Sources and upstream pathways of the densest overflow water in the Nordic Seas

Overflow water from the Nordic Seas comprises the deepest limb of the Atlantic Meridional Overturning Circulation, yet questions remain as to where it is ventilated and how it reaches the Greenland-Scotland Ridge. Here we use historical hydrographic data from 2005-2015, together with satellite altimeter data, to elucidate the source regions of the Denmark Strait and Faroe Bank Channel overflows and the pathways feeding these respective sills. A recently-developed metric is used to calculate how similar two water parcels are, based on potential density and potential spicity. This reveals that the interior of the Greenland Sea gyre is the primary wintertime source of the densest portion of both overflows. After subducting, the water progresses southward along several ridge systems towards the Greenland-Scotland Ridge. Kinematic evidence supports the inferred pathways. Extending the calculation back to the 1980s reveals that the ventilation occurred previously along the periphery of the Greenland Sea gyre.publishedVersio

Steroid saponins and other constituents from the rhizome of Trillium tschonoskii Maxim and their cytotoxic activity

Fourteen compounds were isolated from the rhizome of Trillium tschonoskii Maxim. By spectroscopic analysis, these compounds were established as Gracillin (1), Paris saponins V (2), Paris saponins VI (3), Paris saponins H (4), Paris saponins VII (5), (25R)-17α-hydroxy-5-en-3-O-a-L-arabinofuranosyl-(1→2)-β-Dglucopyranoside (6), (25R)-26-[β-D-glucopyanosyl]-17α,22β-dihydroxy-5-en-3-O-a-L-rhamnopyranosyl- (1→2)-β-D-glucopyranoside (7), Kaempferol-3-O-β-D-rutinoside (8), Quercetin (9), Quercetin-3-O-β-D-galactoside (10), Daucosterol (11), Stigmasterol-3-O-β-D-glucopyranoside (12), 3, 5-Di-O-caffeoyl quinic acid (13), and n-Hexadecanoic acid (14). By GC-MS analysis of the CH2Cl2 extract from Trillium tschonoskii Maxim, twenty compouns were identified, representing 91 % of the area. The cytotoxicity of compounds 1-14 on mouse A549 cells were evaluated.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Structure and variability of the North Icelandic Jet from two years of mooring data

Author Posting. © American Geophysical Union, 2019. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research-Oceans 124(6), (2019): 3987-4002, doi:10.1029/2019JC015134.Mooring data from September 2011 to July 2013 on the Iceland slope north of Denmark Strait are analyzed to better understand the structure and variability of the North Icelandic Jet (NIJ). Three basic configurations of the flow were identified: (1) a strong separated East Greenland Current (EGC) on the mid‐Iceland slope coincident with a weak NIJ on the upper slope, (2) a merged separated EGC and NIJ, and (3) a strong NIJ located at its climatological mean position, coincident with a weak signature of the separated EGC at the base of the Iceland slope. Our study reveals that the NIJ‐dominant scenario was present during different times of the year for the two successive mooring deployments—appearing mainly from September to February the first year and from January to July the second year. Furthermore, when this scenario was active it varied on short timescales. An energetics analysis demonstrates that the high‐frequency variability is driven by mean‐to‐eddy baroclinic conversion at the shoreward edge of the NIJ, consistent with previous modeling work. The seasonal timing of the NIJ dominant scenario is investigated in relation to the atmospheric forcing upstream of Denmark Strait. The resulting lagged correlations imply that strong turbulent heat fluxes in a localized region on the continental slope of Iceland, south of the Spar Fracture zone, lead to a stronger NIJ dominant state with a two‐month lag. This can be explained dynamically in terms of previous modeling work addressing the circulation response to dense water formation near an island.The authors thank the crew members of the R/V Knorr, RRS James Clark Ross, and R/V Bjarni Sæmundsson for the deployment and recovery of the moorings. D. Torres and F. Bahr processed the second year of mooring data. We thank K. Våge, B. Harden, Z. Song, J. Li, and M. Li for helpful discussions regarding the work. Funding was provided by the National Science Foundation under grants OCE‐1558742 (J. H., R. P., P. L., and M. S.) and OCE‐1534618 (M. S.). The mooring data are available at http://kogur.whoi.edu/php/index.php.2019-12-0

Steroid saponins and other constituents from the rhizome of Trillium tschonoskii Maxim and their cytotoxic activity

Fourteen compounds were isolated from the rhizome of Trillium tschonoskii Maxim. By spectroscopic analysis, these compounds were established as Gracillin (1), Paris saponins V (2), Paris saponins VI (3), Paris saponins H (4), Paris saponins VII (5), (25R)-17α-hydroxy-5-en-3-O-a-L-arabinofuranosyl-(1→2)-β-Dglucopyranoside (6), (25R)-26-[β-D-glucopyanosyl]-17α,22β-dihydroxy-5-en-3-O-a-L-rhamnopyranosyl- (1→2)-β-D-glucopyranoside (7), Kaempferol-3-O-β-D-rutinoside (8), Quercetin (9), Quercetin-3-O-β-D-galactoside (10), Daucosterol (11), Stigmasterol-3-O-β-D-glucopyranoside (12), 3, 5-Di-O-caffeoyl quinic acid (13), and n-Hexadecanoic acid (14). By GC-MS analysis of the CH2Cl2 extract from Trillium tschonoskii Maxim, twenty compouns were identified, representing 91 % of the area. The cytotoxicity of compounds 1-14 on mouse A549 cells were evaluated.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Family-clinician shared decision making in intensive care units : cluster randomized trial in China

We thank the China Medical Board, which financially supported our study.Objective To investigate if a Family-Clinician Shared Decision-Making (FCSDM) intervention benefits patients, families and intensive care units (ICUs) clinicians.  Methods Six ICUs in China were allocated to intervention or usual care. 548 patients with critical illness, 548 family members and 387 ICU clinicians were included into the study. Structured FCSDM family meetings were held in the intervention group. Scales of SSDM, HADS, QoL2 and CSACD were used to assess families’ satisfaction and distress, patients’ quality of life, and clinicians’ collaboration respectively.  Results Comparing the intervention group with the control group at post-intervention, there were significant differences in the families’ satisfaction (P =0.0001), depression level (P =0.005), and patients’ quality of life (P =0.0007). The clinicians’ mean CSCAD score was more positive in the intervention group than controls (P < 0.05). There was no significant between-group differences on ICU daily medical cost, but the intervention group demonstrated shorter number of days’ stay in ICU (P=0.0004).  Conclusion The FCSDM intervention improved families’ satisfaction and depression, shortened patients’ duration of ICU stay, and enhanced ICU clinicians’ collaboration.  Practice implications Further improvement and promotion of the FCSDM model are needed to provide more evidence to this field in China.Publisher PDFPeer reviewe

Glycocalyx mechanotransduction mechanisms are involved in renal cancer metastasis

Mammalian cells, including cancer cells, are covered by a surface layer containing cell bound proteoglycans, glycoproteins, associated glycosaminoglycans and bound proteins that is commonly referred to as the glycocalyx. Solid tumors also have a dynamic fluid microenvironment with elevated interstitial flow. In the present work we further investigate the hypothesis that interstitial flow is sensed by the tumor glycocalyx leading to activation of cell motility and metastasis. Using a highly metastatic renal carcinoma cell line (SN12L1) and its low metastatic counterpart (SN12C) we demonstrate in vitro that the small molecule Suberoylanilide Hydroxamic Acid (SAHA) inhibits the heparan sulfate synthesis enzyme N-deacetylase-N-sulfotransferase-1, reduces heparan sulfate in the glycocalyx and suppresses SN12L1 motility in response to interstitial flow. SN12L1 cells implanted in the kidney capsule of SCID mice formed large primary tumors and metastasized to distant organs, but when treated with SAHA metastases were not detected. In another set of experiments, the role of hyaluronic acid was investigated. Hyaluronan synthase 1, a critical enzyme in the synthetic pathway for hyaluronic acid, was knocked down in SN12L1 cells and in vitro experiments revealed inhibition of interstitial flow induced migration. Subsequently these cells were implanted in mouse kidneys and no distant metastases were detected. These findings suggest new therapeutic approaches to the treatment of kidney carcinoma metastasis

Toll-like Receptor 4 Signaling Confers Cardiac Protection against Ischemic Injury via Inducible Nitric Oxide Synthase- and Soluble Guanylate Cyclase-dependent Mechanisms

Background: Prior administration of a small dose of lipopolysaccharide confers a cardiac protection against ischemia-reperfusion injury. However, the signaling mechanisms that control the protection are incompletely understood. We tested the hypothesis that Toll-like receptor 4 (TLR4) mediates the ability of lipopolysaccharide to protect against cardiac ischemia-reperfusion injury through distinct intracellular pathways involving myeloid differentiation factor 88 (MyD88), TIR-domain-containing adaptor protein-inducing interferon-β-mediated transcription factor (Trif), inducible nitric oxide synthase (iNOS), and soluble guanylate cyclase (sGC). Methods: Wild-type mice and genetically modified mice, that is TLR4-deficient (TLR4−def), TLR2 knockout (TLR2−/−), MyD88−/−, Trif−/−, iNOS−/−, and sGCα1−/−, were treated with normal saline or 0.1 mg/kg lipopolysaccharide intraperitoneally. Twenty-four hours later, isolated hearts were perfused in a Langendorff apparatus and subsequently subjected to 30 min global ischemia and reperfusion for as long as 60 min. Left ventricular function and myocardial infarction sizes were examined. Results: Compared with saline-treated mice, lipopolysaccharide-treated mice had markedly improved left ventricular developed pressure and dP/dtmax (P < 0.01) and reduced myocardial infarction sizes (37.2 ± 3.4% vs. 19.8 ± 4.9%, P < 0.01) after ischemia-reperfusion. The cardiac protective effect of lipopolysaccharide was abolished in the TLR4−def and MyD88−/− mice but remained intact in TLR2−/− or Trif−/− mice. iNOS−/− mice or wild-type mice treated with the iNOS inhibitor 1400W failed to respond to the TLR4-induced nitric oxide production and were not protected by the lipopolysaccharide preconditioning. Although sGCα1−/− mice had robust nitric oxide production in response to lipopolysaccharide, they were not protected by the TLR4-elicited cardiac protection. Conclusions: TLR4 activation confers a potent cardiac protection against ischemia-reperfusion injury via a MyD88-dependent, but Trif-independent, mechanism. iNOS/sGC are essential for the TLR4-induced cardiac protection

Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels

Cancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because of its swelling behaviour. Here we show, unexpectedly, that hyaluronan compresses vessels only in collagen-rich tumours, suggesting that collagen and hyaluronan together are critical targets for decompressing tumour vessels. We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-β1, CCN2 and ET-1, downstream of angiotensin-II-receptor-1 inhibition. Consequently, losartan reduces solid stress in tumours resulting in increased vascular perfusion. Through this physical mechanism, losartan improves drug and oxygen delivery to tumours, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Thus, angiotensin inhibitors—inexpensive drugs with decades of safe use—could be rapidly repurposed as cancer therapeutics.National Cancer Institute (U.S.) (Grant P01-CA080124)National Cancer Institute (U.S.) (Grant R01-CA126642)National Cancer Institute (U.S.) (Grant R01-CA085140)National Cancer Institute (U.S.) (Grant R01-CA115767)National Cancer Institute (U.S.) (Grant R01-CA098706)United States. Dept. of Defense. Breast Cancer Research Program (Innovator Award W81XWH-10-1-0016)Lustgarten Foundation (Dana-Farber Cancer Institute/David H. Koch Institute for Integrative Cancer Research at MIT Bridge Project Grant