Stratification in the northern Bering Sea in early summer of 2017 and 2018

We investigated spatial and interannual variation in the physical environment in the northern Bering Sea focusing on stratification, which is one factor affecting biological production in Arctic/subarctic regions. In particular, we analyzed in situ data obtained onboard the training ship Oshoro Maru in early summer in 2017 and 2018. We found that stratification in the areas just north of St. Lawrence Island (around 64.5 degrees N and west of 168.5 degrees W) and south/southwest of St. Lawrence Island was significantly weaker in 2018 than in 2017. These results are consistent with the extremely low sea-ice extent present in the winter of 2017/2018, which would have resulted in less freshwater being supplied to the surface layers and a warmer and less saline bottom water. Conversely, stratification was as strong in 2018 as in 2017 in the area close to the Alaska mainland, including the Bering Strait area, suggesting that the Alaskan Coastal Water dominates stratification in this area in early summer. Moreover, we found that the weakly stratified water column in the Bering Strait area stratified quickly shortly after the occurrence of strong northerly winds, likely because of the Ekman transport of warm and low-salinity Alaskan Coastal Water from the east

Sustained discontinuation of infliximab with a raising-dose strategy after obtaining remission in patients with rheumatoid arthritis: the RRRR study, a randomised controlled trial

Objectives The aim of this study is to determine whether the 'programmed' infliximab (IFX) treatment strategy (for which the dose of IFX was adjusted based on the baseline serum tumour necrosis factor alpha (TNF-alpha)) is beneficial to induction of clinical remission after 54 weeks and sustained discontinuation of IFX for 1 year. Methods In this multicentre randomised trial, patients with IFX-naive rheumatoid arthritis with inadequate response to methotrexate were randomised to two groups; patients in programmed treatment group received 3 mg/kg IFX until week 6 and after 14 weeks the dose of IFX was adjusted based on the baseline levels of serum TNF-alpha until week 54; patients in the standard treatment group received 3 mg/kg of IFX. Patients who achieved a simplified disease activity index (SDAI) <= 3.3 at week 54 discontinued IFX. The primary endpoint was the proportion of patients who sustained discontinuation of IFX at week 106. Results A total of 337 patients were randomised. At week 54, 39.4% (67/170) in the programmed group and 32.3% (54/167) in the standard group attained remission (SDAI <= 3.3). At week 106, the 1-year sustained discontinuation rate was not significantly different between two groups; the programmed group 23.5% (40/170) and the standard group 21.6% (36/167), respectively (2.2% difference, 95% CI -6.6% to 11.0%; p=0.631). Baseline SDAI <26.0 was a statistically significant predictor of the successfully sustained discontinuation of IFX at week 106. Conclusion Programmed treatment strategy did not statistically increase the sustained remission rate after 1 year discontinuation of IFX treatment

Endoplasmic reticulum quality control regulates the fate of transthyretin variants in the cell

The secretion of transthyretin (TTR) variants contributes to the pathogenesis of amyloidosis because they form aggregates in the extracellular environment. However, the mechanism of how TTR variants pass the quality control system in the endoplasmic reticulum (ER) has not yet been elucidated. We investigated here the mechanism of how TTR passes ER monitoring. Monomeric mutation introduced in TTRs (M-TTRs) resulted in the ER retention of amyloidogenic M-TTRs but not non-amyloidogenic M-TTRs. Retention of amyloidogenic M-TTRs induced the unfolded protein response and upregulated the expression of ER chaperones BiP and glucose-regulated protein (GRP) 94. Additionally, we showed that the ER-retained amyloidogenic M-TTRs are subject to ER-associated degradation. On the other hand, the amyloidogenic TTR variants and non-amyloidogenic M-TTRs were secreted normally. These findings suggest that unlike for wild-type TTR, the ER quality control system may differentially regulate the fate of the TTR variants and their monomeric counterparts