A co-ultramicronized palmitoylethanolamide/luteolin composite mitigates clinical score and disease-relevant molecular markers in a mouse model of experimental autoimmune encephalomyelitis

Background: Persistent and/or recurrent inflammatory processes are the main factor leading to multiple sclerosis (MS) lesions. The composite ultramicronized palmitoylethanolamide, an endogenous N-acylethanolamine, combined with the flavonoid luteolin, PEALut, have been found to exert neuroprotective activities in experimental models of spinal and brain injury and Alzheimer disease, as well as a clinical improvement in human stroke patients. Furthermore, PEALut enhances the expression of different myelin proteins in oligodendrocyte progenitor cells suggesting that this composite might have protective effects in MS experimental models. Methods: The mouse model of experimental autoimmune encephalomyelitis (EAE) based on active immunization with a fragment of myelin oligodendrocyte glycoprotein (MOG35-55) was used. The daily assessment of clinical score and the expression of serum amyloid A (SAA1), proinflammatory cytokines TNF-\u3b1, IL-1\u3b2, IFN-\u3b3, and NLRP3 inflammasome, as well as TLR2, Fpr2, CD137, CD3-\u3b3, and TCR-\u3b6 chain, heterodimers that form T cell surface glycoprotein (TCR), and cannabinoid receptors CB1, CB2, and MBP, were evaluated in the brainstem and cerebellum at different postimmunization days (PIDs). Results: Vehicle-MOG35-55-immunized (MOG35-55) mice developed ascending paralysis which peaked several days later and persisted until the end of the experiment. PEALut, given intraperitoneally daily starting on day 11 post-immunization, dose-dependently improved clinical score over the range 0.1-5 mg/kg. The mRNA expression of SAA1, TNF-\u3b1, IL-1\u3b2, IFN-\u3b3, and NLRP3 were significantly increased in MOG35-55 mice at 14 PID. In MOG35-55 mice treated with 5 mg /kg PEALut, the increase of SAA1, TNF- \u3b1, IL-1\u3b2, and IFN-\u3b3transcripts at 14 PID was statistically downregulated as compared to vehicle-MOG35-55 mice (p < 0.05). The expression of TLR2, Fpr2, CD137, CD3-\u3b3, TCR-\u3b6 chain, and CB2 receptors showed a significant upregulation in vehicle-MOG35-55 mice at 14 PID. Instead, CB1 and MBP transcripts have not changed in expression at any time. In MOG/PEALut-treated mice, TLR2, Fpr2, CD137, CD3-\u3b3, TCR-\u3b6 chain, and CB2 mRNAs were significantly downregulated as compared to vehicle MOG35-55 mice. Conclusions: The present results demonstrate that the intraperitoneal administration of the composite PEALut significantly reduces the development of clinical signs in the MOG35-55 model of EAE. The dose-dependent improvement of clinical score induced by PEALut was associated with a reduction in transcript expression of the acute-phase protein SAA1, TNF-\u3b1, IL-1\u3b2, IFN-\u3b3, and NLRP3 proinflammatory proteins and TLR2, Fpr2, CD137, CD3-\u3b3, TCR-\u3b6 chain, and CB2 receptors

From Ivacaftor to Triple Combination: A Systematic Review of Efficacy and Safety of CFTR Modulators in People with Cystic Fibrosis

Over the last years CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown the ability to improve relevant clinical outcomes in patients with cystic fibrosis (CF). This review aims at a systematic research of the current evidence on efficacy and tolerability of CFTR modulators for different genetic subsets of patients with CF. Two investigators independently performed the search on PubMed and included phase 2 and 3 clinical trials published in the study period 1 January 2005\u201331 January 2020. A final pool of 23 papers was included in the systematic review for a total of 4219 patients. For each paper data of interest were extracted and reported in table. In terms of lung function, patients who had the most beneficial effects from CFTR modulation were those patients with one gating mutation receiving IVA (ivacaftor) and patients with p.Phe508del mutation, both homozygous and heterozygous, receiving ELX/TEZ/IVA (elexacaftor/tezacaftor/ivacaftor) had the most relevant beneficial effects in term of lung function, pulmonary exacerbation decrease, and symptom improvement. CFTR modulators showed an overall favorable safety profile. Next steps should aim to systematize our comprehension of scientific data of efficacy and safety coming from real life observational studie

Study on lipid fractions of Streptococcus thermophilus by TLC, GC and GC/MS techniques

In this research the lipid fraction of two strains of Streptococcus thermophilus was studied. Lipids were extracted by applying Folch method and fractioned by thin layer chromatography (TLC). Fatty acid composition was determined both before TLC, on the total fat extracted, and after TLC on diacylglycerol and apolar fractions. Gas chromatographic analysis was performed by using both flame ionization (FID) and mass spectrometer (MS) detector. The main difference between the two strains was the presence of short and medium chain fatty acids in food-born S. thermophilus. Moreover one of the most important bacterial fatty acids, C19 cyclopropane, was detected only in diacylglycerols, which, as reported in literature, are formed transiently as intermediates in the biosynthesis of glycerophospholipids

Cosmic voids in modified gravity models with massive neutrinos

Cosmic voids are progressively emerging as a new viable cosmological probe. Their abundance and density profiles are sensitive to modifications of gravity, as well as to dark energy and neutrinos. The main goal of this work is to investigate the possibility of exploiting cosmic void statistics to disentangle the degeneracies resulting from a proper combination of f(R) modified gravity and neutrino mass. We use N-body simulations to analyse the density profiles and size function of voids traced by both dark matter particles and haloes. We find clear evidence of the enhancement of gravity in f(R) cosmologies in the void density profiles at z = 1. However, these effects can be almost completely overridden by the presence of massive neutrinos because of their thermal free streaming. Despite the limited volume of the analysed simulations does not allow us to achieve a statistically relevant abundance of voids larger than 40 Mpc h-1, we find that the void size function at high redshifts and for large voids is potentially an effective probe to disentangle these degenerate cosmological models, which is key in the prospective of the upcoming wide-field redshift surveys

AMICO galaxy clusters in KiDS-DR3: Cosmological constraints from angular power spectrum and correlation function

We study the tomographic clustering properties of the photometric cluster catalogue derived from the Third Data Release of the Kilo Degree Survey, focusing on the angular correlation function and its spherical harmonic counterpart, the angular power spectrum. We measure the angular correlation function and power spectrum from a sample of 5162 clusters, with an intrinsic richness $\lambda^*\geq 15$, in the photometric redshift range $z\in [0.1, 0.6]$, comparing our measurements with theoretical models, in the framework of the $\Lambda$-Cold Dark Matter cosmology. We perform a Monte Carlo Markov Chain analysis to constrain the cosmological parameters $\Omega_{\mathrm{m}}$, $\sigma_8$ and the structure growth parameter $S_8\equiv\sigma_8 \sqrt{\Omega_{\mathrm{m}}/0.3}$. We adopt Gaussian priors on the parameters of the mass-richness relation, based on the posterior distributions derived from a previous joint analysis of cluster counts and weak lensing mass measurements carried out with the same catalogue. From the angular correlation function, we obtain $\Omega_{\mathrm{m}}=0.32^{+0.05}_{-0.04}$, $\sigma_8=0.77^{+0.13}_{-0.09}$ and $S_8=0.80^{+0.08}_{-0.06}$, in agreement, within $1\sigma$, with 3D clustering result based on the same cluster sample and with existing complementary studies on other datasets. For the angular power spectrum, we derive statistically consistent results, in particular $\Omega_{\mathrm{m}}=0.24^{+0.05}_{-0.04}$ and $S_8=0.93^{+0.11}_{-0.12}$, while the constraint on $\sigma_8$ alone is weaker with respect to the one provided by the angular correlation function, $\sigma_8=1.01^{+0.25}_{-0.17}$. Our results show that the 2D clustering from photometric cluster surveys can provide competitive cosmological constraints with respect to the full 3D clustering statistics, and can be successfully applied to ongoing and forthcoming spectro/photometric surveys.Comment: 14 pages, 9 figures. Submitted to Astronomy & Astrophysics (A&A

AMICO galaxy clusters in KiDS-DR3: cosmological constraints from counts and stacked weak-lensing

We present a cosmological analysis of abundances and stacked weak-lensing profiles of galaxy clusters, exploiting the AMICO KiDS-DR3 catalogue. The sample consists of 3652 galaxy clusters with intrinsic richness $\lambda^*\geq20$, over an effective area of 377 deg$^2$, in the redshift range $z\in[0.1,\,0.6]$. We quantified the purity and completeness of the sample through simulations. The statistical analysis has been performed by simultaneously modelling the comoving number density of galaxy clusters and the scaling relation between the intrinsic richnesses and the cluster masses, assessed through a stacked weak-lensing profile modelling. The fluctuations of the matter background density, caused by super-survey modes, have been taken into account in the likelihood. Assuming a flat $\Lambda$CDM model, we constrained $\Omega_{\rm m}$, $\sigma_8$, $S_8 \equiv \sigma_8(\Omega_{\rm m}/0.3)^{0.5}$, and the parameters of the mass-richness scaling relation. We obtained $\Omega_{\rm m}=0.24^{+0.03}_{-0.04}$, $\sigma_8=0.86^{+0.07}_{-0.07}$, $S_8=0.78^{+0.04}_{-0.04}$. The constraint on $S_8$ is consistent within 1$\sigma$ with the results from WMAP and Planck. Furthermore, we got constraints on the cluster mass scaling relation in agreement with those obtained from a previous weak-lensing only analysis.Comment: 12 pages, 7 figures, 2 tables. Accepted by A&

Oxytocin Signaling in the Central Amygdala Modulates Emotion Discrimination in Mice

Recognition of other's emotions influences the way social animals interact and adapt to the environment. The neuropeptide oxytocin (OXT) has been implicated in different aspects of emotion processing. However, the role of endogenous OXT brain pathways in the social response to different emotional states in conspecifics remains elusive. Here, using a combination of anatomical, genetic, and chemogenetic approaches, we investigated the contribution of endogenous OXT signaling in the ability of mice to discriminate unfamiliar conspecifics based on their emotional states. We found that OXTergic projections from the paraventricular nucleus of the hypothalamus (PVN) to the central amygdala (CeA) are crucial for the discrimination of both positively and negatively valenced emotional states. In contrast, blocking PVN OXT release into the nucleus accumbens, prefrontal cortex, and hippocampal CA2 did not alter this emotion discrimination. Furthermore, silencing each of these PVN OXT pathways did not influence basic social interaction. These findings were further supported by the demonstration that virally mediated enhancement of OXT signaling within the CeA was sufficient to rescue emotion discrimination deficits in a genetic mouse model of cognitive liability. Our results indicate that CeA OXT signaling plays a key role in emotion discrimination both in physiological and pathological conditions. Is endogenous oxytocin implicated in emotion discrimination? Ferretti, Maltese et al. demonstrate that oxytocin signaling in the central amygdala plays a key role in the ability of mice to discriminate unfamiliar conspecifics based on their emotional state, both in physiological and genetically determined pathological conditions