Attenuation of monocyte chemotaxis--a novel anti-inflammatory mechanism of action for the cardio-protective hormone B-type natriuretic peptide

B-type natriuretic peptide (BNP) is a prognostic and diagnostic marker for heart failure (HF). An anti-inflammatory, cardio-protective role for BNP was proposed. In cardiovascular diseases including pressure overload-induced HF, perivascular inflammation and cardiac fibrosis are, in part, mediated by monocyte chemoattractant protein (MCP)1-driven monocyte migration. We aimed to determine the role of BNP in monocyte motility to MCP1. A functional BNP receptor, natriuretic peptide receptor-A (NPRA) was identified in human monocytes. BNP treatment inhibited MCP1-induced THP1 (monocytic leukemia cells) and primary monocyte chemotaxis (70 and 50 %, respectively). BNP did not interfere with MCP1 receptor expression or with calcium. BNP inhibited activation of the cytoskeletal protein RhoA in MCP1-stimulated THP1 (70 %). Finally, BNP failed to inhibit MCP1-directed motility of monocytes from patients with hypertension (n = 10) and HF (n = 6) suggesting attenuation of this anti-inflammatory mechanism in chronic heart disease. We provide novel evidence for a direct role of BNP/NPRA in opposing human monocyte migration and support a role for BNP as a cardio-protective hormone up-regulated as part of an adaptive compensatory response to combat excess inflammation.

Long-term statin therapy in patients with systolic heart failure and normal cholesterol:effects on elevated serum markers of collagen turnover, inflammation, and B-type natriuretic peptide

BACKGROUND: The role of statin therapy in heart failure (HF) is unclear. The amino-terminal propeptide of procollagen type III (PIIINP) predicts outcome in HF, and yet there are conflicting reports of statin therapy effects on PIIINP.

OBJECTIVES: This study determined whether there was an increase in serum markers of inflammation, fibrosis (including PIIINP), and B-type natriuretic peptide (BNP) in patients with systolic HF and normal total cholesterol and determined the effects of long-term treatment with atorvastatin on these markers.

METHODS: Fifty-six white patients with systolic HF and normal cholesterol levels (age 72 [13] years; 68% male; body mass index 27.0 [7.3] kg/m(2); ejection fraction 35 [13]%; 46% with history of smoking) were randomly allocated to atorvastatin treatment for 6 months, titrated to 40 mg/d (A group) or not (C group). Age- and/or sex-matched subjects without HF (N group) were also recruited. Biomarkers were measured at baseline (all groups) and 6 months (A and C groups).

RESULTS: Serum markers of collagen turnover, inflammation, and BNP were significantly elevated in HF patients compared with normal participants (all P < 0.05). There were correlations between these markers in HF patients but not in normal subjects. Atorvastatin treatment for 6 months caused a significant reduction in the following biomarkers compared with baseline: BNP, from median (interquartile range) 268 (190-441) pg/mL to 185 (144-344) pg/mL; high-sensitivity C-reactive protein (hs-CRP), from 5.26 (1.95 -9.29) mg/L to 3.70 (2.34-6.81) mg/L; and PIIINP, from 4.65 (1.86) to 4.09 (1.25) pg/mL (all P < 0.05 baseline vs 6 months). Between-group differences were significant for PIIINP only (P = 0.027). There was a positive interaction between atorvastatin effects and baseline hs-CRP and PIIINP (P < 0.01).

CONCLUSIONS: Long-term statin therapy reduced PIIINP in this small, selected HF population with elevated baseline levels. Further evaluation of statin therapy in the management of HF patients with elevated PIIINP is warranted.

Modeling, Analysis and Performance Comparison of Two Direct Sampling DCSK Receivers under Frequency Nonselective Fading Channels

Two direct sampling correlator-type receivers for differential chaos shift keying (DCSK) communication systems under frequency non-selective fading channels are proposed. These receivers operate based on the same hardware platform with different architectures. In the first scheme, namely sum-delay-sum (SDS) receiver, the sum of all samples in a chip period is correlated with its delayed version. The correlation value obtained in each bit period is then compared with a fixed threshold to decide the binary value of recovered bit at the output. On the other hand, the second scheme, namely delay-sum-sum (DSS) receiver, calculates the correlation value of all samples with its delayed version in a chip period. The sum of correlation values in each bit period is then compared with the threshold to recover the data. The conventional DCSK transmitter, frequency non-selective Rayleigh fading channel, and two proposed receivers are mathematically modelled in discrete-time domain. The authors evaluated the bit error rate performance of the receivers by means of both theoretical analysis and numerical simulation. The performance comparison shows that the two proposed receivers can perform well under the studied channel, where the performances get better when the number of paths increases and the DSS receiver outperforms the SDS one.

CaV channels and cancer: canonical functions indicate benefits of repurposed drugs as cancer therapeutics

The importance of ion channels in the hallmarks of many cancers is increasingly recognised. This article reviews current knowledge of the expression of members of the voltage-gated calcium channel family (CaV) in cancer at the gene and protein level and discusses their potential functional roles. The ten members of the CaV channel family are classified according to expression of their pore-forming α-subunit; moreover, co-expression of accessory α2δ, β and γ confers a spectrum of biophysical characteristics including voltage dependence of activation and inactivation, current amplitude and activation/inactivation kinetics. CaV channels have traditionally been studied in excitable cells including neurones, smooth muscle, skeletal muscle and cardiac cells, and drugs targeting the channels are used in the treatment of hypertension and epilepsy. There is emerging evidence that several CaV channels are differentially expressed in cancer cells compared to their normal counterparts. Interestingly, a number of CaV channels also have non-canonical functions and are involved in transcriptional regulation of the expression of other proteins including potassium channels. Pharmacological studies show that CaV canonical function contributes to the fundamental biology of proliferation, cell-cycle progression and apoptosis. This raises the intriguing possibility that calcium channel blockers, approved for the treatment of other conditions, could be repurposed to treat particular cancers. Further research will reveal the full extent of both the canonical and non-canonical functions of CaV channels in cancer and whether calcium channel blockers are beneficial in cancer treatment.

Searching for swept-up hydrogen and helium in the late-time spectra of 11 nearby Type Ia supernovae

The direct detection of a stellar system that explodes as a Type Ia supernova (SN Ia) has not yet been successful. Various indirect methods have been used to investigate SN Ia progenitor systems but none have produced conclusive results. A prediction of single-degenerate models is that H- (or He-) rich material from the envelope of the companion star should be swept up by the SN ejecta in the explosion. Seven SNe Ia have been analysed to date looking for signs of H-rich material in their late-time spectra and none were detected. We present results from new late-time spectra of 11 SNe Ia obtained at the Very Large Telescope using XShooter and FORS2. We present the tentative detection of Hα emission for SN 2013ct, corresponding to ∼0.007 M_⊙ of stripped/ablated companion star material (under the assumptions of the spectral modelling). This mass is significantly lower than expected for single-degenerate scenarios, suggesting that >0.1 M_⊙ of H-rich is present but not observed. We do not detect Hα emission in the other 10 SNe Ia. This brings the total sample of normal SNe Ia with non-detections (<0.001–0.058 M_⊙) of H-rich material to 17 events. The simplest explanation for these non-detections is that these objects did not result from the explosion of a CO white dwarf accreting matter from a H-rich companion star via Roche lobe overflow or symbiotic channels. However, further spectral modelling is needed to confirm this. We also find no evidence of He-emission features, but models with He-rich companion stars are not available to place mass limits.

Cloning and Characterization of Two Potent Kunitz Type Protease Inhibitors from Echinococcus granulosus

The tapeworm Echinococcus granulosus is responsible for cystic echinococcosis (CE), a cosmopolitan disease which imposes a significant burden on the health and economy of affected communities. Little is known about the molecular mechanisms whereby E. granulosus is able to survive in the hostile mammalian host environment, avoiding attack by host enzymes and evading immune responses, but protease inhibitors released by the parasite are likely implicated. We identified two nucleotide sequences corresponding to secreted single domain Kunitz type protease inhibitors (EgKIs) in the E. granulosus genome, and their cDNAs were cloned, bacterially expressed and purified. EgKI-1 is highly expressed in the oncosphere (egg) stage and is a potent chymotrypsin and neutrophil elastase inhibitor that binds calcium and reduced neutrophil infiltration in a local inflammation model. EgKI-2 is highly expressed in adult worms and is a potent inhibitor of trypsin. As powerful inhibitors of mammalian intestinal proteases, the EgKIs may play a pivotal protective role in preventing proteolytic enzyme attack thereby ensuring survival of E. granulosus within its mammalian hosts. EgKI-1 may also be involved in the oncosphere in host immune evasion by inhibiting neutrophil elastase and cathepsin G once this stage is exposed to the mammalian blood system. In light of their key roles in protecting E. granulosus from host enzymatic attack, the EgKI proteins represent potential intervention targets to control CE. This is important as new public health measures against CE are required, given the inefficiencies of available drugs and the current difficulties in its treatment and control. In addition, being a small sized highly potent serine protease inhibitor, and an inhibitor of neutrophil chemotaxis, EgKI-1 may have clinical potential as a novel anti-inflammatory therapeutic.

Effect of type, form, and dosage of activators on strength of alkali-activated natural pozzolans

It is possible to synthesize environmentally friendly cementitious construction materials from alkali-activated natural pozzolans. The effect of the alkaline medium on the strength of alkali-activated natural pozzolans has been investigated and characterised. This paper highlights the effect of the type and form of the alkaline activator, the dosage of alkali and the SiO2/Na2O ratio (silica modulus, Ms) when using water–glass solutions and different curing conditions on the geopolymerisation of natural pozzolans. Activation of natural and calcined pozzolan for production of geopolymeric binder was verified by using Taftan andesite and Shahindej dacite from Iran as a solid precursor. The optimum range for each factor is suggested based on the different effects they have on compressive strength. The concentration of dissolving silicon, aluminium and calcium in alkaline solution, the formation of gel phase and the factors affecting this have been studied by using leaching tests, ICP–AES, and FTIR.

L’ichtyofaune dans l’organisation biologique d’un système paralique de type lagunaire, la Ria d’Aveiro (Portugal), en 1987-1988 et 1999-2000

Cette étude concerne un écosystème paralique, la lagune d’Aveiro (Portugal). Elle vise à déterminer l’organisation des peuplements de poissons en fonction des caractéristiques et du fonctionnement de cet écosystème. L’ichtyofaune a été échantillonnée mensuellement en 10 stations d’août 1987 à juillet 1988 et de janvier 1999 à décembre 2000, avec une seine de plage traditionnelle. La répartition des peuplements de poissons est étudiée au moyen de descripteurs populationnels (richesses spécifique et familiale, densité, biomasse et indice de diversité) et d’analyses statistiques (groupements et ordination). La lagune d’Aveiro présente de fortes variations, dans l’espace et le temps, de ses paramètres physico- chimiques reflétant ainsi les variations climatiques annuelles. Si l’on considère la mobilité des poissons et la géomorphologie et l’hydrologie du système étudié, nous pouvions nous attendre à une forte homogénéité de la distribution des poissons. À l’inverse, une diminution de l’influence marine a pour conséquence une diminution des richesses spécifiques et familiales, de la densité et de la biomasse. Nous avons également observé une modification de composition de l’assemblage de poissons et la présence d’espèces dominantes caractéristiques des différents niveaux de confinement (taux de renouvellement des eaux marines en un point donné du système). Le peuplement de poissons présente une organisation semblable à la zonation biologique, indépendamment des paramètres physico-chimiques tels que la salinité, décrite par la macrofaune benthique et induite par le confinement. La comparaison des résultats avec des données obtenues douze ans plus tôt, montre que l’organisation générale de la lagune est demeurée inchangée, illustrant ainsi la stabilité des écosystèmes paraliques. De plus, des modifications du niveau de confinement dans les marges nord et sud, induites principalement par des changements locaux de l’hydrodynamisme, ont été constatées. Le déconfinement de la zone nord est la conséquence de l’entretien des canaux de navigation par dragage. À l’inverse, le confinement de la zone sud est l’évolution naturelle des bassins paraliques soumis souvent à une sédimentation élevée et rapide. Cette étude montre que l’organisation du peuplement de poissons valide le concept du confinement pour l’organisation biologique des milieux paraliques, et peut être employé pour expliquer les changements de ces écosystèmes.

Random Access over Multi-Packet Reception Channels: A Mean-Field Approach

Thesis (Ph.D.)--University of Washington, 2016-06

Receptors, sparks and waves in a fire-diffuse-fire framework for calcium release

Calcium ions are an important second messenger in living cells. Indeed calcium signals in the form of waves have been the subject of much recent experimental interest. It is now well established that these waves are composed of elementary stochastic release events (calcium puffs or sparks) from spatially localised calcium stores. The aim of this paper is to analyse how the stochastic nature of individual receptors within these stores combines to create stochastic behaviour on long timescales that may ultimately lead to waves of activity in a spatially extended cell model. Techniques from asymptotic analysis and stochastic phase-plane analysis are used to show that a large cluster of receptor channels leads to a release probability with a sigmoidal dependence on calcium density. This release probability is incorporated into a computationally inexpensive model of calcium release based upon a stochastic generalization of the Fire-Diffuse-Fire (FDF) threshold model. Numerical simulations of the model in one and two dimensions (with stores arranged on both regular and disordered lattices) illustrate that stochastic calcium release leads to the spontaneous production of calcium sparks that may merge to form saltatory waves. Illustrations of spreading circular waves, spirals and more irregular waves are presented. Furthermore, receptor noise is shown to generate a form of array enhanced coherence resonance whereby all calcium stores release periodically and simultaneously.

Involvement of Beta-arrestin 1 and Beta-arrestin 2 in store operated calcium entry

Résumé : La variation de la [Ca2+] intracellulaire participe à nombreux de processus biologiques. Les cellules eucaryotes expriment à la membrane plasmique une variété de canaux par lesquelles le calcium peut entrer. Dans les cellules non excitables, deux mécanismes principaux permettent l'entrée calcique; l'entrée capacitative de Ca2+ via Orai1 (SOCE) et l'entrée calcique activé par un récepteur (ROCE). Plusieurs protéines clés sont impliquées dans la régulation de ces voies d'entrée calcique, ainsi que dans l'homéostasie calcique. TRPC6 est un canal calcique impliquée dans l'entrée calcique dans les cellules à la suite d’une stimulation d’un récepteur hormonal. TRPC6 transloque à la membrane cellulaire et il y demeure jusqu'à ce que le stimulus soit retiré. Les mécanismes qui régulent le trafic et l'activation de TRPC6 sont cependant encore peu connus. Des découvertes récentes ont démontré qu'il y a un rôle potentiel de Rho kinase dans l'activité de TRPC6. Rho kinase est activée par la petite protéine G RhoA qui peut être activée par les protéines G hétérotrimériques Gα12 et Gα13. En plus de Gα12 et Gα13, les protéines de désensibilisation des GPCR β -arrestin 1 et / ou β-arrestin 2 peuvent aussi activer RhoA. Le but de notre étude est d'examiner la participation des protéines Gα12/13 et β-arrestin 1/ β-arrestin 2 dans l'activation de TRPC6 et de la protéine Orai1. Nous avons utilisé des ARN interférant (siRNA) spécifiques pour induire une réduction de l'expression de Gα12/13 ou β-arrestin 1/β-arrestin 2. La conséquence sur l’entrée de Ca2+ dans les cellules a été ensuite déterminée par imagerie calcique en temps réel suite à une stimulation par la vasopressine (AVP), thapsigargin ou carbachol. Nous avons donc identifié que dans des cellules A7r5, une lignée cellulaire de musculaires lisses vasculaires où le canal TRPC6 exprimé de manière endogène, la diminution de l’expression des protéines Gα12 ou Gα13 ne semble pas modifier l’entrée Ca2+ induit par l’AVP par rapport aux cellules témoins. D'autre part, la diminution de l’expression β-arrestin 1 ou β-arrestin 2 dans des cellules HEK 293 ainsi que des cellules HEK 293 exprimant de façon stable TRPC6 (cellules T6.11) ont augmenté l’entrée de Ca2+ induite par thapsigargin, un activateur pharmacologique de SOCE. Des études de co-immunoprécipitation démontrent une interaction entre la β-arrestin 1 et STIM1, alors qu'aucune interaction n'a été observée entre les β-arrestin 1 et Orai1. Nous avons de plus montré à l'aide d'analyse en microscopie confocale que la diminution de l’expression β-arrestin 1 ou β-arrestin 2 n’influence pas la quantité d’Orai1 à la périphérie cellulaire. Cependant, des résultats préliminaires indiquent que la diminution de l’expression β-arrestin 1 ou β-arrestin 2 augmente la quantité de STIM1-YFP dans l'espace intracellulaire et diminue sa quantité à la périphérie cellulaire. En conclusion, nous avons montré que les β-arrestin 1 ou β-arrestin 2 sont impliquées dans l'entrée capacitative de Ca2+ (SOCE) et contrôlent la quantité de STIM1 dans le réticulum endoplasmique.

Calcium oscillations

Changes in cellular calcium concentration control a wide range of physiological processes, from the subsecond release of synaptic neurotransmitters, to the regulation of gene expression over months or years. Calcium can also trigger cell death through both apoptosis and necrosis, and so the regulation of cellular calcium concentration must be tightly controlled through the concerted action of pumps, channels and buffers that transport calcium into and out of the cell cytoplasm. A hallmark of cellular calcium signalling is its spatiotemporal complexity: stimulation of cells by a hormone or neurotransmitter leads to oscillations in cytoplasmic calcium concentration that can vary markedly in time course, amplitude, frequency, and spatial range. In this chapter we review some of the biological roles of calcium, the experimental characterisation of complex dynamic changes in calcium concentration, and attempts to explain this complexity using computational models. We consider the "toolkit" of cellular proteins which influence calcium concentration, describe mechanistic models of key elements of the toolkit, and fit these into the framework of whole cell models of calcium oscillations and waves. Finally, we will touch on recent efforts to use stochastic modelling to elucidate elementary calcium signal events, and how these may evolve into global signals.

Protein encapsulation and release from PEO-b-polyphosphoester templated calcium carbonate particles

International audience

The study of the sedimentation mechanism in channels under the impact of tidal currents

The purpose of this research is to study sedimentation mechanism by mathematical modeling in access channels which are affected by tidal currents. The most important factor for recognizing sedimentation process in every water environment is the flow pattern of that environment. It is noteworthy that the flow pattern is affected by the geometry and the shape of the environment as well as the type of existing affects in area. The area under the study in this thesis is located in Bushehr Gulf and the access channels (inner and outer). The study utilizes the hydrodynamic modeling with unstructured triangular and non-overlapping grids, using the finite volume, From method analysis in two scale sizes: large scale (200 m to 7.5km) and small scale (50m to 7.5km) in two different time durations of 15 days and 3.5 days to obtain the flow patterns. The 2D governing equations used in the model are the Depth-Averaged Shallow Water Equations. Turbulence Modeling is required to calculate the Eddy Viscosity Coefficient using the Smagorinsky Model with coefficient of 0.3. In addition to the flow modeling in two different scales and the use of the data of 3.5 day tidal current modeling have been considered to study the effects of the sediments equilibrium in the area and the channels. This model is capable of covering the area which is being settled and eroded and to identify the effects of tidal current of these processes. The required data of the above mentioned models such as current and sediments data have been obtained by the measurements in Bushehr Gulf and the access channels which was one of the PSO's (Port and Shipping Organization) project-titled, "The Sedimentation Modeling in Bushehr Port" in 1379. Hydrographic data have been obtained from Admiralty maps (2003) and Cartography Organization (1378, 1379). The results of the modeling includes: cross shore currents in northern and north western coasts of Bushehr Gulf during the neap tide and also the same current in northern and north eastern coasts of the Gulf during the spring tide. These currents wash and carry fine particles (silt, clay, and mud) from the coastal bed of which are generally made of mud and clay with some silts. In this regard, the role of sediments in the islands of this area and the islands made of depot of dredged sediments should not be ignored. The result of using 3.5 day modeling is that the cross channels currents leads to settlement places in inner and outer channels in tidal period. In neap tide the current enters the channel from upside bend of the two channels and outer channel. Then it crosses the channel oblique in some places of the outer channel. Also the oblique currents or even almost perpendicular current from up slope of inner channel between No. 15 and No. 18 buoys interact between the parallel currents in the channel and made secondary oblique currents which exit as a down-slope current in the channel and causes deposit of sediments as well as settling the suspended sediments carried by these currents. In addition in outer channel the speed of parallel currents in the bend of the channel which is naturally deeper increases. Therefore, it leads to erosion and suspension of sediments in this area. The speed of suspended sediments carried by this current which is parallel to the channel axis decreases when they pass through the shallower part of the channel where it is in the buoys No.7 and 8 to 5 and 6 are located. Therefore, the suspended sediment settles and because of this process these places will be even shallower. Furthermore, the passing of oblique upstream leads to settlement of the sediments in the up-slope and has an additional effect on the process of decreasing the depth of these locations. On the contrary, in the down-slope channel, as the results of sediments and current modeling indicates the speed of current increases and the currents make the particles of down-slope channel suspended and be carried away. Thus, in a vast area of downstream of both channels, the sediments have settled. At the end of the neap tide, the process along with circulations in this area produces eddies which causes sedimentation in the area. During spring some parts of this active location for sedimentation will enter both channels in a reverse process. The above mentioned processes and the places of sedimentation and erosion in inner and outer channels are validated by the sediments equilibrium modeling. This model will be able to estimate the suspended, bed load and the boundary layer thickness in each point of both channels and in the modeled area.

Dispersion and optimization of a calcium sulfoaluminate mortar prepared with superplasticizer

Calcium sulfoaluminate (CSA) cements/mortars are receiving increasing attention since their manufacture produces less CO2 than ordinary Portland cement (OPC) (up to 22% of decrease depending on its composition). These systems are complex and there are many parameters affecting their hydration mechanism, such as water-to-cement (w/c) ratio, type and amount of sulfate source, and so on. Low w/c ratios, within certain limits, may reduce the porosity and consequently, improve the mechanical strengths. However, it is accompanied by an increasing of viscosity and lack of both workability and homogeneity, with the consequent negative effect on the mechanical properties. The dispersion of the particles through the adsorption of the right amount and type of additives, such as superplasticizers, is a key point to improve the workability of mortars allowing both the preparation of homogeneous mixtures and the reduction of the amount of mixing water. This work deals with the preparation and optimization of homogeneous CSA-mortars with improved mechanical strengths. The optimum amount of superplasticizer was optimized through rheological measurements. The effect of different amounts of the superplasticizer on the viscosity of the mortars, its hydration mechanism and corresponding mechanical properties has been studied and will be discussed.