28 research outputs found
DEM element modelling of silent piling group installation for offshore wind turbine foundations
Offshore wind farms are now built in deeper water and bigger foundations are required to stabilise wind turbines of increasing sizes. Pile driving is the most widespread foundation installation method, but more stringent environmental regulations necessitate costly mitigation methods to reduce underwater noise emissions. The silent piling (push-in) concept presented in this work is composed of a cluster of four piles, progressively installed by successive jacking sequences. During one sequence, each pile is moved downward by 0.5m stroke, while the other piles are used as reaction. This paper presents the results of Discrete Element Method (DEM) of the installation process. This work identifies the main features of the push-in installation method, such as pile interaction, progressive plugging and loss of efficiency as a function of depth. It is shown that the cluster capacity can reach six times the weight of the tool necessary to silently install the piles
Silent piling for offshore jacket foundations in sand:DEM and centrifuge modelling
The race to decarbonise the economy has led to an exponential growth of offshore wind farm developments across the globe. While monopiles are the dominating installed foundations, jacket structures are expected to be more and more common, as wind farms extend to deeper waters [1] and innovative technologies are required to alleviate some important challenges. Firstly, straight shafted piles are not particularly efficient to sustain large tensile demand induced by the push-pull axial loading of the foundations. Secondly, stricter regulations on underwater noise make mitigation methods for pile driving more expensive and silent piling tech-niques could be used as an alternative [2]. Figure 1(a) describes a new screw pile foundation that meets those two challenges [3]. The foundation is installed by rotary jacking, which avoids any impact related noise. The pile is composed of a large upper shaft, that is designed to resist the lateral load applied by the jacket structure, and a smaller lower shaft which reduces the torque demand during installation. A helix is attached close to the pile tip, to provide an enhanced axial resistance and facilitates the installation of the pile [4]. The main challenge during the pile installation is the very low reaction force that may be available offshore at the pile head, which consists only of the pile self-weight and the installation tool. The aim of this work is to demonstrate that screw piles can be installed for offshore applications by rotary jacking at low reaction force, via (geotechnical centrifuge, [2]) and numerical (DEM, [5]) modellin
RIPK3-Dependent Recruitment of Low-Inflammatory Myeloid Cells Does Not Protect from Systemic Salmonella Infection
ABSTRACT Regulated macrophage death has emerged as an important mechanism to defend against intracellular pathogens. However, the importance and consequences of macrophage death during bacterial infection are poorly resolved. This is especially true for the recently described RIPK3-dependent lytic cell death, termed necroptosis. Salmonella enterica serovar Typhimurium is an intracellular pathogen that precisely regulates virulence expression within macrophages to evade and manipulate immune responses, which is a key factor in its ability to cause severe systemic infections. We combined genetic and pharmacological approaches to examine the importance of RIPK3 for S. Typhimurium-induced macrophage death using conditions that recapitulate bacterial gene expression during systemic infection in vivo. Our findings indicate that noninvasive S. Typhimurium does not naturally induce macrophage necroptosis but does so in the presence of pan-caspase inhibition. Moreover, our data suggest that RIPK3 induction (following caspase inhibition) does not impact host survival following S. Typhimurium infection, which differs from previous findings based on inert lipopolysaccharide (LPS) injections. Finally, although necroptosis is typically characterized as highly inflammatory, our data suggest that RIPK3 skews the peritoneal myeloid population away from an inflammatory profile to that of a classically noninflammatory profile. Collectively, these data improve our understanding of S. Typhimurium-macrophage interactions, highlight the possibility that purified bacterial components may not accurately recapitulate the complexity of host-pathogen interactions, and reveal a potential and unexpected role for RIPK3 in resolving inflammation. IMPORTANCE Macrophages employ multiple strategies to limit pathogen infection. For example, macrophages may undergo regulated cell death, including RIPK3-dependent necroptosis, as a means of combatting intracellular bacterial pathogens. However, bacteria have evolved mechanisms to evade or exploit immune responses. Salmonella is an intracellular pathogen that avoids and manipulates immune detection within macrophages. We examined the contribution of RIPK3 to Salmonella-induced macrophage death. Our findings indicate that noninvasive Salmonella does not naturally induce necroptosis, but it does so when caspases are inhibited. Moreover, RIPK3 induction (following caspase inhibition) does not impact host survival following Salmonella systemic infection. Finally, our data show that RIPK3 induction results in recruitment of low-inflammatory myeloid cells, which was unexpected, as necroptosis is typically described as highly inflammatory. Collectively, these data improve our understanding of pathogen-macrophage interactions, including outcomes of regulated cell death during infection in vivo, and reveal a potential new role for RIPK3 in resolving inflammation
The SCN8A encephalopathy mutation p.Ile1327Val displays elevated sensitivity to the anticonvulsant phenytoin
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134291/1/epi13461_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134291/2/epi13461.pd
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CACHD1 is an α2Ύ-like protein that modulates CaV3 voltage-gated calcium channel activity
The putative cache (Ca2+ channel and chemotaxis receptor) domain containing 1 (CACHD1) protein has predicted structural similarities to members of the alpha2delta voltage-gated Ca2+ channel (VGCC) auxiliary subunit family. CACHD1 mRNA and protein were highly expressed in the male mammalian CNS, in particular in the thalamus, hippocampus and cerebellum, with a broadly similar tissue distribution to CaV3 subunits, in particular, CaV3.1. In expression studies, CACHD1 increased cell-surface localization of CaV3.1 and these proteins were in close proximity at the cell surface consistent with the formation of CACHD1-CaV3.1 complexes. In functional electrophysiological studies, co-expression of human CACHD1 with CaV3.1, CaV3.2 and CaV3.3 caused a significant increase in peak current density and corresponding increases in maximal conductance. By contrast, alpha2delta-1 had no effect on peak current density or maximal conductance in either CaV3.1, CaV3.2 or CaV3.3. Comparison of CACHD1-mediated increases in CaV3.1 current density and gating currents revealed an increase in channel open probability. In hippocampal neurons from male and female E19 rats, CACHD1 overexpression increased CaV3-mediated action potential (AP) firing frequency and neuronal excitability. These data suggest that CACHD1 is structurally an alpha2delta-like protein that functionally modulates CaV3 voltage-gated calcium channel activity
Progetto del museo e riqualificazione urbana. Studi per un Museo del Mobile e dell'Arredamento a CantĂč.
Riflessione critica sul significato e il ruolo urbano del museo contemporaneo. Indagando la tradizione canturina dell'arredo di qualitĂ , gli autori riconoscono nel Museo un dispoisitivo funzionale a un nuovo sviluppo dell'artigianato mobiliero e della cultura degli interni abitati. Sono anche illustrati i progetti per un Museo del Mobile e dell'Arredamento a CantĂč elaborati alla FacoltĂ di Architettura Civile del Politecnico di Milano
Activation of pyramidal neurons in mouse medial prefrontal cortex enhances food seeking behavior while reducing impulsivity in the absence of an effect on food intake
The medial prefrontal cortex (mPFC) is involved in a wide range of executive cognitive functions, including reward evaluation, decision-making, memory extinction, mood, and task switching. Manipulation of the mPFC has been shown to alter food intake and food reward valuation, but whether exclusive stimulation of mPFC pyramidal neurons, which form the principle output of the mPFC, is sufficient to mediate food rewarded instrumental behavior is unknown. We sought to determine the behavioral consequences of manipulating mPFC output by exciting pyramidal neurons in mouse mPFC during performance of a panel of behavioral assays, focusing on food reward. We found that increasing mPFC pyramidal cell output using Designer Receptors Exclusively Activated by Designer Drugs (DREADD) enhanced performance in instrumental food reward assays that assess food seeking behavior, while sparing effects in affect and food intake. Specifically, activation of mPFC pyramidal neurons enhanced operant responding for food reward, reinstatement of palatable food seeking, and suppression of impulsive responding for food reward. Conversely, activation of mPFC pyramidal neurons had no effect on unconditioned food intake, social interaction, or behavior in an open field. Furthermore, we found that behavioral outcome is influenced by the degree of mPFC activation, with a low drive sufficient to enhance operant responding and a higher drive required to alter impulsivity. Additionally, we provide data demonstrating that DREADD stimulation involves a nitric oxide synthase dependent pathway, similar to endogenous muscarinic M3 receptor stimulation, a finding that provides novel mechanistic insight into an increasingly widespread method of remote neuronal control
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Caveolar peroxynitrite formation impairs endothelial TRPV4 channels and elevates pulmonary arterial pressure in pulmonary hypertension
Recent studies have focused on the contribution of capillary endothelial TRPV4 channels to pulmonary pathologies, including lung edema and lung injury. However, in pulmonary hypertension (PH), small pulmonary arteries are the focus of the pathology, and endothelial TRPV4 channels in this crucial anatomy remain unexplored in PH. Here, we provide evidence that TRPV4 channels in endothelial cell caveolae maintain a low pulmonary arterial pressure under normal conditions. Moreover, the activity of caveolar TRPV4 channels is impaired in pulmonary arteries from mouse models of PH and PH patients. In PH, up-regulation of iNOS and NOX1 enzymes at endothelial cell caveolae results in the formation of the oxidant molecule peroxynitrite. Peroxynitrite, in turn, targets the structural protein caveolin-1 to reduce the activity of TRPV4 channels. These results suggest that endothelial caveolin-1-TRPV4 channel signaling lowers pulmonary arterial pressure, and impairment of endothelial caveolin-1-TRPV4 channel signaling contributes to elevated pulmonary arterial pressure in PH. Thus, inhibiting NOX1 or iNOS activity, or lowering endothelial peroxynitrite levels, may represent strategies for restoring vasodilation and pulmonary arterial pressure in PH