Internal wave band eddy fluxes above a continental slope

Three weeks of velocity and temperature measurements from the bottom 45 m above the continental slope in the Bay of Biscay are used to evaluate the role of the internal wave band in boundary mixing near a sloping bottom. Utilizing acoustic Doppler current profilers and thermistor strings, internal wave band eddy fluxes of momentum and heat are estimated. The instrumentation is specifically designed to resolve internal wave band processes. Due to unresolved Doppler shifting, this wave band may include turbulence as well as internal waves. A very energetic and highly variable near-bottom environment is found. Periods of mixing and restratification alternate at the M2 tidal frequency. Interpreting the observations in an Ekman sense, the three-week mean current is downwelling-favorable, which is consistent with existing boundary layer theories. However, a bi-directional flow associated with sloping boundary mixing is not found in the near-bottom layer, possibly due to observed strong stratification all the way to the bottom. We evaluated boundary layer dynamics and the effect of internal wave-band fluxes from two frequency ranges (σ ≥ 15 cpd and σ ≥ 1.9 cpd, including tides) on the three-week mean flow. The high-frequency range (σ ≥ 15 cpd) of the internal wave band supports significant momentum and buoyancy fluxes while the low-frequency range (σ ≥ 1.9 cpd) only supports significant momentum fluxes. Mean bottom-normal eddy diffusivities associated with anisotropic, nonlinear internal waves, are negative and O (-10-2 m2s-1). Interpreting these negative eddy diffusivities as indication of a restratification process, high mixing efficiencies are expected throughout the mixing layer, which extends typically 20 m above the bottom. Mean eddy viscosities are positive in cross-slope direction and negative in alongslope direction, implying a strong anisotropy in the interaction between internal wave band eddies and the mean flow. Alongslope momentum is transferred from the internal tide to the mean flow. Buoyancy and pressure gradient forces, which we could not determine directly, may generate a buoyancy-driven secondary flow. The buoyancy equation is dominated by advection, possibly balanced by divergence of cross-slope and alongslope internal wave band fluxes

Leaf-level metabolic changes in response to drought affect daytime CO2 emission and isoprenoid synthesis pathways

In the near future, climate change will cause enhanced frequency and/or severity of droughts in terrestrial ecosystems, including tropical forests. Drought responses by tropical trees may affect their carbon use, including production of volatile organic compounds (VOCs), with implications for carbon cycling and atmospheric chemistry that are challenging to predict. It remains unclear how metabolic adjustments by mature tropical trees in response to drought will affect their carbon fluxes associated with daytime CO2 production and VOC emission. To address this gap, we used position-specific 13C-pyruvate labeling to investigate leaf CO2 and VOC fluxes from four tropical species before and during a controlled drought in the enclosed rainforest of Biosphere 2 (B2). Overall, plants that were more drought-sensitive had greater reductions in daytime CO2 production. Although daytime CO2 production was always dominated by non-mitochondrial processes, the relative contribution of CO2 from the tricarboxylic acid cycle tended to increase under drought. A notable exception was the legume tree Clitoria fairchildiana R.A. Howard, which had less anabolic CO2 production than the other species even under pre-drought conditions, perhaps due to more efficient refixation of CO2 and anaplerotic use for amino acid synthesis. The C. fairchildiana was also the only species to allocate detectable amounts of 13C label to VOCs and was a major source of VOCs in B2. In C. fairchildiana leaves, our data indicate that intermediates from the mevalonic acid (MVA) pathway are used to produce the volatile monoterpene trans-β-ocimene, but not isoprene. This apparent crosstalk between the MVA and methylerythritol phosphate pathways for monoterpene synthesis declined with drought. Finally, although trans-β-ocimene emissions increased under drought, it was increasingly sourced from stored intermediates and not de novo synthesis. Unique metabolic responses of legumes may play a disproportionate role in the overall changes in daytime CO2 and VOC fluxes in tropical forests experiencing drought

RV SONNE 252 Cruise Report / Fahrtbericht, Yokohama : 05.11.2016 - Nouméa : 18.12.2016. SO252 : RITTER ISLAND Tsunami potential of volcanic flank collapses

Large volcanic debris flows associated with volcanic island flank collapses may cause devastating tsunamis as they enter the ocean. Computer simulations show that the largest of these volcanic debris flows on oceanic islands such as Hawaii or the Canaries can cause ocean-wide tsunamis (Løvholt et al., 2008; Waythomas et al., 2009). However, the magnitude of these tsunamis is subject to on-going debate as it depends particularly on landslide transport and emplacement processes (Harbitz et al. 2013). A robust understanding of these factors is thus essential in order to assess the hazard of volcanic flank collapses. Recent studies have shown that emplacement processes are far more complex than assumed previously. With a collapsed volume of about 5 km3 the 1888 Ritter Island flank collapse is the largest in historic times and represents an ideal natural laboratory for several reasons: (I) The collapse is comparatively young and the marine deposits are clearly visible, (II) the pre-collapse shape of the island is historically documented and (III) eyewitness reports documenting tsunami arrival times, run-up heights and inundation levels on neighboring islands are available. We propose to collect bathymetric, high resolution 2D and 3D seismic data as well as seafloor samples from the submarine deposits off Ritter Island to learn about the mobility and emplacement dynamics of the 1888 flank collapse landslide. A comparison to similar studies from other volcanic islands will provide an improved understanding of emplacement processes of volcanic island landslides and their overall tsunamigenic potential. In addition, a detailed knowledge of the 1888 landslide processes in combination with tsunami constraints from eyewitness reports provides a unique possibility to determine the landslide velocity, which can then be used in subsequent hazard analyses for ocean islands.peer-reviewe

Short-term beneficial effects of methylene blue on kidney damage in septic shock patients

Contains fulltext : 71022.pdf (publisher's version ) (Closed access)OBJECTIVE: We previously demonstrated that upregulation of renal inducible nitric oxide synthase (iNOS) is associated with proximal tubule injury during systemic inflammation in humans. In this study we investigated the short-term effect of methylene blue (MB), an inhibitor of the NO pathway, on kidney damage and function in septic shock patients. DESIGN AND SETTING: A prospective clinical study conducted in an intensive care unit. PATIENTS: Nine patients (four men, five women, mean age 71 +/- 3 years) with confirmed or suspected bacterial infection and with refractory septic shock defined as a mean arterial pressure or = 0.2 microg/kg per minute. INTERVENTIONS: A 4 h continuous intravenous infusion of 1 mg/kg MB per hour. MEASUREMENTS AND RESULTS: The urinary excretion of NO metabolites decreased with median 90% (range 75-95%) from baseline to 6 h after MB administration. The first 24 h creatinine clearance improved by 51% (18-173%) after MB treatment but was still strongly impaired. During the first 6 h after the start of MB treatment both the urinary excretion of cytosolic glutathione S-transferase A1-1 and P1-1, markers for proximal and distal tubule damage, respectively, decreased by 45% (10-70%) and 70% (40-85) vs. baseline. After termination of the MB infusion the NO metabolites and markers of tubular injury returned to pretreatment levels. CONCLUSIONS: In septic patients with refractory shock short-term infusion of MB is associated with a decrease in NO production and an attenuation of the urinary excretion of renal tubular injury markers

ECMO for COVID-19 patients in Europe and Israel

Since March 15th, 2020, 177 centres from Europe and Israel have joined the study, routinely reporting on the ECMO support they provide to COVID-19 patients. The mean annual number of cases treated with ECMO in the participating centres before the pandemic (2019) was 55. The number of COVID-19 patients has increased rapidly each week reaching 1531 treated patients as of September 14th. The greatest number of cases has been reported from France (n = 385), UK (n = 193), Germany (n = 176), Spain (n = 166), and Italy (n = 136) .The mean age of treated patients was 52.6 years (range 16–80), 79% were male. The ECMO configuration used was VV in 91% of cases, VA in 5% and other in 4%. The mean PaO2 before ECMO implantation was 65 mmHg. The mean duration of ECMO support thus far has been 18 days and the mean ICU length of stay of these patients was 33 days. As of the 14th September, overall 841 patients have been weaned from ECMO support, 601 died during ECMO support, 71 died after withdrawal of ECMO, 79 are still receiving ECMO support and for 10 patients status n.a. . Our preliminary data suggest that patients placed on ECMO with severe refractory respiratory or cardiac failure secondary to COVID-19 have a reasonable (55%) chance of survival. Further extensive data analysis is expected to provide invaluable information on the demographics, severity of illness, indications and different ECMO management strategies in these patients

The effects of methylene blue infusion on gastric tonometry and intestinal fatty acid binding protein levels in septic shock patients

Objective: We prospectively studied the effect of methylene blue (MB) infusion on gastric mucosal metabolism perfusion ratio, assessed by gastric tonometry, and on mucosal cell damage, assessed by urinary levels of intestinal fatty acid binding protein, in septic shock patients. Methods: Methylene blue (MB) infusion (1 mg/kg per hour) during 4 hours in 10 consecutive patients with a proven or suspected bacterial infection and with severe vasodilatory shock, defined as a mean arterial pressure 70 mm Hg or lower for at least 1 hour despite adequate volume resuscitation and norepinephrine infusion at a rate ≥0.2 μg/kg per minute. Results: Methylene blue infusion did not significantly change the P(g-a)CO2 gradient (P = .16). Post hoc analysis of the subgroup of patients with an elevated baseline P(g-a)CO2 gradient, defined as ≥20 mm Hg, showed that the median P(g-a)CO2 gradient (interquartile range [IQR]) decreased from 45 (41-56) mm Hg before infusion to 41 (28-52) at the end of the 4-hour infusion and decreased further to 32 (26-36) mm Hg 2 hours after cessation of MB infusion (P = .012). The median urinary intestinal fatty acid binding protein concentration at baseline was elevated (210 [79-437] pg/μmol creatinine) and did not change significantly after 24 hours (116 [53-601] pg/μmol creatinine, P = .15). The median mean arterial blood pressure (IQR) increased from 70 (69-71) mm Hg at baseline to 77 (67-83) mm Hg after 1 hour (P = .04), the norepinephrine dose did not change significantly. The median (IQR) cardiac index decreased from 4.4 (3.2-5.5) L min-1 m-2 at baseline to 3.6 (3.3-4.7) L min-1 m-2 after 2 h, returning back to baseline values after cessation of MB infusion P = .02). Conclusion: Although MB infusion in patients with septic shock and advanced multi-organ failure increases mean arterial blood pressure and decreases cardiac index, it does not compromise the gastric mucosal perfusion metabolism ratio as indicated by tonometry, and by the release of a mucosal cellular injury marker

Extrahepatic metabolism of ibrutinib

Ibrutinib is a first-in-class Bruton's kinase inhibitor used in the treatment of multiple lymphomas. In addition to CYP3A4-mediated metabolism, glutathione conjugation can be observed. Subsequently, metabolism of the conjugates and finally their excretion in feces and urine occurs. These metabolites, however, can reach substantial concentrations in human subjects, especially when CYP3A4 is inhibited. Ibrutinib has unexplained nephrotoxicity and high metabolite concentrations are also found in kidneys of Cyp3a knockout mice. Here, a mechanism is proposed where the intermediate cysteine metabolite is bioactivated. The metabolism of ibrutinib through this glutathione cycle was confirmed in cultured human renal proximal tubule cells. Ibrutinib-mediated toxicity was enhanced in-vitro by inhibitors of breast cancer resistance protein (BCRP), P-glycoprotein (P-gp) and multidrug resistance protein (MRP). This was a result of accumulating cysteine metabolite levels due to efflux inhibition. Finally, through inhibition of downstream metabolism, it was shown now that direct conjugation was responsible for cysteine metabolite toxicity

Bisubstrate inhibitors of nicotinamide N-methyltransferase (NNMT) with enhanced activity

Nicotinamide N-methyltransferase (NNMT) catalyzes the methylation of nicotinamide to form N-methylnicotinamide. Overexpression of NNMT is associated with a variety of diseases, including a number of cancers and metabolic disorders, suggesting a role for NNMT as a potential therapeutic target. By structural modification of a lead NNMT inhibitor previously developed in our group, we prepared a diverse library of inhibitors to probe the different regions of the enzyme's active site. This investigation revealed that incorporation of a naphthalene moiety, intended to bind the hydrophobic nicotinamide binding pocket via π-πstacking interactions, significantly increases the activity of bisubstrate-like NNMT inhibitors (half-maximal inhibitory concentration 1.41 μM). These findings are further supported by isothermal titration calorimetry binding assays as well as modeling studies. The most active NNMT inhibitor identified in the present study demonstrated a dose-dependent inhibitory effect on the cell proliferation of the HSC-2 human oral cancer cell line

Tryptophan requirement of the enterally fed term infant in the first month of life

Tryptophan not only is an amino acid essential to protein synthesis but also serves as a precursor in 2 important metabolic pathways: the serotonin and the kynurenine pathways. Tryptophan is related to sleeping patterns. The objective of the present study was to determine the tryptophan requirement of term infants using the indicator amino acid oxidation (IAAO) method with L-[1-C]phenylalanine as the indicator. Enterally fed infants were randomly assigned to tryptophan intakes ranging from 0.5 to 73 mg · kg · day as part of an elemental diet. After 1-day adaptation to the test diet, [C]bicarbonate and L-[1-C]phenylalanine tracers were given enterally. Breath samples were collected at baseline and during isotopic plateaus. The mean tryptophan requirement was determined by using the biphasic linear regression crossover analysis on the fraction of CO2 recovery from L-[1-C]phenylalanine oxidation (FCO2). Data are presented as mean ± standard deviation. A total of 30 term neonates (gestational age 39 ± 1 weeks) were studied at 9 ± 4 days. FCO2 decreased until a tryptophan intake of 15 mg · kg · day; additional increases in tryptophan intake did not affect FCO2. Mean requirement was determined to be 15 mg · kg · day. The mean tryptophan requirement for elemental formula-fed term infants is 15 mg · kg · day. This requirement is lower than the present recommended intake of 29 mg · kg · day, which is based on the average intake of a breastfed infan