420 research outputs found

    Online pricing for demand‐side management in a low‐voltage resistive micro‐grid via a Stackelberg game with incentive strategies

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    It has been demonstrated that online pricing mechanisms are a viable solution for demand side management in power systems. This study deals with the analysis and design of a droop-controlled low-voltage resistive AC micro-grid network system. Such a system is subjected to a dynamic demand obtained from an online pricing mechanism, which is proposed as a novelty in the study of micro-grids. This mechanism is derived from a variation of the Stackelberg game, which includes the use of incentive strategies. First, a configuration in which a supplier announces an incentive function and (Formula presented.) -consumers’ reaction to the resulting personalised price is presented. Then, a detailed stability analysis of the micro-grid is presented as a result of the interaction with the aforementioned online pricing mechanism. The units of the micro-grid (generators as the supplier and loads as the consumers) operate under either conventional or bounded droop control. The novelty of the approach is that it bridges the gap between the physical and the market layers of the problem. The ways in which the existence of multiple equilibrium points is guaranteed for both the consumer's load and the supplier's announced incentive are shown. A detailed design process for the profit functions of the players is shown in conjunction with the parameter selection for their implementation. Finally, simulations that demonstrate the system stability and its convergence to different equilibria are implemented under scenarios with one and multiple consumers

    Regulation of MT1-MMP Activity through Its Association with ERMs

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    Membrane-bound proteases play a key role in biology by degrading matrix proteins or shedding adhesion receptors. MT1-MMP metalloproteinase is critical during cancer invasion, angiogenesis, and development. MT1-MMP activity is strictly regulated by internalization, recycling, autoprocessing but also through its incorporation into tetraspanin-enriched microdomains (TEMs), into invadopodia, or by its secretion on extracellular vesicles (EVs). We identified a juxtamembrane positively charged cluster responsible for the interaction of MT1-MMP with ERM (ezrin/radixin/moesin) cytoskeletal connectors in breast carcinoma cells. Linkage to ERMs regulates MT1-MMP subcellular distribution and internalization, but not its incorporation into extracellular vesicles. MT1-MMP association to ERMs and insertion into TEMs are independent phenomena, so that mutation of the ERM-binding motif in the cytoplasmic region of MT1-MMP does not preclude its association with the tetraspanin CD151, but impairs the accumulation and coalescence of CD151/MT1-MMP complexes at actin-rich structures. Conversely, gene deletion of CD151 does not impact on MT1-MMP colocalization with ERM molecules. At the plasma membrane MT1-MMP autoprocessing is severely dependent on ERM association and seems to be the dominant regulator of the enzyme collagenolytic activity. This newly characterized MT1-MMP/ERM association can thus be of relevance for tumor cell invasion.This work has been supported by grants BFU2014-55478-R, REDIEX. SAF2015-71231-REDT and BIO2017-86500-R from Ministerio Español de Economía y Competitividad (MINECO) and by a grant from Fundación Ramón Areces “Ayudas a la Investigación en Ciencias de la Vida y de la Materia, 2014” to M.Y.-M. H.S. was supported by a FPI-UAM fellowship. The CNIC is supported by the Ministry of Ciencia, Innovacion y Universidades and the Pro CNIC Foundation, is a Severo Ochoa Center of Excellence (SEV-2015-0505), also supported by European Regional Development Fund (FEDER) “Una manera de hacer Europa”.S

    Mass Spectrometry of RNA-Binding Proteins during Liquid-Liquid Phase Separation Reveals Distinct Assembly Mechanisms and Droplet Architectures

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    Liquid-liquid phase separation (LLPS) of hetero-geneous ribonucleoproteins (hnRNPs) drives the formation of membraneless organelles, but structural information about their assembled states is still lacking. Here, we address this challenge through a combination of protein engineering, native ion mobility mass spectrometry, and molecular dynamics simulations. We used an LLPS-compatible spider silk domain and pH changes to control the self-assembly of the hnRNPs FUS, TDP-43, and hCPEB3, which are implicated in neurodegeneration, cancer, and memory storage. By releasing the proteins inside the mass spectrometer from their native assemblies, we could monitor conformational changes associated with liquid-liquid phase separation. We find that FUS monomers undergo an unfolded-to-globular transition, whereas TDP-43 oligomerizes into partially disordered dimers and trimers. hCPEB3, on the other hand, remains fully disordered with a preference for fibrillar aggregation over LLPS. The divergent assembly mechanisms revealed by ion mobility mass spectrometry of soluble protein species that exist under LLPS conditions suggest structurally distinct complexes inside liquid droplets that may impact RNA processing and translation depending on biological context

    IFNβ Protects Neurons from Damage in a Murine Model of HIV-1 Associated Brain Injury.

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    Infection with human immunodeficiency virus-1 (HIV-1) causes brain injury. Type I interferons (IFNα/β) are critical mediators of any anti-viral immune response and IFNβ has been implicated in the temporary control of lentiviral infection in the brain. Here we show that transgenic mice expressing HIV-1 envelope glycoprotein 120 in their central nervous system (HIVgp120tg) mount a transient IFNβ response and provide evidence that IFNβ confers neuronal protection against HIVgp120 toxicity. In cerebrocortical cell cultures, neuroprotection by IFNβ against gp120 toxicity is dependent on IFNα receptor 1 (IFNAR1) and the β-chemokine CCL4, as IFNAR1 deficiency and neutralizing antibodies against CCL4, respectively, abolish the neuroprotective effects. We find in vivo that IFNβ mRNA is significantly increased in HIVgp120tg brains at 1.5, but not 3 or 6 months of age. However, a four-week intranasal IFNβ treatment of HIVgp120tg mice starting at 3.5 months of age increases expression of CCL4 and concomitantly protects neuronal dendrites and pre-synaptic terminals in cortex and hippocampus from gp120-induced damage. Moreover, in vivo and in vitro data suggests astrocytes are a major source of IFNβ-induced CCL4. Altogether, our results suggest exogenous IFNβ as a neuroprotective factor that has potential to ameliorate in vivo HIVgp120-induced brain injury

    The PCSK9-LDL Receptor Axis and Outcomes in Heart Failure:BIOSTAT-CHF Subanalysis

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    Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds low-density lipoprotein receptor (LDLR), preventing its recycling. PCSK9 is a risk predictor and a biotarget in atherosclerosis progression. Objectives: The aim of this study was to determine whether the PCSK9-LDLR axis could predict risk in patients with heart failure (HF). Methods: The BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) is a multicenter, multinational, prospective, observational study that included patients with worsening HF signs and/or symptoms. The primary endpoints were all-cause mortality and the composite of mortality or unscheduled hospitalizations for HF. We implemented Cox proportional hazard regression to determine the simultaneously adjusted effect of PCSK9 and LDLR on both outcomes when added to the previously validated BIOSTAT-CHF risk scores. Results: This study included 2,174 patients (mean age: 68 ± 12 years; 53.2% had a history of ischemic heart disease). Median (interquartile range) PCSK9 and LDLR levels were 1.81 U/ml (1.45 to 2.18) and 2.98 U/ml (2.45 to 3.53), respectively. During follow-up, 569 deaths (26.2%) and 896 (41.2%) composite endpoints were ascertained. A multivariable analysis, which included BIOSTAT-CHF risk scores, LDLR, and statin treatment as covariates, revealed a positive linear association between PCSK9 levels and the risk of mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.04 to 1.49; p = 0.020) and the composite endpoint (HR: 1.21; 95% CI: 1.05 to 1.40; p = 0.010). A similar analysis for LDLR revealed a negative association with mortality (HR: 0.86; 95% CI: 0.76 to 0.98; p = 0.025) and the composite endpoint (HR: 0.92; 95% CI: 0.83 to 1.01; p = 0.087). Including PCSK9 and LDLR improved risk score performance. Conclusions: The PCSK9-LDLR axis was associated with outcomes in patients with HF. Future studies must assess whether PCSK9 inhibition will result in better outcomes in HF

    Pretreatment with corticosteroids attenuates the efficacy of colchicine in preventing recurrent pericarditis: A multi-centre all-case analysis

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    Aims Effective prevention of recurrent pericarditis remains an important yet elusive goal. Corticosteroid therapy often needs to be continued for a prolonged period and causes severe side effects. We performed a multi-centre all-case analysis to investigate the efficacy of colchicine in preventing subsequent relapses of pericarditis, and addressed the hypothesis that pretreatment with corticosteroids may attenuate the beneficial effect of colchicine. Methods and results One hundred and forty published and unpublished cases of patients treated with colchicine after at least two relapses of pericarditis were aggregated from European centres. Of those 119 were included in the study group. Only 18% of the patients had relapses under colchicine therapy, and 30% after its discontinuation. There were significantly more relapses among mate patients after colchicine treatment (36 vs. 17%, P = 0.046), and those with previous corticosteroid treatment (43 vs. 13%, P = 0.02). Multivariate logistic regression analysis identified previous corticosteroid therapy (OR 6.68, 95% Cl: 1.65-27.02) and mate gender (OR 4.20, 95% Cl: 1.16-15.21) as independent risk factors for recurrence following colchicine therapy. Conclusion Treatment with colchicine is highly effective in preventing recurrent pericarditis, white pretreatment with corticosteroids exacerbates and extends the course of recurrent pericarditis

    Particle size and cholesterol content of circulating HDL correlate with cardiovascular death in chronic heart failure

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    Altres ajuts: Fundació la Marató de TV3: 201602-30-31; 201502Evidence regarding any association of HDL-particle (HDL-P) derangements and HDL-cholesterol content with cardiovascular (CV) death in chronic heart failure (HF) is lacking. To investigate the prognostic value of HDL-P size (HDL-Sz) and the number of cholesterol molecules per HDL-P for CV death in HF patients. Outpatient chronic HF patients were enrolled. Baseline HDL-P number, subfractions and HDL-Sz were measured using 1H-NMR spectroscopy. The HDL-C/P ratio was calculated as HDL-cholesterol over HDL-P. Endpoint was CV death, with non-CV death as the competing event. 422 patients were included and followed-up during a median of 4.1 (0-8) years. CV death occurred in 120 (30.5%) patients. Mean HDL-Sz was higher in CV dead as compared with survivors (8.39 nm vs. 8.31 nm, p < 0.001). This change in size was due to a reduction in the percentage of small HDL-P (54.6% vs. 60% for CV-death vs. alive; p < 0.001). HDL-C/P ratio was higher in the CV-death group (51.0 vs. 48.3, p < 0.001). HDL-Sz and HDL-C/P ratio were significantly associated with CV death after multivariable regression analysis (HR 1.22 [95% CI 1.01-1.47], p = 0.041 and HR 1.04 [95% CI 1.01-1.07], p = 0.008 respectively). HDL-Sz and HDL-C/P ratio are independent predictors of CV death in chronic HF patients
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