Three-dimensional steep wave impact on a vertical cylinder

In the present study we investigate the 3-D hydrodynamic slamming problem on a vertical cylinder due to the impact of a steep wave that is moving with a steady velocity. The linear theory of the velocity potential is employed by assuming inviscid, incompressible fluid and irrotational flow. As the problem is set in 3-D space, the employment of the Wagner condition is essential. The set of equations we pose, is presented as a mixed boundary value problem for Laplace's equation in 3-D. Apart from the mixed-type of boundary conditions, the problem is complicated by considering that the region of wetted surface of the cylinder is a set whose boundary depends on the vertical coordinate on the cylinder up to the free-surface. We make some simple assumptions at the start but otherwise we proceed analytically. We find closed-form relations for the hydrodynamic variables, namely the time dependent potential, the pressure impulse, the shape of the wave front (from the contact point to beyond the cylinder) and the slamming force

The role of the meningeal lymphatic system in local meningeal inflammation and trigeminal nociception

A system of lymphatic vessels has been recently characterized in the meninges, with a postulated role in 'cleaning' the brain via cerebral fluid drainage. As meninges are the origin site of migraine pain, we hypothesized that malfunctioning of the lymphatic system should affect the local trigeminal nociception. To test this hypothesis, we studied nociceptive and inflammatory mechanisms in the hemiskull preparations (containing the meninges) of K14-VEGFR3-Ig (K14) mice lacking the meningeal lymphatic system. We recorded the spiking activity of meningeal afferents and estimated the local mast cells population, calcitonin gene-related peptide (CGRP) and cytokine levels as well as the dural trigeminal innervation in freshly-isolated hemiskull preparations from K14-VEGFR3-Ig (K14) or wild type C57BL/6 mice (WT). Spiking activity data have been confirmed in an acquired model of meningeal lymphatic dysfunction (AAV-mVEGFR3(1-4)Ig induced lymphatic ablation). We found that levels of the pro-inflammatory cytokine IL12-p70 and CGRP, implicated in migraine, were reduced in the meninges of K14 mice, while the levels of the mast cell activator MCP-1 were increased. The other migraine-related pro-inflammatory cytokines (basal and stimulated), did not differ between the two genotypes. The patterns of trigeminal innervation in meninges remained unchanged and we did not observe alterations in basal or ATP-induced nociceptive firing in the meningeal afferents associated with meningeal lymphatic dysfunction. In summary, the lack of meningeal lymphatic system is associated with a new balance between pro- and anti-migraine mediators but does not directly trigger meningeal nociceptive state.Peer reviewe

Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors

Purpose: Sphingosine kinase 1 (SK1) is a protooncogenic enzyme expressed in many human tumours and is associated with chemoresistance and poor prognosis. It is a potent therapy target and its inhibition chemosensitises solid tumours. Despite recent advances in SK1 inhibitors synthesis and validation, their clinical safety and chemosensitising options are not well described. In this study, we have designed, synthesised and tested a new specific SK1 inhibitor with a low toxicity profile. Methods: Field template molecular modelling was used for compound design. Lead compounds were tested in cell and mouse cancer models. Results: Field template analysis of three known SK1 inhibitors, SKI-178, 12aa and SK1-I, was performed and compound screening identified six potential new SK1 inhibitors. SK1 activity assays in both cell-free and in vitro settings showed that two compounds were effective SK1 inhibitors. Compound SK-F has potently decreased cancer cell viability in vitro and sensitised mouse breast tumours to docetaxel (DTX) in vivo, without significant whole-body toxicity. Conclusion: Through field template screening, we have identified a new SK1 inhibitor, SK-F, which demonstrated antitumour activity in vitro and in vivo without overt toxicity when combined with DTX

Overexpression of sphingosine kinase 1 is associated with salivary gland carcinoma progression and might be a novel predictive marker for adjuvant therapy

<p>Abstract</p> <p>Background</p> <p>Overexpression of sphingosine kinase-1 (SPHK1) has been demonstrated to be associated with the development and progression in various types of human cancers. The current study was to characterize the expression of SPHK1 in salivary gland carcinomas (SGC) and to investigate the association between SPHK1 expression and progression of SGC.</p> <p>Methods</p> <p>The expression of SPHK1 was examined in 2 normal salivary gland tissues, 8 SGC tissues of various clinical stages, and 5 pairs of primary SGC and adjacent salivary gland tissues from the same patient, using real-time PCR and western blot analysis. Furthermore, the SPHK1 protein expression was analyzed in 159 clinicopathologically characterized SGC cases by immunohistochemistry. Statistical analyses were performed to determine the prognostic and diagnostic associations.</p> <p>Results</p> <p>SPHK1 expression was found to be markedly upregulated in SGC tissues than that in the normal salivary gland tissues and paired adjacent salivary gland tissues, at both mRNA and protein levels. Statistical analysis revealed a significant correlation of SPHK1 expression with the clinical stage (<it>P </it>= 0.005), T classification (<it>P </it>= 0.017), N classification (<it>P </it>= 0.009), M classification (<it>P </it>= 0.002), and pathological differentiation (<it>P </it>= 0.013). Patients with higher SPHK1 expression had shorter overall survival time, whereas patients with lower SPHK1 expression had better survival. Importantly, patients in the group without adjuvant therapy who exhibited high SPHK1 expression had significantly lower overall survival rates compared with those with low SPHK1 expression. Moreover, multivariate analysis suggested that SPHK1 expression might be an independent prognostic indicator for the survival of SGC patients.</p> <p>Conclusions</p> <p>Our results suggest that SPHK1 expression is associated with SGC progression, and might represent as a novel and valuable predictor for adjuvant therapy to SGC patients.</p

A rotating annulus driven by localized convective forcing: a new atmosphere-like experiment

We present an experimental study of flows in a cylindrical rotating annulus convectively forced by local heating in an annular ring at the bottom near the external wall and via a cooled circular disk near the axis at the top surface of the annulus. This new configuration is distinct from the classical thermally-driven annulus analogue of the atmosphere circulation, in which thermal forcing is applied uniformly on the sidewalls, but with a similar aim to investigate the baroclinic instability of a rotating, stratified flow subject to zonally symmetric forcing. Two vertically and horizontally displaced heat sources/sinks are arranged so that, in the absence of background rotation, statically unstable Rayleigh-Bénard convection would be induced above the source and beneath the sink, thereby relaxing strong constraints placed on background temperature gradients in previous experimental configurations based on the conventional rotating annulus. This better emulates local vigorous convection in the tropics and polar regions of the atmosphere whilst also allowing stably-stratified baroclinic motion in the central zone of the annulus, as in midlatitude regions in the Earth’s atmosphere. Regimes of flow are identified, depending mainly upon control parameters that in turn depend on rotation rate and the strength of differential heating. Several regimes exhibit baroclinically unstable flows which are qualitatively similar to those previously observed in the classical thermally-driven annulus, However, in contrast to the classical configuration, they typically exhibit more spatiotemporal complexity. Thus, several regimes of flow demonstrate the equilibrated co-existence of, and interaction between, free convection and baroclinic wave modes. These new features were not previously observed in the classical annulus and validate the new setup as a tool for exploring fundamental atmosphere-like dynamics in a more realistic framework. Thermal structure in the fluid is investigated and found to be qualitatively consistent with previous numerical results, with nearly isothermal conditions respectively above and below the heat source and sink, and stably-stratified, sloping isotherms in the near-adiabatic interior

A rotating annulus driven by localized convective forcing: a new atmosphere-like experiment

We present an experimental study of flows in a cylindrical rotating annulus convectively forced by local heating in an annular ring at the bottom near the external wall and via a cooled circular disk near the axis at the top surface of the annulus. This new configuration is distinct from the classical thermally-driven annulus analogue of the atmosphere circulation, in which thermal forcing is applied uniformly on the sidewalls, but with a similar aim to investigate the baroclinic instability of a rotating, stratified flow subject to zonally symmetric forcing. Two vertically and horizontally displaced heat sources/sinks are arranged so that, in the absence of background rotation, statically unstable Rayleigh-Bénard convection would be induced above the source and beneath the sink, thereby relaxing strong constraints placed on background temperature gradients in previous experimental configurations based on the conventional rotating annulus. This better emulates local vigorous convection in the tropics and polar regions of the atmosphere whilst also allowing stably-stratified baroclinic motion in the central zone of the annulus, as in midlatitude regions in the Earth’s atmosphere. Regimes of flow are identified, depending mainly upon control parameters that in turn depend on rotation rate and the strength of differential heating. Several regimes exhibit baroclinically unstable flows which are qualitatively similar to those previously observed in the classical thermally-driven annulus, However, in contrast to the classical configuration, they typically exhibit more spatiotemporal complexity. Thus, several regimes of flow demonstrate the equilibrated co-existence of, and interaction between, free convection and baroclinic wave modes. These new features were not previously observed in the classical annulus and validate the new setup as a tool for exploring fundamental atmosphere-like dynamics in a more realistic framework. Thermal structure in the fluid is investigated and found to be qualitatively consistent with previous numerical results, with nearly isothermal conditions respectively above and below the heat source and sink, and stably-stratified, sloping isotherms in the near-adiabatic interior

A rotating annulus driven by localized convective forcing: a new atmosphere-like experiment

We present an experimental study of flows in a cylindrical rotating annulus convectively forced by local heating in an annular ring at the bottom near the external wall and via a cooled circular disk near the axis at the top surface of the annulus. This new configuration is distinct from the classical thermally-driven annulus analogue of the atmosphere circulation, in which thermal forcing is applied uniformly on the sidewalls, but with a similar aim to investigate the baroclinic instability of a rotating, stratified flow subject to zonally symmetric forcing. Two vertically and horizontally displaced heat sources/sinks are arranged so that, in the absence of background rotation, statically unstable Rayleigh-Bénard convection would be induced above the source and beneath the sink, thereby relaxing strong constraints placed on background temperature gradients in previous experimental configurations based on the conventional rotating annulus. This better emulates local vigorous convection in the tropics and polar regions of the atmosphere whilst also allowing stably-stratified baroclinic motion in the central zone of the annulus, as in midlatitude regions in the Earth’s atmosphere. Regimes of flow are identified, depending mainly upon control parameters that in turn depend on rotation rate and the strength of differential heating. Several regimes exhibit baroclinically unstable flows which are qualitatively similar to those previously observed in the classical thermally-driven annulus, However, in contrast to the classical configuration, they typically exhibit more spatiotemporal complexity. Thus, several regimes of flow demonstrate the equilibrated co-existence of, and interaction between, free convection and baroclinic wave modes. These new features were not previously observed in the classical annulus and validate the new setup as a tool for exploring fundamental atmosphere-like dynamics in a more realistic framework. Thermal structure in the fluid is investigated and found to be qualitatively consistent with previous numerical results, with nearly isothermal conditions respectively above and below the heat source and sink, and stably-stratified, sloping isotherms in the near-adiabatic interior

Flow-destabilized seiches in a reservoir with a movable dam

Using a combination of theoretical modelling and experiments, seiches in a reservoir are shown to become linearly unstable due to the coupling with flow under a dam that opens and closes in response to the upstream water pressure. The phenomenon is related to the mechanism commonly attributed to generate sound in musical instruments like the clarinet. Shallow water theory is used to model waves in the reservoir, and these are coupled, by an outflow condition, to a nonlinear oscillator equation for the dam opening. In general, several modes of oscillation are predicted to be unstable, and the frequency of the most unstable mode compares well with the dominant frequencies observed in the experiments. The experiments also show a systematic variation of the amplitude and spatial structure of the oscillations with the weight of the dam, reflecting the nonlinear coupling between the unstable modes of the system. © 2011 Cambridge University Press