae

The γ-butyrolactone autoregulator signaling cascades have been shown to control secondary metabolism and/or morphological development among many Streptomyces species. However, the conservation and variation of the regulatory systems among actinomycetes remain to be clarified. The genome sequence of Kitasatospora setae, which also belongs to the family Streptomycetaceae containing the genus Streptomyces, has revealed the presence of three homologues of the autoregulator receptor: KsbA, which has previously been confirmed to be involved only in secondary metabolism; KsbB; and KsbC. We describe here the characterization of ksbC, whose regulatory cluster closely resembles the Streptomyces virginiae barA locus responsible for the autoregulator signaling cascade. Deletion of the gene ksbC resulted in lowered production of bafilomycin and a defect of aerial mycelium formation, together with the early and enhanced production of a novel β-carboline alkaloid named kitasetaline. A putative kitasetaline biosynthetic gene cluster was identified, and its expression in a heterologous host led to the production of kitasetaline together with JBIR-133, the production of which is also detected in the ksbC disruptant, and JBIR-134 as novel β-carboline alkaloids, indicating that these genes were biosynthetic genes for β-carboline alkaloid and thus are the first such genes to be discovered in bacteria.     

MOCA is an integrator of the neuronal death signals that are activated by familial Alzheimer's disease-related mutants of amyloid β precursor protein and presenilins

The death of cholinergic neurons in the cerebral cortex and certain subcortical regions is linked to irreversible dementia relevant to AD (Alzheimer's disease). Although multiple studies have shown that expression of a FAD (familial AD)-linked APP (amyloid β precursor protein) or a PS (presenilin) mutant, but not that of wild-type APP or PS, induced neuronal death by activating intracellular death signals, it remains to be addressed how these signals are interrelated and what the key molecule involved in this process is. In the present study, we show that the PS1-mediated (or possibly the PS2-mediated) signal is essential for the APP-mediated death in a γ-secretase-independent manner and vice versa. MOCA (modifier of cell adhesion), which was originally identified as being a PS- and Rac1-binding protein, is a common downstream constituent of these neuronal death signals. Detailed molecular analysis indicates that MOCA is a key molecule of the AD-relevant neuronal death signals that links the PS-mediated death signal with the APP-mediated death signal at a point between Rac1 [or Cdc42 (cell division cycle 42)] and ASK1 (apoptosis signal-regulating kinase 1).     

Effects of antidepressants and mood stabilizers on serum levels of adiponectin

The effect of antidepressants and mood stabilizers on serum levels of adiponectin was investigated. Fluvoxamine (30 and 50?mg/kg/day) or lithium (40 and 60?mg/kg/day) was dissolved in distilled water and administered orally to rats every day for 4 weeks. Fluvoxamine (50 mg/kg/day) alone significantly elevated the serum level of adiponectin, but no significant difference was found between other drug-treated groups and the control group. This difference of these drugs' effectiveness on serum adiponectin might contribute to their differences of action mechanisms and therapeutic effects.     

Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis

The signaling molecule Wnt regulates bone homeostasis through β-catenin-dependent canonical and β-catenin-independent noncanonical pathways. Impairment of canonical Wnt signaling causes bone loss in arthritis and osteoporosis; however, it is unclear how noncanonical Wnt signaling regulates bone resorption. Wnt5a activates noncanonical Wnt signaling through receptor tyrosine kinase-like orphan receptor (Ror) proteins. We showed that Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhanced osteoclastogenesis. Osteoblast-lineage cells expressed Wnt5a, whereas osteoclast precursors expressed Ror2. Mice deficient in either Wnt5a or Ror2, and those with either osteoclast precursor-specific Ror2 deficiency or osteoblast-lineage cell-specific Wnt5a deficiency showed impaired osteoclastogenesis. Wnt5a-Ror2 signals enhanced receptor activator of nuclear factor-κB (RANK) expression in osteoclast precursors by activating JNK and recruiting c-Jun on the promoter of the gene encoding RANK, thereby enhancing RANK ligand (RANKL)-induced osteoclastogenesis. A soluble form of Ror2 acted as a decoy receptor of Wnt5a and abrogated bone destruction in mouse arthritis models. Our results suggest that the Wnt5a-Ror2 pathway is crucial for osteoclastogenesis in physiological and pathological environments and represents a therapeutic target for bone diseases, including arthritis.     

Characterization of Functional Primary Cilia in Human Induced Pluripotent Stem Cell-Derived Neurons

Neurochemical Research - Recent advances in human induced pluripotent stem cells (hiPSCs) offer new possibilities for biomedical research and clinical applications. Neurons differentiated from...     

FR290581, a novel sordarin derivative: Synthesis and antifungal activity

Sordarin is a unique natural product antifungal agent that is an inhibitor of elongation factor 2. To improve biological activity, we synthesized various compounds by novel modification of the aglycone, sordaricin. As a result, we have discovered the novel sordarin derivative FR290581. This compound exhibited superior activity and a good pharmacokinetic profile, and also displayed good in vivo activity against Candida albicans.     

Smaller Fixation Target Size Is Associated with More Stable Fixation and Less Variance in Threshold Sensitivity

The aims of this randomized observational case control study were to quantify fixation behavior during standard automated perimetry (SAP) with different fixation targets and to evaluate the relationship between fixation behavior and threshold variability at each test point in healthy young participants experienced with perimetry. SAP was performed on the right eyes of 29 participants using the Octopus 900 perimeter, program 32, dynamic strategy. The fixation targets of Point, Cross, and Ring were used for SAP. Fixation behavior was recorded using a wearable eye-tracking glass. All participants underwent SAP twice with each fixation target in a random fashion. Fixation behavior was quantified by calculating the bivariate contour ellipse area (BCEA) and the frequency of deviation from the fixation target. The BCEAs (deg²) of Point, Cross, and Ring targets were 1.11, 1.46, and 2.02, respectively. In all cases, BCEA increased significantly with increasing fixation target size (p < 0.05). The logarithmic value of BCEA demonstrated the same tendency (p < 0.05). A positive correlation was identified between fixation behavior and threshold variability for the Point and Cross targets (ρ = 0.413–0.534, p < 0.05). Fixation behavior increased with increasing fixation target size. Moreover, a larger fixation behavior tended to be associated with a higher threshold variability. A small fixation target is recommended during the visual field test.