These findings indicate that AGP secretion is regulated via thapsigargin-sensitive pathway that might be further controlled by the intracellular calcium concentrations.Pancreatic cancer remains one of the most lethal diseases with dismal five-year survival rates. Although mutant KRas protein-driven activation of downstream MAPK Raf/MEK/ERK and PI3K/Akt signaling pathways represent major oncogenic alterations, signaling blockade with MEK and PI3K inhibitors has shown that intrinsic resistance may hamper the effectiveness of this targeted approach. However, there have been no mass spectrometry-based proteomic studies for in-depth comparison of protein expression differences between pancreatic cancer cells with sensitivity and resistance to MEK and PI3K kinase inhibitors. In this work, we compared PANC-1 and MIA PaCa-2 pancreatic cancer cells which are, respectively, resistant and sensitive to MEK- and PI3K-targeted therapy. We conducted a label-free data-independent acquisition mass spectrometry (SWATH-MS) study with extensive peptide fractionation to quantitate 4808 proteins and analyze differential expression of 743 proteins between resistant and sensitive cells. This allowed identification of the tumor suppressor protein phosphatase 2A (PP2A) and proteins from mitochondrial respiratory complex I implicated in oxidative phosphorylation as alternative candidate drug targets for cells resistant to MEK and PI3K inhibition. PP2A activator DT-061 decreased viability of PANC-1 cells and this was accompanied by reduced expression of c-Myc. PANC-1 cells also showed response to metformin and the novel complex I inhibitor IACS-010759. These findings provide insights into the distinct cellular proteomes and point out alternative pharmacological targets for MEK and PI3K inhibition-resistant pancreatic cancer cells.Serine proteases are fundamental components of biology, including innate immunity, which is systematically orchestrated in an orderly, balanced fashion in the healthy host. Such serine proteases are found in two well-recognized pathways of an innate immune network, coagulation and complement. Both pathways, if uncontrolled due to a variety of causes, are pathogenic in numerous diseases, including coagulation disorders and infectious diseases. Previous studies have reported sequence homologies, functional similarities and interplay between these two pathways with some implications in health and disease. The current study newly reveals that complement component factor B (Bf), the second component of the alternative complement pathway, has thrombin-like activity, which is supported by a characteristic homology of the trypsin-like domain of Bf to that of thrombin. Moreover, we newly report that the trypsin-like domain of Bf is closely related to Limulus clotting factor C, the LPS sensitive clotting factor of the innate immune system. We will also discuss potential implications of our findings in diseases.The degradation of nucleolar proteins - nucleophagy - is elicited by nutrient starvation or the inactivation of target of rapamycin complex 1 (TORC1) protein kinase in budding yeast. Prior to nucleophagy, nucleolar proteins migrate to the nucleus-vacuole junction (NVJ), where micronucleophagy occurs, whereas rDNA (rRNA gene) repeat regions are condensed and escape towards NVJ-distal sites. This suggests that the NVJ controls nucleolar dynamics from outside of the nucleus after TORC1 inactivation, but its molecular mechanism is unclear. Here, we show that sorting nexin (SNX) Mdm1, an inter-organelle tethering protein at the NVJ, mediates TORC1 inactivation-induced nucleolar dynamics.  https://www.selleckchem.com/products/vt103.html  Furthermore, Mdm1 was required for proper nucleophagic degradation of nucleolar proteins after TORC1 inactivation, where it was dispensable for the induction of nucleophagic flux itself. This indicated that nucleophagy and nucleolar dynamics are independently regulated by TORC1 inactivation. Finally, Mdm1 was critical for survival during nutrient starvation conditions. Mutations of SNX14, a human Mdm1 homolog, cause neurodevelopmental disorders. This study provides a novel insight into relationship between sorting nexin-mediated microautophagy and neurodevelopmental disorders.This is the first regional, multi-annual assessment of floating microplastics in Scotland's seas. Sea surface samples were collected from 2014 to 2020, using a catamaran swimmer body/neuston net trawl and evaluated for the presence of microplastics. Microplastics were present in the surface waters of all Scottish Marine Regions (SMR) and Offshore Marine Regions (OMR) though almost 35% of sample sites contained no microplastics. Concentrations ranged from 0 to 91,128 microplastics km-2 sea surface. Potential hotspots were identified in the Clyde (0-77,168 microplastics km-2), Forth & Tay (0-83,729 microplastics km-2) and the Solway (607-91,128 microplastics km-2). Fragmented plastics accounted for almost 50% of the microplastics recovered and this may suggest that the microplastics in Scotland's seas are predominantly from the breakdown of larger items. Due to the variable geographic and temporal extents of the data it was not possible to carry out a trend assessment.This study aimed to assess the biological responses of oysters from an urban estuary in Northeast Brazil, through the evaluation of biochemical and physiological biomarkers, and integrate these responses with the investigation of mercury seasonal contamination. Oysters and sediment were collected from three sites in the estuary of the Ceará River during dry and rainy seasons. Biomarkers (AchE, CaE, GST, CAT, and Condition Index) were analyzed in different tissues. Hg bioaccumulation was higher in animals sampled in the rainy season, with increases varying from 5% to 136%, compared to the dry season. The changes in biomarkers highlight already elevated stresses for the organisms at the inner portion of the estuary, near the confluence with the Maranguapinho River, mainly during the rainy season, corroborating other studies that showed ecotoxicological effects with water and sediment samples. Finally, no correlation between Hg in sediment/oyster and biomarker results was observed.