Regulation of Amyloid Oligomer Binding to Neurons and Neurotoxicity by the Prion Protein-mGluR5 Complex

The prion protein (PrPC) has been suggested to operate as a scaffold/receptor protein in neurons, participating in both physiological and pathological associated events. PrPC, laminin, and metabotropic glutamate receptor 5 (mGluR5) form a protein complex on the plasma membrane that can trigger signaling pathways involved in neuronal differentiation. PrPC and mGluR5 are co-receptors also for -amyloid oligomers (AOs) and have been shown to modulate toxicity and neuronal death in Alzheimer\u27s disease. In the present work, we addressed the potential crosstalk between these two signaling pathways, laminin-PrPC-mGluR5 or AO-PrPC-mGluR5, as well as their interplay. Herein, we demonstrated that an existing complex containing PrPC-mGluR5 has an important role in AO binding and activity in neurons. A peptide mimicking the binding site of laminin onto PrPC (Ln-1) binds to PrPC and induces intracellular Ca2+ increase in neurons via the complex PrPC-mGluR5. Ln-1 promotes internalization of PrPC and mGluR5 and transiently decreases AO biding to neurons; however, the peptide does not impact AO toxicity. Given that mGluR5 is critical for toxic signaling by AOs and in prion diseases, we tested whether mGlur5 knock-out mice would be susceptible to prion infection. Our results show mild, but significant, effects on disease progression, without affecting survival of mice after infection. These results suggest that PrPC-mGluR5 form a functional response unit by which multiple ligands can trigger signaling. We propose that trafficking of PrPC-mGluR5 may modulate signaling intensity by different PrPC ligands

Highlights from the NA60 experiment

The NA60 experiment is a fixed-target experiment at the CERN SPS. It has measured the dimuon yield in Indium--Indium collisions with an In beam of 158 AGeV/c and in p-A collisions with a proton beam of 400 and 158 AGeV/c. The results allow to address three important physics topics, namely the study of the rho spectral function in nuclear collisions, the clarification of the origin of the dimuon excess measured by NA50 in the intermediate mass range, and the J/psi suppression pattern in a collision system different from Pb-Pb. An overview of these results will be given in this paper

Hidden chromosomal abnormalities in pleuropulmonary blastomas identified by multiplex FISH

BACKGROUND: Pleuropulmonary blastoma (PPB) is a rare childhood dysontogenetic intrathoracic neoplasm associated with an unfavourable clinical behaviour. CASES PRESENTATION: We report pathological and cytogenetic findings in two cases of PPB at initial diagnosis and recurrence. Both tumors were classified as type III pneumoblastoma and histological findings were similar at diagnosis and relapse. In both cases, conventional cytogenetic techniques revealed complex numerical and structural chromosomal abnormalities. Molecular cytogenetic analysis (interphase/metaphase FISH and multicolor FISH) identified accurately chromosomal aberrations. In one case, TP53 gene deletion was detected on metaphase FISH. To date, only few cytogenetic data have been published about PPB. CONCLUSION: The PPB genetic profile remains to be established and compared to others embryonal neoplasia. Our cytogenetic data are discussed reviewing cytogenetics PPBs published cases, illustrating the contribution of multicolor FISH in order to identify pathogenetically important recurrent aberrations in PPB

A high-resolution map of human evolutionary constraint using 29 mammals.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease

Joint Europa Mission (JEM): a multi-scale study of Europa to characterize its habitability and search for extant life

Europa is the closest and probably the most promising target to search for extant life in the Solar System, based on complementary evidence that it may fulfil the key criteria for habitability: the Galileo discovery of a sub-surface ocean; the many indications that the ice shell is active and may be partly permeable to transfer of chemical species, biomolecules and elementary forms of life; the identification of candidate thermal and chemical energy sources necessary to drive a metabolic activity near the ocean floor. In this article we are proposing that ESA collaborates with NASA to design and fly jointly an ambitious and exciting planetary mission, which we call the Joint Europa Mission (JEM), to reach two objectives: perform a full characterization of Europa's habitability with the capabilities of a Europa orbiter, and search for bio-signatures in the environment of Europa (surface, subsurface and exosphere) by the combination of an orbiter and a lander. JEM can build on the advanced understanding of this system which the missions preceding JEM will provide: Juno, JUICE and Europa Clipper, and on the Europa lander concept currently designed by NASA (Maize, report to OPAG, 2019). We propose the following overarching goals for our Joint Europa Mission (JEM): Understand Europa as a complex system responding to Jupiter system forcing, characterize the habitability of its potential biosphere, and search for life at its surface and in its sub-surface and exosphere. We address these goals by a combination of five Priority Scientific Objectives, each with focused measurement objectives providing detailed constraints on the science payloads and on the platforms used by the mission. The JEM observation strategy will combine three types of scientific measurement sequences: measurements on a high-latitude, low-altitude Europan orbit; in-situ measurements to be performed at the surface, using a soft lander; and measurements during the final descent to Europa's surface. The implementation of these three observation sequences will rest on the combination of two science platforms: a soft lander to perform all scientific measurements at the surface and sub-surface at a selected landing site, and an orbiter to perform the orbital survey and descent sequences. We describe a science payload for the lander and orbiter that will meet our science objectives. We propose an innovative distribution of roles for NASA and ESA; while NASA would provide an SLS launcher, the lander stack and most of the mission operations, ESA would provide the carrier-orbiter-relay platform and a stand-alone astrobiology module for the characterization of life at Europa's surface: the Astrobiology Wet Laboratory (AWL). Following this approach, JEM will be a major exciting joint venture to the outer Solar System of NASA and ESA, working together toward one of the most exciting scientific endeavours of the 21st century: to search for life beyond our own planet