Alterations in lysosomal enzymes of the proximal tubule in gentamicin nephrotoxicity

Alterations in lysosomal enzymes of the proximal tubule in gentamicin nephrotoxicity. Gentamicin accumulates in proximal tubule lysosomes, increases their number, and changes their structure. An important lysosomal function is degradation of intracellular proteins. To evaluate the effect of gentamicin on this lysosomal function, we measured the activity of the key lysosomal proteinases, cathepsin B and L, in microdissected S1, S2, and S3 segments of rat proximal tubules by means of a fluorometric microassay. The cathepsin activities were decreased in S1 and S2 following one and four gentamicin injections of 100 mg/kg body weight. The lysosomal enzyme, acid phosphatase, was also measured and was not decreased by gentamicin. The urine excretion of cathepsins B and L was decreased after gentamicin. This excludes an increase in urinary loss of cathepsins as the cause of decreased tubule activity. Structural changes of the lysosomes per se were excluded as the factor responsible for the reduced cathepsin activity by demonstrating increased cathepsin B and L activity in proximal tubule segments from rats injected with dextran, since dextran induces an increase in number and size of proximal tubule lysosomes. In vitro incubation of urine and tubule segments with gentamicin demonstrated a concentration-dependent reversible inhibition of cathepsin B and L. We conclude that gentamicin per se decreased cathepsin B and L activities in proximal tubule segments as early as 24 hours following one injection due to either enzyme inhibition or reduced generation of active intralysosomal cathepsin B and L. Gentamicin may, therefore, reduce renal protein catabolism by decreasing the activity of the key proteolytic enzymes, cathepsin B and L. Since cathepsin B and L are proteolytic activators of other lysosomal enzymes, their reduced activity may also decrease the activities of other lysosomal enzymes

Bi-objective facility location in the presence of uncertainty

Multiple and usually conflicting objectives subject to data uncertainty are main features in many real-world problems. Consequently, in practice, decision-makers need to understand the trade-off between the objectives, considering different levels of uncertainty in order to choose a suitable solution. In this paper, we consider a two-stage bi-objective single source capacitated model as a base formulation for designing a last-mile network in disaster relief where one of the objectives is subject to demand uncertainty. We analyze scenario-based two-stage risk-neutral stochastic programming, adaptive (two-stage) robust optimization, and a two-stage risk-averse stochastic approach using conditional value-at-risk (CVaR). To cope with the bi-objective nature of the problem, we embed these concepts into two criterion space search frameworks, the $\epsilon$-constraint method and the balanced box method, to determine the Pareto frontier. Additionally, a matheuristic technique is developed to obtain high-quality approximations of the Pareto frontier for large-size instances. In an extensive computational experiment, we evaluate and compare the performance of the applied approaches based on real-world data from a Thies drought case, Senegal

Air-sea interactions and water mass transformation during a katabatic storm in the Irminger Sea

We use a global 5-km resolution model to analyse the air-sea interactions during a katabatic storm in the Irminger Sea originating from the Ammassalik valleys. Katabatic storms have not yet been resolved in global climate models, raising the question of whether and how they modify water masses in the Irminger Sea. Our results show that dense water forms along the boundary current and on the shelf during the katabatic storm due to the heat loss caused by the high wind speeds and the strong temperature contrast. The dense water contributes to the North Atlantic Deep Water and thus to the Atlantic Meridional Overturning Circulation (AMOC). The katabatic storm triggers a polar low, which in turn amplifies the near-surface wind speed in a positive feedback, in addition to acceleration from a breaking mountain wave. Resolving katabatic storms in global models is therefore important for the formation of dense water in the Irminger Sea, which is relevant to the AMOC, and for the large-scale atmospheric circulation by triggering polar low

Modelling global-scale climate impacts of the late Miocene Messinian Salinity Crisis

Late Miocene tectonic changes in Mediterranean–Atlantic connectivity and climatic changes caused Mediterranean salinity to fluctuate dramatically, including a ten-fold increase and near-freshening. Recent proxy- and model-based evidence suggests that at times during this Messinian Salinity Crisis (MSC, 5.96–5.33 Ma), highly saline and highly fresh Mediterranean water flowed into the North Atlantic Ocean, whilst at others, no Mediterranean Outflow Water (MOW) reached the Atlantic. By running extreme, sensitivity-type experiments with a fully coupled ocean–atmosphere general circulation model, we investigate the potential of these various MSC MOW scenarios to impact global-scale climate. The simulations suggest that although the effect remains relatively small, MOW had a greater influence on North Atlantic Ocean circulation and climate than it does today. We also find that depending on the presence, strength and salinity of MOW, the MSC could have been capable of cooling mid–high northern latitudes by a few degrees, with the greatest cooling taking place in the Labrador, Greenland–Iceland–Norwegian and Barents seas. With hypersaline MOW, a component of North Atlantic Deep Water formation shifts to the Mediterranean, strengthening the Atlantic Meridional Overturning Circulation (AMOC) south of 35° N by 1.5–6 Sv. With hyposaline MOW, AMOC completely shuts down, inducing a bipolar climate anomaly with strong cooling in the north (mainly −1 to −3 °C, but up to −8 °C) and weaker warming in the south (up to +0.5 to +2.7 °C). These simulations identify key target regions and climate variables for future proxy reconstructions to provide the best and most robust test cases for (a) assessing Messinian model performance, (b) evaluating Mediterranean–Atlantic connectivity during the MSC and (c) establishing whether or not the MSC could ever have affected global-scale climate

Differential inhibition of human cytomegalovirus (HCMV) by toll-like receptor ligands mediated by interferon-beta in human foreskin fibroblasts and cervical tissue

Human cytomegalovirus (HCMV) can be acquired sexually and is shed from the genital tract. Cross-sectional studies in women show that changes in genital tract microbial flora affect HCMV infection and/or shedding. Since genital microbial flora may affect HCMV infection or replication by stimulating cells through Toll-like receptors (TLR), we assessed the effects of defined TLR-ligands on HCMV replication in foreskin fibroblasts and ectocervical tissue. Poly I:C (a TLR3-ligand) and lipopolysaccharide (LPS, a TLR4-ligand) inhibited HCMV and induced secretion of IL-8 and Interferon-beta (IFNβ) in both foreskin fibroblasts and ectocervical tissue. The anti-HCMV effect was reversed by antibody to IFNβ. CpG (TLR9 ligand) and lipoteichoic acid (LTA, TLR2 ligand) also inhibited HCMV infection in ectocervical tissue and this anti-HCMV effect was also reversed by anti-IFNβ antibody. In contrast, LTA and CpG did not inhibit HCMV infection in foreskin fibroblasts. This study shows that TLR ligands induce an HCMV-antiviral effect that is mediated by IFNβ suggesting that changes in genital tract flora may affect HCMV infection or shedding by stimulating TLR. This study also contrasts the utility of two models that can be used for assessing the interaction of microbial flora with HCMV in the genital tract. Clear differences in the response to different TLR ligands suggests the explant model more closely reflects in vivo responses to genital infections

Response of northern North Atlantic and Atlantic meridional overturning circulation to reduced and enhanced wind stress forcing

Surface wind stress strongly influences AMOC variability on interannual time scales. On longer time scales, however, its role in AMOC variations is less clear. Here, we show a non-linear AMOC response to globally reduced and enhanced wind stress forcing, based on sensitivity experiments with MPI-ESM1.2. Under reduced wind stress forcing, the AMOC strength strongly decreases. In contrast, under enhanced wind stress forcing the AMOC strength increases only in the first decades and then decreases, stabilizing at a value similar to the reference simulation. To reveal possible mechanisms underlying this response, we assess the response of the northern North Atlantic circulation and climate to the changed wind stress forcing. Initially, the response is linear: reduced wind stress forcing weakens the gyre circulation and the associated heat and salt transport, leading to larger winter sea ice extent and a shutdown of subpolar deep convection. In the Nordic Seas, the fresher and lighter subsurface state leads to a decrease in the baroclinic pressure and the overflow strength. Under enhanced wind stress forcing, initially the opposite is happening. However, eventually subpolar surface density anomalies are determined by warmer temperature rather than increased salinity, leading to a decrease in surface density and a weakening of subpolar deep convection. The resulting AMOC weakening reduces the Atlantic inflow salinity, and subsequently the Nordic Seas baroclinic pressure and overflow strength. The quasi-equilibrium response of the northern North Atlantic circulation and climate under enhanced wind stress forcing differs from the reference simulation, even though the AMOC strength converges

Surface flux drivers for the slowdown of the Atlantic Meridional Overturning Circulation in a high resolution global coupled climate model

This paper investigates the causation for the decline of the Atlantic Meridional Overturning Circulation (AMOC) from approximately 17 Sv to about 9 Sv, when the atmospheric resolution of the Max Planck Institute-Earth System Model is enhanced from ∼1° to ∼0.5°. The results show that the slowdown of the AMOC is caused by the cessation of deep convection. In most modeling studies, this is thought to be controlled by buoyancy fluxes in the convective regions, for example, by surface freshwater flux that is introduced locally or via enormous input from glacier or iceberg melts. While we find that freshwater is still the key to the reduction of AMOC seen in the higher-resolution run, the freshening of the North Atlantic does not need to be directly caused by local freshwater fluxes. Instead, it can be caused indirectly through winds via a reduced wind-driven gyre circulation and salinity transport associated to this circulation, as seen in the higher-resolution run. © 2019. The Authors

Comparison of ocean vertical mixing schemes in the Max Planck Institute Earth System Model (MPI-ESM1.2)

For the first time, we compare the effects of four different ocean vertical mixing schemes on the mean state of the ocean and atmosphere in the Max Planck Institute Earth System Model (MPI-ESM1.2). These four schemes are namely the default Pacanowski and Philander (1981) (PP) scheme, the K-profile parameterization (KPP) from the Community Vertical Mixing (CVMix) library, a recently implemented scheme based on turbulent kinetic energy (TKE), and a recently developed prognostic scheme for internal wave dissipation, energy, and mixing (IDEMIX) to replace the often assumed constant background diffusivity in the ocean interior. In this study, the IDEMIX scheme is combined with the TKE scheme (collectively called the TKE+IDEMIX scheme) to provide an energetically more consistent framework for mixing, as it does not rely on the unwanted effect of creating spurious energy for mixing. Energetic consistency can have implications on the climate. Therefore, we focus on the effects of TKE+IDEMIX on the climate mean state and compare them with the first three schemes that are commonly used in other models but are not energetically consistent. We find warmer sea surface temperatures (SSTs) in the North Atlantic and Nordic Seas using KPP or TKE(+IDEMIX), which is related to 10 % higher overflows that cause a stronger and deeper upper cell of the Atlantic meridional overturning circulation (AMOC) and thereby an enhanced northward heat transport and higher inflow of warm and saline water from the Indian Ocean into the South Atlantic. Saltier subpolar North Atlantic and Nordic Seas lead to increased deep convection and thus to the increased overflows. Due to the warmer SSTs, the extratropics of the Northern Hemisphere become warmer with TKE(+IDEMIX), weakening the meridional gradient and thus the jet stream. With KPP, the tropics and the Southern Hemisphere also become warmer without weakening the jet stream. Using an energetically more consistent scheme (TKE+IDEMIX) produces a more heterogeneous and realistic pattern of vertical eddy diffusivity, with lower diffusivities in deep and flat-bottom basins and elevated turbulence over rough topography. IDEMIX improves in particular the diffusivity in the Arctic Ocean and reduces the warm bias in the Atlantic Water layer. We conclude that although shortcomings due to model resolution determine the global-scale bias pattern, the choice of the vertical mixing scheme may play an important role for regional biases.. © 2021 American Society of Civil Engineers (ASCE). All rights reserve

Effect of low molecular weight proteins and dextran on renal cathepsin B and L activity

Effect of low molecular weight proteins and dextran on renal cathepsin B and L activity. Renal extraction of low molecular weight proteins (LMWP) accounts for 30% to 80% of their total metabolic clearance. Extraction includes glomerular filtration, proximal tubular uptake, and intralysosomal proteolysis. To characterize the anatomic sites and enzymes involved in digestion of reabsorbed LMWP, the lysosomal proteases, cathepsin B and L, were measured by ultramicroassay in isolated S1, S2 and S3 segments of the proximal tubule of proteinuric rats. Increased glomerular filtration and tubular uptake of LMWP were induced by i.v. and i.p. injections of myoglobin and cationic and anionic lysozyme. Both cationic lysozyme and myoglobin increased cathepsin B and L activities in the proximal tubule, while anionic lysozyme had no effect. Morphologic examination of kidney tissue suggested that proximal tubular uptake of anionic lysozyme was negligible in comparison with the cationic form. Hence, only LMWP absorbed by the proximal tubule cells stimulated cathepsin B and L activities. Proximal tubular uptake of cationic lysozyme was determined by measurement of lysozyme activities in S1, S2, and S3. S1 segments contained the highest lysozyme activity, while S2 and S3 had much lower activities, and cathepsin B and L activity following cationic lysozyme injection was stimulated only in S1 segments. These results suggest that cathepsin B and L participate in lysosomal digestion of certain LMWP. Furthermore, the activities of cathepsin B and L adapt to increased uptake of LMWP. To gain additional insight into the mechanism of cathepsin adaptation, the cathepsin B and L activities were measured following injection of dextran with a similar low molecular weight. Dextran uptake in proximal tubules was confirmed by morphologic examination of kidney tissue. Dextran increased cathepsin B and L activities in the proximal tubule. Hence, increased endocytic activity of proximal tubule cells or increased lysosomal load of macromolecules or both rather than direct protein-enzyme interaction seem to be involved in cathepsin stimulation

Changes of the Atlantic meridional overturning circulation of the past 30ka recorded in a depth transect at the Blake Outer Ridge

Oceans and climate are a tightly coupled system interacting with each other in various ways such as storage of carbon dioxide in the deep ocean. Within the global conveyor belt the Atlantic Meridional Overturning Circulation (AMOC) holds a key function, transporting warm salty surface waters from the tropical to the northern Atlantic where deep water formation takes place. Following the continental rise of North America this newly formed deep water propagates southward as Western Boundary Undercurrent (WBUC) ventilating the deep Atlantic. In the past (e.g. the last glacial cycle) strength and geometry of the AMOC have changed significantly. This study aims to provide a better understanding of the temporal and spatial (also depth depended) evolution of the AMOC in the western Atlantic sector since the last glacial (∼30 ka). We have investigated four sediment cores of the Blake Outer Ridge (30°N, 74°W; ODP 1059 to 1062) in a depth transect from 3000 to 4700 m water depth in the main flow path of the WBUC. We measured four down-core profiles of neodymium (εNd) and 231Pa/230Th isotopes for the reconstruction of water mass provenance and circulation strength of the last ∼30 ka. In contrast to published Nd isotope and 231Pa/230Th records from the Blake Ridge area our records are of unprecedented resolution, resolving climate key features of the North Atlantic region: Heinrich Stadials (HS) 1 and 2, the Last Glacial Maximum (LGM), the Bølling-Allerød and Younger Dryas (YD). Radiogenic Nd isotope signatures during the LGM reveal AABW to be the prevalent water mass in the deep western North Atlantic. The trend to more unradiogenic signatures during the deglaciation point to an increased formation of NADW which was again replaced by AABW during YD. The Holocene shows the most unradiogenic signatures and therefore established NADW. The circulation strength-proxy 231Pa/230Th indicates reduced LGM deep circulation, a pronounced slowdown during HS1 and a strong and deep circulation during the Holocene. Compared to isotopic records from the Bermuda Rise (ODP 1063) we found depth depended geometry changes of the WBUC which have occurred through the last glacial. Here, we focus on how deep northern sourced water has reached during phases of reduced circulation (indicated by increased 231Pa/230Th ratios) and the timing of this southward progradation of lower NADW