Molecular properties of the proteasome activator PA28 family proteins and γ-interferon regulation

The proteasome is a large multicatalytic protease complex with an apparent sedimentation coefficient of 20S. It exists as a latent from in cells, being activated fully by the novel identified endogenous prtein, named proteasome activator PA28. The native PA28 is approximately 200 kDa protein, which binds directly to both ends of the cylindrical 20S proteasome to form a football-like complex. By recent cDNA cloning for two homologous PA28 proteins, called PA28α and PA28β, Ki antigen found previously as a nuclear protein detected with autoantibodies in human sera was identified as a structurally related third protein, but a relationship between Ki antigen and two PA28 proteins or the 20S proteasome is unknown. In the present study, we showed that Ki antigen belongs to a new member of the PA28 family proteins, because it was co-purified and co-sedimented with PA28α and PA28β, and because it was associated reversibly with the 20S proteasome, and thus Ki antigen was renamed as PA28α. Moreover, anti-PA28γ antibody did not precipitate immunologically with PA28α and PA28β, although the latter two proteins were co-immunoprecipitated by respective antibodies, suggesting that the complex containing PA28γ differs from that consisting of PA28α and PA28β. Recombinant PA28α expressed in E. coli activated greatly on the proteasomal peptidase activity solely, but PA28β and PA28γ did not reveal notable effects, although PA28β enhanced the PA28α-dependent activation observed only at the low concentration of PA28α without affecting the maximal activity. Intrigutingly, a major immunomodulatory cytokine γ-interferon (γ-IFN) induced almost complete loss of the PA28γ protein without affecting the mRNA level in cells, whereas the messages and proteins of both PA28α and PA28β were coordinately upregulated by γ-IFN. Thus, γ-IFN inducible PA28α and PA28β are assumed o play an important role for processing of endogeous antigens. Moreover, PA28γ may be involved in distinct biological processes from other two PA28 proteins, judging from their reciprocal expression in response to γ-IFN

研究速報 : On the characteristics of eddies in DNS, GS, and SGS velocity fields in homogeneous isotropic turbulence

特集1 乱流シミュレーションと流れの設計(TSFD

Efficacy of Endovascular Treatment for Acute Cerebral Large-Vessel Occlusion: Analysis of Nationwide Prospective Registry

BackgroundThe aim of this nationwide, prospective registry of acute cerebral large-vessel occlusion was to assess the efficacy of endovascular treatment (EVT) on outcome in the “real-world” settings.MethodsMedical information of the patients was anonymized and registered prospectively through a Web site from 84 medical centers in Japan. Reperfusion of the affected arteries was evaluated by the Thrombolysis in Cerebral Infarction grade on cerebral angiography or by the modified Mori grade on magnetic resonance angiography. Clinical outcome was evaluated by modified Rankin Scale (mRS) at 90 days after onset. Symptomatic intracranial hemorrhage and procedure-related complications were also analyzed.ResultsAmong intravenous tissue plasminogen activator (IV t-PA)–failed patients, no significant difference in favorable outcome was seen with or without EVT overall (41.7% versus 36.8%, P = .55). However, EVT significantly increased favorable outcomes (mRS score 0-2) in patients with internal carotid artery (ICA)/middle cerebral artery M1/basilar artery (BA) occlusion (41.3% versus 20.5%, P = .019). In contrast, among t-PA–ineligible patients, EVT significantly increased favorable outcomes overall (29.1% versus 19.5%; odds ratio, 1.70; P = .007). Furthermore, favorable outcomes were more common in patients with ICA/M1/BA occlusion (29.0% versus 10.3%; odds ratio, 3.56; P < .0001). Multivariate analysis also confirmed the efficacy of IV t-PA, EVT, and their combination for favorable outcome.ConclusionsEVT significantly improved clinical outcomes in IV t-PA–failed and t-PA–ineligible patients with ICA/M1/BA occlusion. These findings support the introduction of EVT for acute proximal artery occlusion

Acupuncture Treatment for Social Defeat Stress

Depression is a mood disorder characterized by disordered affect, thoughts, cognition, and behavior. Antidepressant therapy is often the primary treatment for depression. However, antidepressant therapy may cause unwanted side effects, and its effects are slow. Therefore, some patients are seeking alternative treatments for depression, such as acupuncture. However, there are many unclear points regarding the mechanism of the effect of acupuncture on depression. In recent years, we have reported that acupuncture improves the symptoms of mild depression induced by water-immersion stress in a rat model and depression induced by forced swimming in a mouse model. In this study, we examined the effect of acupuncture on the symptoms of social defeat stress (SDS)-induced depression in mice that most closely resemble human symptoms. In this study, we investigated the preventive and therapeutic effects of acupuncture as part of GV20 'Bai-Hui' and Ex-HN3 'Yintang' on model mice with depression induced by SDS. To examine the mechanism of the preventive and therapeutic effects of acupuncture on depression model mice, we examined the expression of neurotrophic factors in the brains of SDS mice. Two weeks of simultaneous acupuncture stimulation as part of GV20 and Ex-HN3 restored SDS-reduced brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3, and NT-4/5 expression, which was not observed with antidepressants. In contrast, acupuncture stimulation suppressed nerve growth factor (NGF) expression induced by SDS. These results suggest that acupuncture treatment could be effective in correcting the imbalance in the expression of neurotrophic factors. Furthermore, the effects of acupuncture on the expression of neurotrophic factors appear earlier than those of antidepressants, suggesting that it may be a useful treatment for depression

Changes in fatigue, autonomic functions, and blood biomarkers due to sitting isometric yoga in patients with chronic fatigue syndrome

Abstract Background In a previous randomized controlled trial, we found that sitting isometric yoga improves fatigue in patients with chronic fatigue syndrome (CFS) who are resistant to conventional therapy. The aim of this study was to investigate possible mechanisms behind this finding, focusing on the short-term fatigue-relieving effect, by comparing autonomic nervous function and blood biomarkers before and after a session of isometric yoga. Methods Fifteen patients with CFS who remained symptomatic despite at least 6 months of conventional therapy practiced sitting isometric yoga (biweekly 20 min practice with a yoga instructor and daily home practice) for eight weeks. Acute effects of sitting isometric yoga on fatigue, autonomic function, and blood biomarkers were investigated after the final session with an instructor. The effect of a single session of sitting isometric yoga on fatigue was assessed by the Profile of Mood Status (POMS) questionnaire immediately before and after the session. Autonomic nervous function (heart rate (HR) variability) and blood biomarkers (cortisol, DHEA-S, TNF-α, IL-6, IFN-γ, IFN-α, prolactin, carnitine, TGF-β1, BDNF, MHPG, and HVA) were compared before and after the session. Results Sitting isometric yoga significantly reduced the POMS fatigue score (p < 0.01) and increased the vigor score (p < 0.01). It also reduced HR (p < 0.05) and increased the high frequency power (p < 0.05) of HR variability. Sitting isometric yoga increased serum levels of DHEA-S (p < 0.05), reduced levels of cortisol (p < 0.05) and TNF-α (p < 0.05), and had a tendency to reduce serum levels of prolactin (p < 0.1). Decreases in fatigue scores correlated with changes in plasma levels of TGF-β1 and BDNF. In contrast, increased vigor positively correlated with HVA. Conclusions A single session of sitting isometric yoga reduced fatigue and increased vigor in patients with CFS. Yoga also increased vagal nerve function and changed blood biomarkers in a pattern that suggested anti-stress and anti-inflammatory effects. These changes appear to be related to the short-term fatigue-relieving effect of sitting isometric yoga in patients with CFS. Furthermore, dopaminergic nervous system activation might account for sitting isometric yoga-induced increases in energy in this patient population. Trial registration University Hospital Medical Information Network (UMIN CTR) UMIN000009646. Registered Dec 27, 2012

Highly prevalent LIPH founder mutations causing autosomal recessive woolly hair/hypotrichosis in Japan and the genotype/phenotype correlations.

Mutations in LIPH cause of autosomal recessive woolly hair/hypotrichosis (ARWH), and the 2 missense mutations c.736T>A (p.Cys246Ser) and c.742C>A (p.His248Asn) are considered prevalent founder mutations for ARWH in the Japanese population. To reveal genotype/phenotype correlations in ARWH cases in Japan and the haplotypes in 14 Japanese patients from 14 unrelated Japanese families. 13 patients had woolly hair, and 1 patient had complete baldness since birth. An LIPH mutation search revealed homozygous c.736T>A mutations in 10 of the patients. Compound heterozygous c.736T>A and c.742C>A mutations were found in 3 of the patients, and homozygous c.742C>A mutation in 1 patient. The phenotype of mild hypotrichosis with woolly hair was restricted to the patients with the homozygous c.736T>A mutation. The severe phenotype of complete baldness was seen in only 1 patient with homozygous c.742C>A. Haplotype analysis revealed that the alleles containing the LIPH c.736T>A mutation had a haplotype identical to that reported previously, although 4 alleles out of 5 chromosomes containing the LIPH c.742C>A mutation had a different haplotype from the previously reported founder allele. These alleles with c.742C>A are thought to be the third founder LIPH mutation causing ARWH. To accurately determine the prevalence of the founder mutations, we investigated allele frequencies of those mutations in 819 Japanese controls. Heterozygous c.736T>A mutations were found in 13 controls (allele frequency: 0.0079; carrier rate: 0.016), and heterozygous c.742C>A mutations were found in 2 controls (allele frequency: 0.0012; carrier rate: 0.0024). In conclusion, this study confirms the more accurate allele frequencies of the pathogenic founder mutations of LIPH and shows that there is a third founder mutation in Japan. In addition, the present findings suggest that the mutation patterns of LIPH might be associated with hypotrichosis severity in ARWH

Immunoproteasome assembly and antigen presentation in mice lacking both PA28α and PA28β

Two members of the proteasome activator, PA28α and PA28β, form a heteropolymer that binds to both ends of the 20S proteasome. Evidence in vitro indicates that this interferon-γ (IFN-γ)-inducible heteropolymer is involved in the processing of intracellular antigens, but its functions in vivo remain elusive. To investigate the role of PA28α/β in vivo, we generated mice deficient in both PA28α and PA28β genes. The ATP-dependent proteolytic activities were decreased in PA28α(–/–)/β(–/–) cells, suggesting that ‘hybrid proteasomes’ are involved in protein degradation. Treatment of PA28α(–/–)/β(–/–) cells with IFN-γ resulted in sufficient induction of the ‘immunoproteasome’. Moreover, splenocytes from PA28α(–/–)/β(–/–) mice displayed no apparent defects in processing of ovalbumin. These results are in marked contrast to the previous finding that immunoproteasome assembly and immune responses were impaired in PA28β(–/–) mice. PA28α(–/–)/β(–/–) mice also showed apparently normal immune responses against infection with influenza A virus. However, they almost completely lost the ability to process a melanoma antigen TRP2-derived peptide. Hence, PA28α/β is not a prerequisite for antigen presentation in general, but plays an essential role for the processing of certain antigens