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Monocyte-derived miRNA and Extracellular Vesicles in patients with Multiple Sclerosis: evaluation as biomarkers MED/26
Full text linkLa sclerosi multipla (SM) è una patologia infiammatoria autoimmune cronica, demielinizzante e invalidante, del sistema nervoso centrale (SNC). Recentemente, un crescente interesse è stato rivolto alle vescicole extracellulari (EVs), in particolare microvescicole (MVs) ed esosomi (EXOs), risultati essere importanti mediatori della comunicazione tra cellule, in condizioni sia fisiologiche che patologiche. Diverse evidenze indicano che il rilascio delle MVs aumenta nelle cellule immunitarie, in particolare quelle della linea mieloide, dopo stimolazione con APT del recettore purinergico P2X7 (un recettore di segnale dell’ATP), attraverso l'attivazione della sfingomielinasi acida (A-SMase), che media anche il rilascio della citochina infiammatoria IL-1β. Il contenuto delle MVs comprende acidi nucleici, proteine cellulari e lipidi che possono essere trasferiti alle cellule target. In particolare, le MVs sono in grado di trasferire piccole sequenze di RNA non codificanti (miRNA), che sono deregolati nel sistema immunitario e nel SNC di pazienti affetti da SM e che stanno emergendo come nuovi biomarcatori di malattia. Il principale obiettivo di questo studio è indagare l’effetto del Fingolimod, un trattamento di seconda linea per la SM, sulla produzione delle MVs e dei pathways cellulari coinvolti in monociti di pazienti affetti, utilizzando un approccio sperimentale che sfrutta la quantificazione spettrofotometrica e la valutazione dell’espressione genica mediante Real-time PCR. Trentasette pazienti con SM sono stati arruolati, diciannove dei quali in trattamento con il Fingolimod e valutati dopo 12 mesi di trattamento. Diciotto donatori sani (HDs) sono stati inoltre reclutati e analizzati nello stesso modo. Le MVs, marcate con NBD C6-Spingomielina, sono state quantificate mediante metodo spettrofotometrico. L'attività di A-SMase è stata determinata utilizzando il dosaggio fluorimetrico del reagente Amplex Red, mentre l'espressione del recettore P2X7, IL-1β e A-SMase nei monociti è stata quantificata mediante qRT-PCR. Abbiamo riscontrato che la produzione basale di MVs è più alta nei monociti di pazienti con SM non trattati rispetto ai pazienti trattati con Fingolimod o HDs. La stimolazione con il Benzoil-ATP, un analogo sintetico dell’ATP, incrementa significativamente la produzione di MVs negli HDs e nei pazienti trattati con Fingolimod, ma non nei pazienti con SM. Abbiamo osservato che il trattamento è in grado di ridurre la produzione delle MVs nei monociti rispetto ai pazienti SM non trattati, sia in condizioni di stimolo che di non stimolo. L'espressione del recettore P2X7 aumenta, invece, nei pazienti trattati con Fingolimod rispetto ai HDs in entrambe le condizioni. Tuttavia, il farmaco riduce l'espressione di IL-1β e l'attività di A-SMase nei monociti stimolati con BzATP in pazienti con SM. Complessivamente, i nostri risultati suggeriscono che le MVs aumentano in corso di malattia e che il trattamento con Fingolimod è in grado di ridurre la produzione delle stesse inibendo l'attività di A-SMase. I nostri dati suggeriscono, inoltre, che le MVs monocitarie possono essere considerate come un possibile biomarker di malattia. In secondo luogo, abbiamo valutato l’espressione di alcuni microRNA nelle EVs e la relativa espressione degli stessi miRNA nei monociti di pazienti affetti da SM e HDs. A tale scopo, sono stati arruolati 35 pazienti affetti da SM (21 RRMS e 14 PPMS) e 16 HDs, analizzati in maniera analoga. Sono stati valutati dei miRNA specifici, noti per essere importanti nella regolazione del sistema immunitario e del SNC, così come nel crosstalk tra monociti/macrofagi e oligodendrociti o neuroni. Risultati preliminari rivelano livelli detectabili di un set di miRNAs, per esempio il miR- 146a, miR-181a, miR-223, miR-23a, miR- 30c e il miR125a noti per essere alterati nella SM, in EVs isolate da monociti di pazienti e HDs. Successivamente abbiamo valutato l’espressione differenziale di questi miRNAs in monociti da pazienti e HDs. Complessivamente, i nostri dati suggeriscono che lo studio dei miRNAs cellulari può fornire informazioni sul loro ruolo nella risposta infiammatoria. Inoltre, il loro possibile coinvolgimento nelle funzioni sinaptiche, nella SM e in altre malattie neuroinfiammatorie, è sicuramente meritevole di ulteriori considerazioni per studi futuri. L’ottimizzazione e la standardizzazione dei protocolli per isolare e caratterizzare il contenuto di EVs rappresenta la sfida che la ricerca futura dovrà affrontare al fine di identificare nuovi biomarcatori.Multiple Sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disease of the central nervous system (CNS). Recently, growing attention has been given to extracellular vesicles (EVs), microvesicles (MVs) and exosomes (EXOs), as important mediators of intercellular communication, in both physiological and pathological conditions such as MS. In immune cells, especially of the myeloid lineage, MV shedding is induced by the stimulation of the ATP receptor P2X7 through activation of acid sphingomyelinase (A-SMase) and mediates release of the inflammatory cytokine IL-1β. Accumulating evidence indicates that MVs may contain and transfer between cells small non-coding RNAs (miRNAs), which are deregulated in the immune and CNS of MS patients and are emerging as diseases biomarkers. In this study project we firstly evaluated how Fingolimod, a second line treatment for MS, may affect MVs production by the monocytes of the affected patients, as well as P2X7R, IL-1β expression and A-SMase activity. Thirty-seven MS patients were enrolled, nineteen of which started assuming Fingolimod. Purified monocytes from PBMCs were isolated from venous blood samples after 12 months of treatment. Eighteen healthy donors (HDs) were also recruited and similarly investigated. NBD C6- Sphingomyelin-labelled MVs were quantified by fluorimetry. A-SMase activity was determined using Amplex Red sphingomyelinase assay. P2X7R, IL-1β, A-SMase expression in monocytes were quantified by qRT-PCR. We found that basal production of MVs was higher in monocytes from untreated MS patients than Fingolimod treated patients or HDs. Upon BzATP stimulation, MVs production significantly increased in HDs and in patients treated with Fingolimod but not in untreated MS patients. Fingolimod was able to decrease such production compared to MS patients. Treatment, instead, increases P2X7R expression in Fingolimod treated patients compared to HDs in both conditions (KRH and BzATP stimulation). However, the drug reduced IL-1β expression and A-SMase activity in BzATP-stimulated monocytes from MS patients. This evidence reveals that treatment with Fingolimod reduces MVs production in MS patients by inhibiting A-SMase activity and suggests that monocyte MVs can be considered as a possible disease biomarker. As a second aim, we evaluated EV-miRNA cargo and the relative expression of the same miRNAs in parental cells of MS patients and HDs. For this purpose, 35 MS patients (21 RRMS and 14 PPMS) were enrolled and 16 HDs were similarly investigated. A set of specific miRNAs, important in the immune system and CNS as well as in the crosstalk between monocytes/macrophages and oligodendrocytes or neurons, was evaluated. In preliminary results we found detectable levels of a set of miRNAs, known to be altered in MS, in monocyte-derived EVs from both MS and HDs, i.e.miR-146a, miR-181a, miR-223, miR-23a, miR-30c, and miR125a. Differential expression analysis of these miRNAs in monocytes from HDs and MS patients was then evaluated. Taken together, our results suggest that the study of cellular miRNAs provides interesting information about their role in inflammatory response. Moreover their possible involvement in the synaptic function, in MS as well as in other neuroinflammatory disorders (OND), may certainly deserve consideration for future investigation. The challenge facing future research will be the optimization and standardization of methods to isolate and characterize EVs content in order to consider them as a possible diagnostic biomarker
Nonlinear Shallow-Water Tides Observed with Excellent Signal-to-Noise Ratio by Two Geodetic Laser Strainmeters at the Canfranc (Spain) Underground Laboratory.
No full textTo what extent is the volume change of pressurized ellipsoidal sources retrievable from deformation and seismic data?
No full textEffects of crustal layering on the inversion of deformation and gravity data in volcanic areas: An application to the Campi Flegrei caldera, Italy.
No full textWe study the effects of crustal layering on ground displacements and gravity changes due to a spheroidal expanding source. Soft superficial layers affect the
deformation pattern (giving an apparent shallower source if layering is not taken into account), the ratio of horizontal to vertical displacements (biasing the source shape), and the subsurface mass redistribution effects on gravity changes. Retrieved intrusion density is biased toward very low values if the source is modelled as a penny-shaped crack (point and finite) in a homogeneous half-space and the resulting density misestimate can lead to a possibly incorrect assessment of volcanic hazard. As an application, we
consider the 1982 - 1984 Campi Flegrei unrest. We show that the large discrepancy between densities of spherical and penny-shaped sources, given in the literature and obtained inverting ground displacement and gravity data
in a homogeneous half-space, is at least partially a consequence of the homogeneous half-space assumption
Strain tides observed by two geodetic laser strainmeters at Canfranc (Spain): clues on nonlinear and minor ocean tides in the Bay of Biscay.
No full textGlobal ocean tidal models are very accurate in deep ocean, but errors still arise in coastal areas. While tide gauge and bottom pressure data have strictly local spatial sensitivity and satellite altimetry may suffer temporal aliasing, continuous geodetic measurements of tidal loading (e. g. strain, tilt, and gravity) can provide useful benchmarks to validate ocean tidal models at regional scale without temporal aliasing. Strain and tilt are spatially more discriminative than gravity, because the decrease of strain and tilt with distance to the source is more rapid than the decrease of gravity. Thus, strainmeters and tiltmeters provide an intermediate spatial resolution between tidal gauges and gravimeters.
Despite the potential utility of geodetic observations of nonlinear tides, few studies (mainly focused on M4) have been published so far, using data from superconducting gravimeters, tiltmeters, and continuous GPS. To our best knowledge, strain data have never been used to investigate nonlinear and minor ocean tides and validate ocean tidal models.
We present and analyze about 2.5 years of strain data recorded by two near-orthogonally-oriented 70-m-long high-resolution geodetic laser strainmeters (interferometers), which have been installed in the Canfranc underground laboratory under the Central Pyrenees (Spain) and can provide precise measurements of the Earth crustal deformation. Strain spectra show clear tidal peaks whose frequencies range from the diurnal band to at least 8 cycles per day. Most tidal peaks at frequencies higher than 2 cpd are ascribable to ocean loading by nonlinear shallow-water constituents, mainly from the Bay of Biscay (more than 120 km from the measurement site); strain amplitudes (relative change in length for each strainmeter) range from few picostrains (e. g. 2MK6) to tens of nanostrains (M4).
First, we use diurnal and semidiurnal strain tides to (i) estimate local strain distortions, (ii) check the goodness of the computed coupling coefficients between remote and local strain, and (iii) validate FES2012 minor semidiurnal tides.The reliability of observations and corrections for local distortions are testified by the excellent agreement between measurements and computations for all the diurnal and semi-diurnal tides included in TPXO8-atlas and/or FES2012 ocean models, except maybe L2, regardless of the relative size of load and body tides.
Observed higher-frequency strain tides are quantitatively compared with computations using TPXO8-atlas (MN4, M4, and MS4) and FES2012 (M3, N4, MN4, M4, MS4, and M6). Computations fully agree with M4 observations for one strainmeter, overestimate M4 by about 30% for the other strainmeter and M6 by about a factor of two, and underestimate the other tides. These results are supported by tidal gauge data.
This work shows that data from high-sensitivity strainmeters installed in high-quality sites may provide useful peculiar information for studying the nonlinear tidal dynamics and energetics of coastal waters and minor ocean tides, at spatial resolutions of tens to thousands square kilometers, depending on the strainmeter location with respect to the coastline
Pre-seismic phenomena from continuous near-field strain measurements: a brief review and the case of the 2009 L'Aquila, Italy, earthquake
No full textAfter a brief (incomplete) review of pre-seismic (strain-producing) phenomena, we describe our findings about the pre-seismic phase of the the April 6, 2009 L’Aquila earthquake, giving a few more details with respect to previous papers. Most past observations of crustal strain did not detect any pre-seismic deformation and have been used to constrain the size and strength of the source of possible pre-seismic phenomena. With respect to these, we performed a rather more sophisticated approach to the physics of the model; limited the volume of the possible earthquake preparation zone to less than 100 km3; showed some evidence of dilatancy of saturated rock over the earthquake causative fault (maybe related to the foreshocks) and constrained the prerupture nucleation slip in the hypocentral region to a moment less than 0.00005% of the main shock seismic moment (lowering the previous thresholds)
Source fault parameters and slip distribution: the importance of crustal layering for the 1908 Messina Straits earthquake.
No full textWhat is behind Campi Flegrei inflations and deflations? Clues from 35 years of geodetic monitoring.
No full textVolcanic risk in the explosive Campi Flegrei (CF) caldera is extremely high, because of its location in a densely populated area about 15 km west of Naples inside the Campanian Plain. CF is renowned as a site of continual slow vertical movements. Since the last eruption in 1538, the caldera generally subsided until 1969 then uplift began in the early 1970s (about 1.5 m max), a further large uplift episode occurred from 1982 to 1984 (about 1.8 m max), and a few smaller uplift episodes occurred in 1989, 1994, 2000, and 2006. From 2006, CF is mostly uplifting.
Ground deformation monitoring of CF started in 1905, when the Istituto Geografico Militare established a first leveling line from Naples to Serapeum; since then the leveling line has been much extended and now the leveling network consists of 350 altimetric benchmarks. Geodetic precise-traversing surveys-distance (EDM) and angular measurements were carried out from time to time, starting from June 1970. A Continuous Global Positioning System (CGPS) network began operating at the end of the 1990s. Ground displacement data from Synthetic Aperture Radar (SAR) Interferometry are available since 1992.
Such an abundance of data has allowed detailed studies of the ground deformation time history. In particular, we have recently found that CF ground deformation, within data uncertainties, is always given by the sum of two "stationary contributions" at least since 1980. Large-scale deformation can be explained by a quasi-horizontal source, oriented NW/SE and mathematically represented by a pressurized finite thin triaxial ellipsoid (PTE) embedded in a layered medium at about 4 km; residual deformation not accounted for by PTE can be mathematically explained by a small (point) pressurized oblate spheroid about 2 km below the Solfatara fumarolic field. The location and geometry of the two sources are constant with the exception of volume changes (potency); potency time histories are somewhat similar but not identical.
A long-standing controversy characterizes the interpretation of CF inflation and deflation phases, which are generally ascribed to fluid injections at the basis of the hydrothermal system or to shallow magma injections. As a matter of fact, all published models of both processes predict complex spatial and/or temporal patterns of CF ground deformation.
We will give a review of our knowledge about CF ground deformation and present a new model of magma intrusion, which is consistent with the observed constancy of the ground deformation pattern
Free Core Resonance parameters from diurnal strain tides recorded by the Gran Sasso (Italy) and Canfranc (Spain) underground geodetic interferometers
No full textClues of the deformation source at Campi Flegrei (Italy) from the use of the Akaike Information Criterion
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