Ball release experiments on a centrifuge : misalignment between the buoyancy force and the axis of rotation

Author Posting. © Cambridge University Press, 2006. This article is posted here by permission of Cambridge University Press for personal use, not for redistribution. The definitive version was published in Journal of Fluid Mechanics 564 (2006): 435-454, doi:10.1017/S0022112006001522.Motivated by work on tilted convection (Sheremet, J. Fluid Mech., vol. 506, 2004, p. 217), a set of experiments is presented here using the same set-up of a tilted tank attached to a rotating centrifuge with a 2.5 m arm. Within the tank small, almost neutrally buoyant, spheres are released, and their trajectories are recorded. Thus the forces acting on a sphere can be analysed in the case of misalignment between the buoyancy force and the axis of rotation. The angles of descent characterizing the trajectory are compared with inviscid linear theory developed by Stewartson (Q. J. Math. Appl. Mech., vol. 6, 1953, p. 141), and the agreement is found to be good. The angles should be independent of the density anomaly of the spheres compared to their environment. Using the descent velocity from non-rotating experiments, the density of the spheres is estimated and used to determine the drag acting on them in the rotating experiments. It is found that the drag is up to 50% larger than expected from Stewartson's theory. The agreement is best, not for infinitesimal, but for small Rossby numbers. The results are consistent with observations recorded by Maxworthy (J. Fluid Mech., vol. 40, 1970, p. 453)

Intracellular APP Domain Regulates Serine-Palmitoyl-CoA Transferase Expression and Is Affected in Alzheimer's Disease

Lipids play an important role as risk or protective factors in Alzheimer's disease (AD), a disease biochemically characterized by the accumulation of amyloid beta peptides (Aβ), released by proteolytic processing of the amyloid precursor protein (APP). Changes in sphingolipid metabolism have been associated to the development of AD. The key enzyme in sphingolipid de novo synthesis is serine-palmitoyl-CoA transferase (SPT). In the present study we identified a new physiological function of APP in sphingolipid synthesis. The APP intracellular domain (AICD) was found to decrease the expression of the SPT subunit SPTLC2, the catalytic subunit of the SPT heterodimer, resulting in that decreased SPT activity. AICD function was dependent on Fe65 and SPTLC2 levels are increased in APP knock-in mice missing a functional AICD domain. SPTLC2 levels are also increased in familial and sporadic AD postmortem brains, suggesting that SPT is involved in AD pathology

Regulatory feedback cycle of the insulin-degrading enzyme and the amyloid precursor protein intracellular domain: Implications for Alzheimer's disease

One of the major pathological hallmarks of Alzheimer´s disease (AD) is an accumulation of amyloid-β (Aβ) in brain tissue leading to formation of toxic oligomers and senile plaques. Under physiological conditions, a tightly balanced equilibrium between Aβ-production and -degradation is necessary to prevent pathological Aβ-accumulation. Here, we investigate the molecular mechanism how insulin-degrading enzyme (IDE), one of the major Aβ-degrading enzymes, is regulated and how amyloid precursor protein (APP) processing and Aβ-degradation is linked in a regulatory cycle to achieve this balance. In absence of Aβ-production caused by APP or Presenilin deficiency, IDE-mediated Aβ-degradation was decreased, accompanied by a decreased IDE activity, protein level, and expression. Similar results were obtained in cells only expressing a truncated APP, lacking the APP intracellular domain (AICD) suggesting that AICD promotes IDE expression. In return, APP overexpression mediated an increased IDE expression, comparable results were obtained with cells overexpressing C50, a truncated APP representing AICD. Beside these genetic approaches, also AICD peptide incubation and pharmacological inhibition of the γ-secretase preventing AICD production regulated IDE expression and promoter activity. By utilizing CRISPR/Cas9 APP and Presenilin knockout SH-SY5Y cells results were confirmed in a second cell line in addition to mouse embryonic fibroblasts. In vivo, IDE expression was decreased in mouse brains devoid of APP or AICD, which was in line with a significant correlation of APP expression level and IDE expression in human postmortem AD brains. Our results show a tight link between Aβ-production and Aβ-degradation forming a regulatory cycle in which AICD promotes Aβ-degradation via IDE and IDE itself limits its own production by degrading AICD

Improving oceanic overflow representation in climate models : the Gravity Current Entrainment Climate Process Team

Author Posting. © American Meteorological Society, 2009. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Bulletin of the American Meteorological Society 90 (2009): 657-670, doi:10.1175/2008BAMS2667.1.Oceanic overflows are bottom-trapped density currents originating in semienclosed basins, such as the Nordic seas, or on continental shelves, such as the Antarctic shelf. Overflows are the source of most of the abyssal waters, and therefore play an important role in the large-scale ocean circulation, forming a component of the sinking branch of the thermohaline circulation. As they descend the continental slope, overflows mix vigorously with the surrounding oceanic waters, changing their density and transport significantly. These mixing processes occur on spatial scales well below the resolution of ocean climate models, with the result that deep waters and deep western boundary currents are simulated poorly. The Gravity Current Entrainment Climate Process Team was established by the U.S. Climate Variability and Prediction (CLIVAR) Program to accelerate the development and implementation of improved representations of overflows within large-scale climate models, bringing together climate model developers with those conducting observational, numerical, and laboratory process studies of overflows. Here, the organization of the Climate Process Team is described, and a few of the successes and lessons learned during this collaboration are highlighted, with some emphasis on the well-observed Mediterranean overflow. The Climate Process Team has developed several different overflow parameterizations, which are examined in a hierarchy of ocean models, from comparatively well-resolved regional models to the largest-scale global climate models.The Gravity Current Entrainment Climate Process Team was funded by NSF grants OCE-0336850 and OCE-0611572 and NOAA as a contribution to U.S.CLIVAR

The dynamics of rotating two-layer exchange flows : an analytical and numerical modelling study

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The dynamics of rotating two-layer exchange flows : an analytical and numerical modelling study

Two-layer hydraulic exchange flows with zero potential vorticity and zero net flux are modelled analytically for rectangular channels with a constriction, a sill and a combination of the two. Controlled flows are determined for a range of non-dimensional channel widths L, scaled by the Rossby radius, and Bernoulli potentials ΔE; and these are traced along the channels. The interface between the two layers is linear and may separate from either side wall of the channel, all possible flow regimes are considered when tracing the solutions.The flows are traced using a method analogue to the Froude number plane developed by Armi (1986), for channels with L ∝ √D, where D is the non dimensional channel depth. Flow along other geometries is traced using the Gill functional approach (Gill, 1977). Maximal and submaximal flows are derived and discussed for a variety of channel geometries.Analogous to the non-rotating case, most flows through a flat bottom channel are traceable. Flow through a channel with a sill is traceable only for a limited range of Bernoulli potentials, which depend on the width of the channel at the control. It is shown that the virtual control of a maximal flow over a sill does not need to coincide with the entrance of the channel, as has been assumed in most previous studies of hydraulically controlled flows over a sill. The controlled fluxes are derived for a comprehensive range of Bernoulli potentials as well as channel widths L. A method for determining the long wave-speeds in the channel is outlined.In the second part of this thesis two-layer exchange flows are modelled numerically using MICOM (Miami Isopycnic Coordinate Ocean Model) in an idealised set up with two rectangular basins separated by a rectangular channel with a sill. A comprehensive set of 71 experiments is run varying the rotation rate f, the density difference between the two layers Δρ, and the interface level in the dense reservoir, ΔH.The flow features in the top and bottom layer are described for two experiments and compared to the theoretical results in the thesis, as well as observations and laboratory experiments. The typical 'crossing-over' of the bottom layer at the top of the sill is found and a boundary current forms on the left-hand side looking upstream. The majority of the transport in the top layer is confined to a boundary current on the left-hand side of the channel, a feature that has never been described before, but which is also predicted by the theory. It is shown that all flows exhibit inherent time variability, which is disregarded in the steady hydraulic theory.The flux results confirm that as rotation and therefore L, increases the non-dimensional flux reaches a maximum, and so rotation imposes an upper limit on the flow. An empirical parameterisation for two-layer exchange flows is derived using the MICOM results. The transport across the sill is found to depend on ΔH.3/2 a result expected for non-rotating flows, but that does not derive from the scaling of the rotating theory.Idealised models of the Faroe-Bank-Channel and the Denmark Strait are run and transport results are compared to observations in these straits. The Denmark Strait is only poorly modelled by a two-layer exchange while agreements for the Faroe-Bank-Channel is somewhat better.</p

Metformin inhibits proliferation and migration of glioblastoma cells independently of TGF-β2

<p>To this day, glioblastoma (GBM) remains an incurable brain tumor. Previous research has shown that metformin, an oral anti-diabetic drug, may decrease GBM cell proliferation and migration especially in brain tumor initiating cells (BTICs). As transforming growth factor β 2 (TGF-β₂) has been reported to promote high-grade glioma and is inhibited by metformin in other tumors, we explored whether metformin directly interferes with TGF-β₂-signaling. Functional investigation of proliferation and migration of primary BTICs after treatment with metformin+/−TGF-β₂ revealed that metformin doses as low as 0.01 mM metformin thrice a day were able to inhibit proliferation of susceptible cell lines, whereas migration was impacted only at higher doses. Known cellular mechanisms of metformin, such as increased lactate secretion, reduced oxygen consumption and activated AMPK-signaling, could be confirmed. However, TGF-β₂ and metformin did not act as functional antagonists, but both rather inhibited proliferation and/or migration, if significant effects were present. We did not observe a relevant influence of metformin on TGF-β₂ mRNA expression (qRT-PCR), TGF-β₂ protein expression (ELISA) or SMAD-signaling (Western blot). Therefore, it seems that metformin does not exert its inhibitory effects on GBM BTIC proliferation and migration by altering TGF-β₂-signaling. Nonetheless, as low doses of metformin are able to reduce proliferation of certain GBM cells, further exploration of predictors of BTICs' susceptibility to metformin appears justified.</p