Neuronal plasticity is especially active in the young, during short windows of time termed critical periods, and loss of a critical period leads to functional limitations in the adults. The mechanism ...that governs the length of critical periods remains unknown. Here we show that levels of the NMDA receptor GluN2B subunit, which functions as a Ca
channel, declines in spinal cord synapses toward the end of the critical period for activity-dependent corticospinal synapse elimination. This period could be prolonged by blocking the decline of GluN2B, and after its termination the critical period could be reopened through upregulation of GluN2B. It is known that inhibitory neural activity increases with development in the CNS including the spinal cord. Suppression of the increasing inhibitory activity using low-dose strychnine also prolonged this critical period. During the strychnine-widened time window, Ca
influx through GluN2B channels returned to a level comparable to that seen during the critical period, though the level of GluN2B was slightly reduced. These findings indicate that loss of GluN2B subunits and the associated reduction in Ca
influx determines the end of the critical period in our in vitro CS system.
Distinct anatomical regions of the neocortex subserve different sensory modalities and neuronal integration functions, but mechanisms for these regional specializations remain elusive. Involvement of ...epigenetic mechanisms for such specialization through the spatiotemporal regulation of gene expression is an intriguing possibility. Here we examined whether epigenetic mechanisms might play a role in the selective gene expression in the association areas (AAs) and the primary visual cortex (V1) in macaque neocortex. By analyzing the two types of area-selective gene promoters that we previously identified, we found a striking difference of DNA methylation between these promoters, i.e., hypermethylation in AA-selective gene promoters and hypomethylation in V1-selective ones. Methylation levels of promoters of each area-selective gene showed no areal difference, but a specific methyl-binding protein (MBD4) was enriched in the AAs, in correspondence with expression patterns of AA-selective genes. MBD4 expression was mainly observed in neurons. MBD4 specifically bound to and activated the AA-selective genes both in vitro and in vivo. Our results demonstrate that methylation in the promoters and specific methyl-binding proteins play an important role in the area-selective gene expression profiles in the primate neocortex.
An adipokine resistin, a small cysteine-rich protein, is one of the major risk factors of insulin resistance. In the present study, transiently resistin-expressing mice using adenovirus method showed ...an impaired glucose tolerance due to insulin resistance. We found that resistin-expressing mice exhibited impaired insulin secretory response to glucose. In addition,
in vitro treatment with resistin for 1 day induced insulin resistance in pancreatic islets and impaired glucose-stimulated insulin secretion by elevating insulin release at basal glucose (2.8
mM) and suppressing insulin release at stimulatory glucose (8.3
mM). In addition, resistin inhibited insulin-induced phosphorylation of Akt in islets as well as other insulin target organs. Furthermore, resistin induced SOCS-3 expression in β-cells. In conclusion, resistin induces insulin resistance in islet β-cells at least partly via induction of SOCS-3 expression and reduction of Akt phosphorylation and impairs glucose-induced insulin secretion.
We previously reported on a monoclonal antibody (mAb) that targeted amyloid beta (Aß) protein. Repeated injection of that mAb reduced the accumulation of Aß protein in the brain of human Aß ...transgenic mice (Tg2576). In the present study, cDNA encoding the heavy and light chains of this mAb were subcloned into an adeno-associated virus type 1 (AAV) vector with a 2A/furin adapter. A single intramuscular injection of 3.0×10(10) viral genome of these AAV vectors into C57BL/6 mice generated serum anti-Aß Ab levels up to 0.3 mg/ml. Anti-Aß Ab levels in excess of 0.1 mg/ml were maintained for up to 64 weeks. The effect of AAV administration on Aß levels in vivo was examined. A significant decrease in Aß levels in the brain of Tg2576 mice treated at 5 months (prophylactic) or 10 months (therapeutic) of age was observed. These results support the use of AAV vector encoding anti-Aß Ab for the prevention and treatment of Alzheimer's disease.
FKHRL1 (also called FOXO3a) is a member of the Forkhead Box, class O (FOXO) subfamily of forkhead transcription factors and functions downstream of Bcr–Abl tyrosine kinase as a phosphorylated ...inactive form in chronic myelogenous leukemia (CML). The Bcr–Abl tyrosine kinase inhibitor imatinib induces cell cycle arrest and subsequent apoptosis via the conversion of FKHRL1 from the phosphorylated inactive form to the dephosphorylated active form in CML‐derived cell lines. In the present study, we examined whether active FKHRL1 can overcome resistance to imatinib. To this end, we generated a 4‐hydroxytamoxifen‐inducible active FKHRL1 (FKHRL1‐TM; a triple mutant of FKHRL1 in which all three Akt phosphorylation sites have been mutated)–estrogen receptor fusion protein expression system in CML‐derived imatinib‐resistant cell lines. 4‐Hydroxytamoxifen inhibited cell growth and cell cycle progression, and subsequently induced apoptosis, accompanied by upregulation of tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL). Thus, active FKHRL1 antagonized deregulated proliferation and induced apoptosis in these cell lines. In addition, imatinib‐resistant cells underwent apoptosis after transfection with full‐length TRAIL cDNA. Collectively, our results suggest that active FKHRL1 can overcome imatinib resistance in CML cells, in part via TRAIL production. (Cancer Sci 2007; 98: 1949–1958)
The Japanese National Research Group on Idiopathic Bone Marrow Failure Syndromes has been conducting prospective registration, central review, and follow-up study for patients with aplastic anemia ...and myelodysplastic syndrome (MDS) since 2006. Using this database, we retrospectively analyzed the prognosis of patients with MDS. As of May 2016, 351 cases were registered in this database, 186 of which were eligible for the present study. Kaplan–Meier analysis showed that overall survival (OS) curves of the five risk categories stipulated by the revised international prognostic scoring system (IPSS-R) were reasonably separated. 2-year OS rates for the very low-, low-, intermediate-, high-, and very high-risk categories were 95, 89, 79, 35, and 12%, respectively. In the same categories, incidence of leukemic transformation at 2 years was 0, 10, 8, 56, and 40%, respectively. Multivariate analysis revealed that male sex, low platelet counts, increased blast percentage (>2%), and high-risk karyotype abnormalities were independent risk factors for poor OS. Based on these data, we classified Japanese MDS patients who were classified as intermediate-risk in IPSS-R, into the lower risk MDS category, highlighting the need for careful assessment of treatments within low- and high-risk treatment protocols.
Paroxysmal nocturnal hemoglobinuria (PNH) is a progressive and life-threatening disease characterized by complement-mediated chronic hemolysis, resulting in serious life-threatening complications and ...early mortality. Eculizumab, a humanized anti-C5 monoclonal antibody that inhibits terminal complement activation, has been shown to reduce hemolysis in PNH patients. The pivotal open-label, 12-week phase II registration study (AEGIS) was designed to evaluate the efficacy and safety of eculizumab in Japanese patients with PNH. This trial achieved its primary endpoint of reducing intravascular hemolysis with high statistical significance. Twenty-seven of the 29 patients responded to eculizumab treatment, resulting in an 87% reduction in hemolysis (
P
< 0.0001) and subsequent improvement in anemia (
P
= 0.0003) despite reduction in transfusion requirements (
P
= 0.006). Fatigue and dyspnea significantly improved within 1–2 weeks of eculizumab treatment and the improvement was independent of changes in hemoglobin. Chronic kidney disease (CKD) was common (66%) and eculizumab treatment improved CKD in 41% of patients at 12 weeks (
P
< 0.001). Elevated thrombotic risk was evident in Japanese PNH patients and eculizumab treatment normalized
d
-dimer levels in 45% of patients with elevated
d
-dimers at baseline (
P
< 0.001). The AEGIS results demonstrate that eculizumab is effective, safe and well tolerated in Japanese patients with PNH.
Controlling lymph node metastasis is currently a key issue in cancer therapy. Lymph node metastasis is one of the most important prognostic factors in various types of cancers, including endometrial ...cancer. Vascular endothelial growth factor‐C (VEGF‐C) plays a crucial role in lymphangiogenesis, and is implicated to play an important role in lymph node metastasis. To evaluate the role of VEGF‐C in lymph node metastasis, we developed an animal model by using an endometrial cancer cell line, HEC1A. This cell line is not invasive by nature and secretes moderate amounts of VEGF‐C; intrauterine injection of HEC1A cells into Balb/c nude mice resulted in uterine cancer with lymph node metastasis after 8 weeks. To analyze the contribution of VEGF‐C to lymph node metastasis, its corresponding gene was stably introduced into HEC1A cells (HEC1A/VEGF‐C), which then produced more than 10 times the amount of VEGF‐C. The number of lymph node metastases was significantly higher in HEC1A/VEGF‐C cells than in HEC1A cells (3.2 vs 1.1 nodes/animal, respectively). Augmented lymphangiogenesis was observed within tumors when HEC1A/VEGF‐C cells were inoculated. These results indicate that VEGF‐C plays a critical role in lymph node metastasis, in addition to serving as a platform to test the efficacy of various therapeutic modalities against lymph node metastasis. (Cancer Sci 2011; 102: 2272–2277)
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