Degeneration and regeneration of peripheral nerves: role of thrombin and its receptor PAR-1

The peripheral nervous system has a striking regeneration potential and after damage extensive changes in the differentiation state both of the injured neurons and of the Schwann cells are observed. Schwann cells, in particular, undergo a large scale change in gene expression becoming able to support axonal regeneration. Nerve injury is generally associated to inflammation and activation of the coagulation cascade. Thrombin acts as a polyfunctional signalling molecule exerting its physiological function through soluble target proteins and G-protein-coupled receptors, the protease-activated receptors (PARs) [1]. Recently, we have demonstrated that the activation of the main thrombin receptor, PAR-1, in Schwann cells favours their regenerative potential determining the release of factors which promote axonal regrowth [2]. The pro-regenerative potential of thrombin seems to be exerted in a narrow range of concentrations (pM-nM range). In fact, our preliminary data indicate that high levels of thrombin in the micromolar range slow down Schwann cell proliferation and induce cell death. On the contrary, PAR-1 activating peptides mimic the pro-survival but not the pro-apoptotic effects of thrombin. Controlling thrombin concentration may preserve neuronal health during nerve injury and represent a novel target for pharmacologic therapies

PAR1 activation induces the release by Schwann cells of factors promoting cell survival and neuritogenesis

Protease-activated receptor 1 (PAR1) is a member of a family of four G-protein-coupled receptors which are activated by proteolytic cleavage of their N-terminal extracellular domain. The expression and the role of PAR1 in peripheral nervous system (PNS) is still poorly investigated, although high PAR1 mRNA expression was found in the dorsal root ganglia and in the non-compacted Schwann cell myelin microvilli at the nodes of Ranvier. Schwann cells (SCs) are the principal population of glial cells of the PNS which myelinate axons and play a key role in axonal regeneration and remyelination. Aim of the present study was to determine if the activation of PAR1 affects the neurotrophic properties of SCs. By double immunofluorescence we observed a specific staining for PAR1 in S100ȕ-positive cells of rat sciatic nerve and sciatic teased fibers. Moreover, PAR1 was highly expressed in SC cultures obtained from both neonatal and adult rat sciatic nerves. When PAR1 specific agonists were added to these cultures an increased proliferation rate was observed. Moreover, the conditioned medium obtained from primary SCs treated with PAR1 agonists increased cell survival and neurite outgrowth on PC12 cells respect to controls. By proteomics, western blot and RT-PCR analyses we identified five proteins which are released by SCs following PAR1 stimulation: Macrophage migration inhibitory factor (Mif), Aldose reductase (Akr1b1), Matrix metalloproteinase-2 (Mmp2), Syndecan-4 (Sdc) and Decorin (Dcn). Conversely, a significant decrease in the level of three proteins was observed: Complement C1r subcomponent (C1r) and Complement component 1 Q subcomponent-bindingprotein (C1qbp). When PAR1 expression was silenced by siRNA the observed pro-survival and neurotrophic properties of SCs appear to be reduced respect to controls. References PAR1 activation affects the neurotrophic properties of Schwann cells. Pompili E1, Fabrizi C2, Somma F2, Correani V3, Maras B3, Schininà ME3, Ciraci V2, Artico M4, Fornai F5, Fumagalli L2. 2017 Jan 4;79:23-33. doi: 10.1016/j.mcn.2017.01.001.Schwann cells (SCs) regulate a wide variety of axonal functions in the peripheral nervous system, providing a supportive growth environment following nerve injury (1). Here we show that rat SCs express the protease-activated receptor-1 (PAR1) both in vivo and in vitro. PAR1 is a G-protein coupled receptor eliciting cellular responses to thrombin and other proteases (2). To investigate if PAR1 activation affects the neurotrophic properties of SCs, this receptor was activated by a specific agonist peptide (TFLLR) and the conditioned medium was transferred to PC12 pheocromocytoma cells for assessing cell survival and neurite outgrowth. Culture medium from SCs treated with 10 µM TFLLR reduced significantly the release of LDH and increased the viability of PC12 cells with respect to the medium of the untreated SCs. Furthermore, conditioned medium from TFLLR-treated SCs increased neurite outgrowth on PC12 cells respect to control medium from untreated cells. To identify putative neurotrophic candidates we performed proteomic analysis on SC secretoma and real time PCR experiments after PAR1 activation. Stimulation of SCs with TFLLR increased specifically the release of a subset of five proteins: Macrophage migration inhibitory factor (Mif), Aldose reductase (Akr1b1), Matrix metalloproteinase-2 (Mmp2), Syndecan-4 (Sdc) and Decorin (Dcn). At the same time there was a significant decrease in the level of three proteins: Complement C1r subcomponent (C1r), Complement component 1 Q subcomponent-binding protein (C1qbp) and Angiogenic factor with G patch and FHA domains 1 (Aggf1). These data indicate that PAR1 stimulation does induce the release by SCs of factors promoting cell survival and neuritogenesis. Among these proteins, Mif, Sdc, Dcn and Mmp2 are of particular interest

Partisanship Predicts COVID-19 Vaccine Brand Preference: The Insightful Case of Argentina

The COVID-19 pandemic highlighted the importance of not only diminishing the resistance to vaccine adoption in general, but also to reduce both real and perceived barriers to a swift vaccination campaign. One major problem faced by health systems around the world was that people’s preferences for a specific brand of vaccine often delayed vaccination efforts as people canceled or delayed appointments to receive their preferred brand. Therefore, in the event of another pandemic, it is important to know which factors influence preferences for specific vaccine brands. Previous literature showed that consumers choose products that are congruent with their self-concept, which includes their political affiliation. Given that the discourse around vaccine brands has been strongly politicized during the pandemic, in our work, we test whether partisanship influences preferences for COVID-19 vaccine brands. To test this, we collected survey data from Argentina (N = 432), a country with a clear bipartisan structure and where a variety of vaccine brands were administered, both from Western and Eastern laboratories. We found that supporters of the ruling party, which had strong ties with Eastern countries such as Russia and China, perceived Eastern vaccine brands (e.g., Sputnik V) to be more effective and safe than Western ones (e.g., Pfizer) whereas the contrary was true for supporters of the opposition. Our results also showed that supporters of the opposing party were more likely to wish to hypothetically switch vaccines, to delay their appointment in case of not receiving their preferred brand, and to disapprove of their local vaccination campaign. Our results demonstrate that political party affiliation biases perceptions of both vaccine brands’ quality and vaccination campaign effectiveness. We anticipate that our results can inform public policy strategies when it comes to an efficient vaccine supply allocation, as political affiliation is a measurable and predictable consumer trait.Este artículo se encuentra publicado en SSRN 4292235

Dispersion, damping, and intensity of spin excitations in the single-layer (Bi,Pb)2_{2}(Sr,La)2_{2}CuO6+δ_{6+\delta} cuprate superconductor family

Using Cu-$L_3$ edge resonant inelastic x-ray scattering (RIXS) we measured the dispersion and damping of spin excitations (magnons and paramagnons) in the high-$T_\mathrm{c}$ superconductor (Bi,Pb)$_{2}$(Sr,La)$_{2}$CuO$_{6+\delta}$ (Bi2201), for a large doping range across the phase diagram ($0.03\lesssim p\lesssim0.21$). Selected measurements with full polarization analysis unambiguously demonstrate the spin-flip character of these excitations, even in the overdoped sample. We find that the undamped frequencies increase slightly with doping for all accessible momenta, while the damping grows rapidly, faster in the (0,0)$\rightarrow$(0.5,0.5) nodal direction than in the (0,0)$\rightarrow$(0.5,0) antinodal direction. We compare the experimental results to numerically exact determinant quantum Monte Carlo (DQMC) calculations that provide the spin dynamical structure factor $S(\textbf{Q},\omega)$ of the three-band Hubbard model. The theory reproduces well the momentum and doping dependence of the dispersions and spectral weights of magnetic excitations. These results provide compelling evidence that paramagnons, although increasingly damped, persist across the superconducting dome of the cuprate phase diagram; this implies that long range antiferromagnetic correlations are quickly washed away, while short range magnetic interactions are little affected by doping.Comment: 11 pages, 9 figure

Experimental Determination of Momentum-Resolved Electron-Phonon Coupling

We provide a novel experimental method to quantitatively estimate the electron-phonon coupling and its momentum dependence from resonant inelastic x-ray scattering (RIXS) spectra based on the detuning of the incident photon energy away from an absorption resonance. We apply it to the cuprate parent compound NdBa$_2$Cu$_3$O$_6$ and find that the electronic coupling to the oxygen half-breathing phonon mode is strongest at the Brillouin zone boundary, where it amounts to $\sim 0.17$ eV, in agreement with previous studies. In principle, this method is applicable to any absorption resonance suitable for RIXS measurements and will help to define the contribution of lattice vibrations to the peculiar properties of quantum materials.Comment: 6 pages, 3 figure

Probing coherence in metal absorption towards multiple images of strong gravitationally lensed quasars

We present a tomographic analysis of metal absorption lines arising from the circumgalactic medium (CGM) of galaxies at z~0.5-2, using Multi Unit Spectroscopic Explorer (MUSE) observations of two background quasars at z~2.2 and 2.8, which are two of the few currently known quasars with multiple images due to strong gravitational lensing by galaxy clusters at z~0.6 and 0.5, respectively. The angular separations between different pairs of quasar multiple images enable us to probe the absorption over transverse physical separations of ~0.4-150 kpc, which are based on strong lensing models exploiting MUSE observations. The fractional difference in rest-frame equivalent width (Delta Wr) of MgII, FeII, CIV absorption increases on average with physical separation, indicating that the metal-enriched gaseous structures become less coherent with distance, with a likely coherence length scale of ~10 kpc. However, Delta Wr for all the ions vary considerably over ~0.08-0.9, indicating a clumpy CGM over the full range of length scales probed. At the same time, paired MgII absorption is detected across ~100-150 kpc at similar line-of-sight velocities, which could be probing cool gas clouds within the same halo. No significant dependence of Delta Wr is found on the equivalent width and redshift of the absorbing gas and on the galaxy environment associated with the absorption. The high-ionization gas phase traced by CIV shows a higher degree of coherence than the low-ionization gas phase traced by MgII, with ~90 percent of CIV systems exhibiting Delta Wr <=0.5 at separations <=10 kpc compared to ~50 percent of MgII systems.Comment: 9 pages + appendix, 8 figures, accepted in MNRA

Polarization resolved Cu L3L_3-edge resonant inelastic x-ray scattering of orbital and spin excitations in NdBa2_{2}Cu3_{3}O7−δ_{7-\delta}

High resolution resonant inelastic x-ray scattering (RIXS) has proven particularly effective in the determination of crystal field and spin excitations in cuprates. Its strength lies in the large Cu $L_{3}$ resonance and in the fact that the scattering cross section follows quite closely the single-ion model predictions, both in the insulating parent compounds and in the superconducting doped materials. However, the spectra become increasingly broader with (hole) doping, hence resolving and assigning spectral features has proven challenging even with the highest energy resolution experimentally achievable. Here we have overcome this limitation by measuring the complete polarization dependence of the RIXS spectra as function of momentum transfer and doping in thin films of NdBa$_{2}$Cu$_{3}$O$_{7-\delta}$. Besides confirming the previous assignment of $dd$ and spin excitations (magnon, bimagnon) in the antiferromagnetic insulating parent compound, we unequivocally single out the actual spin-flip contribution at all dopings. We also demonstrate that the softening of $dd$ excitations is mainly attributed to the shift of the $xy$ peak to lower energy loss. These results provide a definitive assessment of the RIXS spectra of cuprates and demonstrate that RIXS measurements with full polarization control are practically feasible and highly informative.Comment: 14 pages, 10 figure

Pentraxin 3 in cardiovascular disease

The long pentraxin PTX3 is a member of the pentraxin family produced locally by stromal and myeloid cells in response to proinflammatory signals and microbial moieties. The prototype of the pentraxin family is C reactive protein (CRP), a widely-used biomarker in human pathologies with an inflammatory or infectious origin. Data so far describe PTX3 as a multifunctional protein acting as a functional ancestor of antibodies and playing a regulatory role in inflammation. Cardiovascular disease (CVD) is a leading cause of mortality worldwide, and inflammation is crucial in promoting it. Data from animal models indicate that PTX3 can have cardioprotective and atheroprotective roles regulating inflammation. PTX3 has been investigated in several clinical settings as possible biomarker of CVD. Data collected so far indicate that PTX3 plasma levels rise rapidly in acute myocardial infarction, heart failure and cardiac arrest, reflecting the extent of tissue damage and predicting the risk of mortality

Dynamical charge density fluctuations pervading the phase diagram of a Cu-based high-Tc superconductor

Charge density waves are a common occurrence in all families of high critical temperature superconducting cuprates. Although consistently observed in the underdoped region of the phase diagram and at relatively low temperatures, it is still unclear to what extent they influence the unusual properties of these systems. Using resonant x-ray scattering we carefully determined the temperature dependence of charge density modulations in (Y,Nd)Ba$_2$Cu$_3$O$_{7-{\delta}}$ for three doping levels. We discovered short-range dynamical charge density fluctuations besides the previously known quasi-critical charge density waves. They persist up to well above the pseudogap temperature T*, are characterized by energies of few meV and pervade a large area of the phase diagram, so that they can play a key role in shaping the peculiar normal-state properties of cuprates.Comment: 34 pages, 4 figures, 11 supplementary figure