AAA-ATPase p97/Cdc48p, a Cytosolic Chaperone Required for Endoplasmic Reticulum-Associated Protein Degradation

Endoplasmic reticulum-associated degradation (ERAD) disposes of aberrant proteins in the secretory pathway. Protein substrates of ERAD are dislocated via the Sec61p translocon from the endoplasmic reticulum to the cytosol, where they are ubiquitinated and degraded by the proteasome. Since the Sec61p channel is also responsible for import of nascent proteins, this bidirectional passage should be coordinated, probably by molecular chaperones. Here we implicate the cytosolic chaperone AAA-ATPase p97/Cdc48p in ERAD. We show the association of mammalian p97 and its yeast homologue Cdc48p in complexes with two respective ERAD substrates, secretory immunoglobulin M in B lymphocytes and 6myc-Hmg2p in yeast. The membrane 6myc-Hmg2p as well as soluble lumenal CPY*, two short-lived ERAD substrates, are markedly stabilized in conditional cdc48 yeast mutants. The involvement of Cdc48p in dislocation is underscored by the accumulation of ERAD substrates in the endoplasmic reticulum when Cdc48p fails to function, as monitored by activation of the unfolded protein response. We propose that the role of p97/Cdc48p in ERAD, provided by its potential unfoldase activity and multiubiquitin binding capacity, is to act at the cytosolic face of the endoplasmic reticulum and to chaperone dislocation of ERAD substrates and present them to the proteasome

Modified ISTH pregnancy-specific DIC score in parturients with liver rupture: population-based case series

<p><b>Objectives:</b> Liver rupture and hematoma are rare life-threatening complications of pregnancy. The aims of the current study are to: (1) characterize in a population-based study all cases of liver hematoma and/or rupture; and (2) validate the utility of the International Society on Thrombosis and Haemostasis (ISTH) modified pregnancy specific disseminated intravascular coagulation (DIC) score in those cases.</p> <p><b>Study design:</b> A retrospective cohort study including all patients with liver subcapsular hematoma or rupture between the years 1996 and 2012 was conducted. Information on maternal characteristics, clinical presentation, diagnostic studies, therapeutic modalities, as well as maternal and fetal outcomes was collected. The pregnancy-specific modified ISTH DIC scores were calculated from admission to discharge, a score >26 is suggestive of DIC.</p> <p><b>Results:</b> Out of 175,000 births in our database, seven patients were identified with liver rupture or subcapsular hematoma, representing a prevalence of 4:100,000 deliveries. Of those, six had liver rupture and one had subcapsular liver hematoma. One patient died of hemorrhagic shock. Four patients underwent surgical liver packing and one also underwent hepatic artery ligation. Four out of seven patients were diagnosed during the immediate postpartum period with severe features of preeclampsia or with hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. Modified ISTH pregnancy-specific DIC scores were calculated for five out of seven patients, and three (60%) had a score higher than 26. Patients with higher scores received more blood product transfusions, had longer hospitalizations, and their neonates had lower 1 and 5 minutes Apgar scores.</p> <p><b>Conclusions:</b> Elevated pregnancy-specific modified ISTH DIC score (>26) in patients with liver hematoma or rupture was associated with adverse maternal and neonatal outcomes and appeared to perform well in distinguishing high and low-risk cases. Postpartum preeclampsia may be associated with severe features and a more complicated disease course.</p

An Assessment of the diversity in scenario-based tsunami forecasts for the Indian Ocean

This work examines the extent to which tsunami forecasts from different numerical forecast systems might be expected to differ under real-time conditions. This is done through comparing tsunami amplitudes from a number of existing tsunami scenario databases for eight different hypothetical tsunami events within the Indian Ocean. Forecasts of maximum tsunami amplitude are examined at ten output points distributed throughout the Indian Ocean at a range of depths. The results show that there is considerable variability in the forecasts and on average, the standard deviation of the maximum amplitudes is approximately 62% of the mean value. It is also shown that a significant portion of this diversity can be attributed to the different lengths of the scenario time series. These results have implications for the interoperability of Regional Tsunami Service Providers in the Indian Ocean