Collapse Simulation of Elevated Expressway Bridges with Single Piers due to the 1995 Hyogo-ken Nanbu Earthquake

小特集 地震時の挙動を再現/検証す

The transcription factor NRF1 (NFE2L1) activates aggrephagy by inducing p62 and GABARAPL1 after proteasome inhibition to maintain proteostasis

Abstract The ubiquitin‒proteasome system (UPS) and autophagy are the two primary cellular pathways of misfolded or damaged protein degradation that maintain cellular proteostasis. When the proteasome is dysfunctional, cells compensate for impaired protein clearance by activating aggrephagy, a type of selective autophagy, to eliminate ubiquitinated protein aggregates; however, the molecular mechanisms by which impaired proteasome function activates aggrephagy remain poorly understood. Here, we demonstrate that activation of aggrephagy is transcriptionally induced by the transcription factor NRF1 (NFE2L1) in response to proteasome dysfunction. Although NRF1 has been previously shown to induce the expression of proteasome genes after proteasome inhibition (i.e., the proteasome bounce-back response), our genome-wide transcriptome analyses identified autophagy-related p62/SQSTM1 and GABARAPL1 as genes directly targeted by NRF1. Intriguingly, NRF1 was also found to be indispensable for the formation of p62-positive puncta and their colocalization with ULK1 and TBK1, which play roles in p62 activation via phosphorylation. Consistently, NRF1 knockdown substantially reduced the phosphorylation rate of Ser403 in p62. Finally, NRF1 selectively upregulated the expression of GABARAPL1, an ATG8 family gene, to induce the clearance of ubiquitinated proteins. Our findings highlight the discovery of an activation mechanism underlying NRF1-mediated aggrephagy through gene regulation when proteasome activity is impaired

Possible association between dysfunction of vitamin D binding protein (GC Globulin) and migraine attacks.

To identify the genetic causality of migraine and acute, severe melalgia, we performed a linkage analysis and exome sequencing in a family with four affected individuals. We identified a variant (R21L) in exon 2 of the GC globulin gene, which is involved in the transportation of vitamin D metabolites and acts as a chemotaxic factor; this variant was co-segregated within the family. To investigate the relationship between GC globulin and melalgia, we investigated the cytokine levels in serum samples from the patients and control subjects using a cytokine antibody array. GC globulin can bind to both MCP-1 and RANTES in human serum but has a higher affinity to MCP-1. In cell culture systems, MCP-1 was able to bind to overexpressed wild-type GC globulin but not to the GC globulin variant, and the GC globulin binding affinity to MCP-1 was significantly lower in sera from the patients than in sera from control subjects. A higher concentration of MCP-1 was also observed in sera from the patients. Thus, the dysfunctional GC globulin affected cytokine release, especially the release of MCP-1, and MCP-1 might play important roles in melalgia and migraine

Cytokine antibody array for GC globulin binding activity and serum cytokines.

<p>The GC globulin binding affinity to MCP-1 was the highest among all the serum cytokines (A), while RANTES had the highest concentration among the serum cytokines (B). In sera from the patients, the GC globulin binding affinity to MCP-1 was significantly lower than that in sera from the control subjects (A), while the concentration of MCP-1 in sera from the patients tended to be lower than that in sera from the control subjects (B). White bars: healthy control subjects; Black bars: patients with severe myalgia and migraine.</p

Profile of family pedigree.

<p>Four women with the <i>GC</i> gene mutation exhibited repeated episodes of transient, severe myalgia during childhood accompanied by migraines. However, one man with the <i>GC</i> gene mutation had never experienced myalgia or a migraine. F: female; M: male; MA: migraine with aura; MO: migraine without aura.</p

Serum concentrations of CGRP (pg/mL).

<p>No significant difference in the serum CGRP concentration was seen between the patients and the healthy control subjects.</p><p>*: no significant difference.</p

Analysis of the Comorbidity of Bronchial Asthma and Allergic Rhinitis by Questionnaire in 10,009 Patients

Background: Bronchial asthma (BA) and allergic rhinitis (AR) are thought to share a common pathogenesis. However, reports concerning the comorbidity of the two diseases in a large-scaled population are rare in Japan. In the present study, we performed an analysis on the two diseases using questionnaires that addressed the diagnosis, symptoms and period of occurrence in more than 10,000 patients with BA or AR. Methods: Patients with BA (adult: n = 2,781, childhood: n = 3,283) and AR (n = 3,945) were enrolled in the present study during the 3 months from August 1, 2006 to October 31, 2006. Results: Sixty one percent of the patients with adult BA showed symptoms of AR. Among them, 68% of the patients were diagnosed with AR. Among the patients with childhood BA, 68% showed AR symptoms and 60% were diagnosed with AR. On the other hand, 49% of AR patients showed BA symptoms and 35% of them were diagnosed with BA. The symptoms of both BA and AR in the BA and AR patients were frequent in two seasons, March and April, and September and October. In addition, BA and AR symptoms often co-occurred in the patients with BA and AR. Conclusions: Comorbidity of BA and AR was high in both populations of BA and AR. The symptoms of both BA and AR co-occurred on both a daily and seasonal basis. These results suggested that BA and AR share a common immuno-pathogenesis in the airway and need to be treated as a single airway disease