Explore the vast range of titles available.

Mapping the extents and terminations of surface ruptures is essential for a better seismic hazard assessment, as these factors indicate the magnitude and location of future earthquakes. The Himalayas and its active Himalayan Frontal Thrust (HFT) plate boundary, have experienced numerous damaging earthquakes in both recent and medieval times. The variability of the associated surface ruptures and the extent of the medieval earthquakes remain poorly understood. This study aims to improve the understanding of rupture extents and behavior along the ~ 650 km Central Seismic Gap (CSG) segment by analyzing paleoseismic trench data from sixteen previously published trenches, including new excavations during this study at Teliwara and Goujani. Evidence from Goujani suggests a penultimate event between calAD1437 and calAD1576 and Most Recent Earthquake (MRE) between calAD1662 and AD1894 with a minimum cumulative slip of at least 7 m. The Teliwara site reveals evidence of MRE occurring between calAD1665 and calAD1956 with a cumulative slip of 12.3 m. Integrating these findings with data from other paleoseismic sites allows for a detailed reconstruction of rupture patterns and timing along the CSG segment. Analysis of age probability density functions (PDFs) indicate three significant events: Earthquake 1 dated between calAD1320 and calAD1412, likely ruptured 259–360 km of the HFT. Earthquake 2, dated between calAD1437 and calAD1576, appears to have ruptured 490 km with rupture termination near the Faizabad Ridge, suggesting it was an asperity confined rupture. Earthquake 3 occurred between calAD1748 and calAD1894. These events correspond temporally to the 1344, 1505, and 1803 historical earthquakes, or to unrecorded events of similar age. Estimated moment magnitudes (Mw) for Earthquakes 1 and 2 are approximately 8.3–8.5 and 8.7, respectively. These findings suggest that the CSG segment has experienced large ruptures influenced by structural asperities.

Recent research shows that active fault systems produce multisegment earthquakes; however, we have yet to understand the faulting behavior of various spatial patterns of segments. We conducted a three‐dimensional trenching survey to reconstruct the detailed slip history of a fault segment that ruptured as one of the multisegment ruptures along the North Anatolian fault system. The trench site, on the Gerede segment, recorded a maximum right‐lateral slip of up to 6 m that was associated with the 1944 Bolu‐Gerede earthquake (M 7.4). Fault exposures show evidence of four paleoearthquakes. Radiocarbon dates, a refined probability density distribution, and correlation with historical earthquakes place the mean repeat time at ∼330 years. Four discrete paleoslips yield a slip per event of 5.0 ± 0.8 m with a coefficient of variation of 0.2. Our research suggests that multisegment earthquakes exhibit various spatial patterns, regardless of recurrence with quasiperiodicity and characteristic slip. Coincidentally, the fault geometry exhibits extremely linear traces, suggesting simple stress accumulation and release through earthquake cycles. Furthermore, the 1944 event did not occur in a single segment, and the Gerede segment probably ruptured within a slip‐pulse‐like rupture during a multisegment earthquake. A comparable geological slip rate of ∼17 mm a−1 based on a GPS‐based strain rate supports the persistence of macroscopic asperity through recent geological time. Therefore we conclude that a segment with simple fault geometry along a strike‐slip fault system plays an important role in forecasting the timing of future multisegment earthquakes, but the spatial extent of such earthquakes needs to be explored further.

Two distinct p97 membrane fusion pathways are required for Golgi biogenesis: the p97/p47 and p97/p37 pathways. VCIP135 is necessary for both pathways, while its deubiquitinating activity is required only for the p97/p47 pathway. We have now identified a novel VCIP135‐binding protein, WAC. WAC localizes to the Golgi as well as the nucleus. In Golgi membranes, WAC is involved in a complex containing VCIP135 and p97. WAC directly binds to VCIP135 and increases its deubiquitinating activity. siRNA experiments revealed that WAC is required for Golgi biogenesis. In an in vitro Golgi reformation assay, WAC was necessary only for p97/p47‐mediated Golgi reassembly, but not for p97/p37‐mediated reassembly. WAC is hence thought to function in p97/p47‐mediated Golgi membrane fusion by activating the deubiquitinating function of VCIP135. We also showed that the two p97 pathways function in ER membrane fusion as well. An in vitro ER reformation assay revealed that both pathways required VCIP135 but not its deubiquitinating activity for their ER membrane fusion. This was consistent with the finding that WAC is unnecessary for p97‐mediated ER membrane fusion. The deubiquitinating enzyme VCIP135 plays an important role in a number of different p97 ATPase‐dependent membrane fusion events. This study identifies the protein WAC as a VCIP135 interaction partner that activates its deubiquitination activity and specifically regulates the p97/p47‐mediated Golgi membrane fusion pathway.

The AAA ATPase p97/VCP is involved in many cellular events including ubiquitin‐dependent processes and membrane fusion. In the latter, the p97 adaptor protein p47 is of central importance. In order to provide insight into the molecular basis of p97 adaptor binding, we have determined the crystal structure of p97 ND1 domains complexed with p47 C‐terminal domain at 2.9 Å resolution. The structure reveals that the p47 ubiquitin regulatory X domain (UBX) domain interacts with the p97 N domain via a loop (S3/S4) that is highly conserved in UBX domains, but is absent in ubiquitin, which inserts into a hydrophobic pocket between the two p97 N subdomains. Deletion of this loop and point mutations in the loop significantly reduce p97 binding. This hydrophobic binding site is distinct from the predicted adaptor‐binding site for the p97/VCP homologue N‐ethylmaleimide sensitive factor (NSF). Together, our data suggest that UBX domains may act as general p97/VCP/CDC48 binding modules and that adaptor binding for NSF and p97 might involve different binding sites. We also propose a classification for ubiquitin‐like domains containing or lacking a longer S3/S4 loop.

The AAA+ATPase p97/VCP, helped by adaptor proteins, exerts its essential role in cellular events such as endoplasmic reticulum‐associated protein degradation or the reassembly of Golgi, ER and the nuclear envelope after mitosis. Here, we report the three‐dimensional cryo‐electron microscopy structures at ∼20 Å resolution in two nucleotide states of the endogenous hexameric p97 in complex with a recombinant p47 trimer, one of the major p97 adaptor proteins involved in membrane fusion. Depending on the nucleotide state, we observe the p47 trimer to be in two distinct arrangements on top of the p97 hexamer. By combining the EM data with NMR and other biophysical measurements, we propose a model of ATP‐dependent p97(N) domain motions that lead to a rearrangement of p47 domains, which could result in the disassembly of target protein complexes.

At least two distinct ATPases, NSF and p97, are known to be involved in the heterotypic fusion of transport vesicles with their target membranes and the homotypic fusion of membrane compartments. The NSF-mediated fusion pathway is the best characterized, many of the components having been identified and their functions analysed. In contrast, none of the accessory proteins for the p97-mediated fusion pathway has been identified. Now we have identified the first such component, a protein of relative molecular mass 47,000 (p47), which forms a tight, stoichiometric complex with cytosolic p97 (one trimer of p47 per hexamer of p97). It is essential for the p97-mediated regrowth of Golgi cisternae from mitotic Golgi fragments, a process restricted to animal cells. As a homologue of p47 exists in budding yeast, this indicates that it might also be involved in other membrane fusion reactions catalysed by p97, such as karyogamy.

p47 is a major adaptor molecule of the cytosolic AAA ATPase p97. The principal role of the p97–p47 complex is in regulation of membrane fusion events. Mono‐ubiquitin recognition by p47 has also been shown to be crucial in the p97–p47‐mediated Golgi membrane fusion events. Here, we describe the high‐resolution solution structures of the N‐terminal UBA domain and the central domain (SEP) from p47. The p47 UBA domain has the characteristic three‐helix bundle fold and forms a highly stable complex with ubiquitin. We report the interaction surfaces of the two proteins and present a structure for the p47 UBA–ubiquitin complex. The p47 SEP domain adopts a novel fold with a βββααβ secondary structure arrangement, where β4 pairs in a parallel fashion to β1. Based on biophysical studies, we demonstrate a clear propensity for the self‐association of p47. Furthermore, p97 N binding abolishes p47 self‐association, revealing the potential interaction surfaces for recognition of other domains within p97 or the substrate.

Background and Objective: Stroke patients with severe leg paralysis are often bedridden in the acute and subacute phase, which increases the risk of disuse muscle atrophy in the chronic phase. The evidence to date indicates that oxidative stress plays an important role in the mechanism of disuse muscle atrophy. Therefore, the aim of this study was to determine if long-term radical scavenger treatment with edaravone following an acute stroke prevents the progression of disuse muscle atrophy and improves leg locomotor function in the chronic phase. Methods: This randomized controlled pilot study was conducted at 19 acute stroke and rehabilitation centers across Japan. Forty-seven ischemic stroke patients with at least leg motor weakness admitted within 24 hours of onset were randomly assigned to receive continuous intravenous infusions of edaravone 30 mg twice daily for 3 days (short-term group) or 10–14 days (long-term group). The primary endpoints of the study included the degree of leg disuse muscle atrophy, as measured by the percentage change from baseline in femoral muscle circumference 15 cm above the knee, and the improvement in leg locomotor function, as assessed by the maximum walking speed over 10 m, 3 months after the onset of stroke. Results: Three-month follow-up was completed by a total of 41 patients (21 in the short-term group and 20 in the long-term group). On admission, there was no significant difference in the severity of stroke or the grade of leg paresis between the two treatment groups. The grade of disuse muscle atrophy and incidence of gait impairment 3 weeks after stroke onset were also similar between the short- and long-term groups. However, disuse muscle atrophy of the paretic and non-paretic legs was significantly less severe in the long-term versus the short-term treatment group (3.6±5.9% and 1.5±6.0% vs 8.3±5.2% and 5.7±6.4%; p<0.01 and p<0.05) 3 months after stroke onset. Additionally, the maximum walking speed over a distance of 10 m was significantly greater in the long-term group (98±67 vs 54±55 cm/sec; p<0.05). Conclusion: Edaravone treatment for up to 14 days suppresses the progression of disuse muscle atrophy and improves leg locomotor function to a greater extent than shorter-term treatment in acute stroke patients. This suggests that the management of stroke may be improved with long-term edaravone therapy by providing myoprotective effects that ameliorate functional outcome in the chronic phase.