Water level changes, subsidence, and sea level rise in the Ganges-Brahmaputra-Meghna delta.

Being one of the most vulnerable regions in the world, the Ganges-Brahmaputra-Meghna delta presents a major challenge for climate change adaptation of nearly 200 million inhabitants. It is often considered as a delta mostly exposed to sea-level rise and exacerbated by land subsidence, even if the local vertical land movement rates remain uncertain. Here, we reconstruct the water-level (WL) changes over 1968 to 2012, using an unprecedented set of 101 water-level gauges across the delta. Over the last 45 y, WL in the delta increased slightly faster (∼3 mm/y), than global mean sea level (∼2 mm/y). However, from 2005 onward, we observe an acceleration in the WL rise in the west of the delta. The interannual WL fluctuations are strongly modulated by El Niño Southern Oscillation (ENSO) and Indian Ocean Dipole (IOD) variability, with WL lower than average by 30 to 60 cm during co-occurrent El Niño and positive IOD events and higher-than-average WL, by 16 to 35 cm, during La Niña years. Using satellite altimetry and WL reconstructions, we estimate that the maximum expected rates of delta subsidence during 1993 to 2012 range from 1 to 7 mm/y. By 2100, even under a greenhouse gas emission mitigation scenario (Representative Concentration Pathway [RCP] 4.5), the subsidence could double the projected sea-level rise, making it reach 85 to 140 cm across the delta. This study provides a robust regional estimate of contemporary relative WL changes in the delta induced by continental freshwater dynamics, vertical land motion, and sea-level rise, giving a basis for developing climate mitigation strategies.

The Biodistribution and Immune Suppressive Effects of Breast Cancer-Derived Exosomes.

Small membranous secretions from tumor cells, termed exosomes, contribute significantly to intercellular communication and subsequent reprogramming of the tumor microenvironment. Here, we use optical imaging to determine that exogenously administered fluorescently labeled exosomes derived from highly metastatic murine breast cancer cells distributed predominantly to the lung of syngeneic mice, a frequent site of breast cancer metastasis. At the sites of accumulation, exosomes were taken up by CD45+ bone marrow-derived cells. Subsequent long-term conditioning of naïve mice with exosomes from highly metastatic breast cancer cells revealed the accumulation of myeloid-derived suppressor cells in the lung and liver. This favorable immune suppressive microenvironment was capable of promoting metastatic colonization in the lung and liver, an effect not observed from exosomes derived from nonmetastatic cells and liposome control vesicles. Furthermore, we determined that breast cancer exosomes directly suppressed T-cell proliferation and inhibited NK cell cytotoxicity, and hence likely suppressed the anticancer immune response in premetastatic organs. Together, our findings provide novel insight into the tissue-specific outcomes of breast cancer-derived exosome accumulation and their contribution to immune suppression and promotion of metastases. Cancer Res; 76(23); 6816-27. ©2016 AACR.

Clearing the Air About Surgical Smoke: An Education Program.

Evidence of the harmful effects of surgical smoke has been recognized in the literature and by professional organizations for many years, yet surgical smoke continues to pose a safety hazard for patients and perioperative personnel. A team of perioperative nurses and educators sought to improve compliance with policies and procedures for surgical smoke management in the OR. The team quantified smoke-evacuator use, assessed staff members' knowledge using a pre-education survey, and presented a three-part multimodal education program. The team conducted a posteducation survey that showed significant improvement in staff members' knowledge. Ninety-day postimplementation quantitative data showed a 14.6% increase in surgical smoke-evacuation use. This educational initiative increased staff members' awareness about reducing the presence of surgical smoke in the OR and helped ensure a safer environment for patients, staff members, and the surgical team.

Optimized exosome isolation protocol for cell culture supernatant and human plasma.

Extracellular vesicles represent a rich source of novel biomarkers in the diagnosis and prognosis of disease. However, there is currently limited information elucidating the most efficient methods for obtaining high yields of pure exosomes, a subset of extracellular vesicles, from cell culture supernatant and complex biological fluids such as plasma. To this end, we comprehensively characterize a variety of exosome isolation protocols for their efficiency, yield and purity of isolated exosomes. Repeated ultracentrifugation steps can reduce the quality of exosome preparations leading to lower exosome yield. We show that concentration of cell culture conditioned media using ultrafiltration devices results in increased vesicle isolation when compared to traditional ultracentrifugation protocols. However, our data on using conditioned media isolated from the Non-Small-Cell Lung Cancer (NSCLC) SK-MES-1 cell line demonstrates that the choice of concentrating device can greatly impact the yield of isolated exosomes. We find that centrifuge-based concentrating methods are more appropriate than pressure-driven concentrating devices and allow the rapid isolation of exosomes from both NSCLC cell culture conditioned media and complex biological fluids. In fact to date, no protocol detailing exosome isolation utilizing current commercial methods from both cells and patient samples has been described. Utilizing tunable resistive pulse sensing and protein analysis, we provide a comparative analysis of 4 exosome isolation techniques, indicating their efficacy and preparation purity. Our results demonstrate that current precipitation protocols for the isolation of exosomes from cell culture conditioned media and plasma provide the least pure preparations of exosomes, whereas size exclusion isolation is comparable to density gradient purification of exosomes. We have identified current shortcomings in common extracellular vesicle isolation methods and provide a potential standardized method that is effective, reproducible and can be utilized for various starting materials. We believe this method will have extensive application in the growing field of extracellular vesicle research.

Circulating concentrations of GLP-1 are associated with coronary atherosclerosis in humans.

BACKGROUND: GLP-1 is an incretine hormone which gets secreted from intestinal L-cells in response to nutritional stimuli leading to pancreatic insulin secretion and suppression of glucagon release. GLP-1 further inhibits gastric motility and reduces appetite which in conjunction improves postprandial glucose metabolism. Additional vasoprotective effects have been described for GLP-1 in experimental models. Despite these vasoprotective actions, associations between endogenous levels of GLP-1 and cardiovascular disease have yet not been investigated in humans which was the aim of the present study. METHODS: GLP-1 serum levels were assessed in a cohort of 303 patients receiving coronary CT-angiography due to typical or atypical chest pain. RESULTS: GLP-1 was found to be positively associated with total coronary plaque burden in a fully adjusted model containing age, sex, BMI, hypertension, diabetes mellitus, smoking, triglycerides, LDL-C (low density lipoprotein cholesterol), hsCRP (high-sensitive C-reactive protein), and eGFR (estimated glomerular filtration rate) (OR: 2.53 (95% CI: 1.12 - 6.08; p = 0.03). CONCLUSION: Circulating GLP-1 was found to be positivity associated with coronary atherosclerosis in humans. The clinical relevance of this observation needs further investigations.

The N-terminal region of acyl-CoA synthetase 3 is essential for both the localization on lipid droplets and the function in fatty acid uptake.

Cytosolic lipid droplets (LDs) are storage organelles for neutral lipids derived from endogenous metabolism. Acyl-CoA synthetase family proteins are essential enzymes in this biosynthetic pathway, contributing activated fatty acids. Fluorescence microscopy showed that ACSL3 is localized to the endoplasmic reticulum (ER) and LDs, with the distribution dependent on the cell type and the supply of fatty acids. The N-terminus of ACSL3 was necessary and sufficient for targeting reporter proteins correctly, as demonstrated by subcellular fractionation and confocal microscopy. The N-terminal region of ACSL3 was also found to be functionally required for the enzyme activity. Selective permeabilization and in silico analysis suggest that ACSL3 assumes a hairpin membrane topology, with the N-terminal hydrophobic amino acids forming an amphipathic helix restricted to the cytosolic leaflet of the ER membrane. ACSL3 was effectively translocated from the ER to nascent LDs when neutral lipid synthesis was stimulated by the external addition of fatty acids. Cellular fatty acid uptake was increased by overexpression and reduced by RNA interference of ACSL3. In conclusion, the structural organization of ACSL3 allows the fast and efficient movement from the ER to emerging LDs. ACSL3 not only esterifies fatty acids with CoA but is also involved in the cellular uptake of fatty acids, presumably indirectly by metabolic trapping. The unique localization of the acyl-CoA synthetase ACSL3 on LDs suggests a function in the local synthesis of lipids.

Expression of human chemerin induces insulin resistance in the skeletal muscle but does not affect weight, lipid levels, and atherosclerosis in LDL receptor knockout mice on high-fat diet.

OBJECTIVE: Chemerin is a recently discovered hepatoadipokine that regulates adipocyte differentiation as well as chemotaxis and activation of dendritic cells and macrophages. Chemerin was reported to modulate insulin sensitivity in adipocytes and skeletal muscle cells in vitro and to exacerbate glucose intolerance in several mouse models in vivo. In humans, chemerin was shown to be associated with multiple components of the metabolic syndrome including BMI, triglycerides, HDL cholesterol, and hypertension. This study aimed to examine the effect of chemerin on weight, glucose and lipid metabolism, as well as atherosclerosis in vivo. RESEARCH DESIGN AND METHODS: We used recombinant adeno-associated virus to express human chemerin in LDL receptor knockout mice on high-fat diet. RESULTS: Expression of chemerin did not significantly alter weight, lipid levels, and extent of atherosclerosis. Chemerin, however, significantly increased glucose levels during the intraperitoneal glucose tolerance test without affecting endogenous insulin levels and the insulin tolerance test. Chemerin reduced insulin-stimulated Akt1 phosphorylation and activation of 5'AMP-activated protein kinase (AMPK) in the skeletal muscle, but had no effect on Akt phosphorylation and insulin-stimulated AMPK activation in the liver and gonadal adipose tissue. CONCLUSIONS: Chemerin induces insulin resistance in the skeletal muscle in vivo. Chemerin is involved in the cross talk between liver, adipose tissue, and skeletal muscle.

Interaction of progestins with the human multidrug resistance-associated protein 2 (MRP2).

Progestins are widely used as oral contraceptives and hormone replacement therapy. Recently it has been demonstrated that many progestins are inhibitors of P-glycoprotein, possibly explaining gender differences in drug actions. In vitro evidence suggested that at least norgestimate might also inhibit other transporters like the multidrug resistance-associated protein 2 (MRP2). We therefore investigated whether norgestimate, desogestrel, medroxyprogesterone acetate, norethisterone, progesterone, cyproterone acetate, chlormadinone acetate, and levonorgestrel inhibit MRP2 in vitro using confocal laser scanning microscopy and 5-chloromethylfluorescein diacetate as a prodrug of the fluorescent 5-chloromethylfluorescein (CMF), which is actively transported by MRP2 as glutathione conjugate. Of the progestins tested, only norgestimate (50 microM) and progesterone (100 microM) significantly increased intracellular CMF fluorescence by 62% and 53%, respectively. In conclusion, the progestins norgestimate and progesterone significantly inhibit the transport activity of MRP2 in vitro.