Repurposing the KCa3.1 inhibitor senicapoc for Alzheimer's disease.

ObjectiveMicroglia play a pivotal role in the initiation and progression of Alzheimer's disease (AD). We here tested the therapeutic hypothesis that the Ca2+-activated potassium channel KCa3.1 constitutes a potential target for treating AD by reducing neuroinflammation.MethodsTo determine if KCa3.1 is relevant to AD, we tested if treating cultured microglia or hippocampal slices with Aβ oligomer (AβO) activated KCa3.1 in microglia, and if microglial KCa3.1 was upregulated in 5xFAD mice and in human AD brains. The expression/activity of KCa3.1 was examined by qPCR, Western blotting, immunohistochemistry, and whole-cell patch-clamp. To investigate the role of KCa3.1 in AD pathology, we resynthesized senicapoc, a clinically tested KCa3.1 blocker, and determined its pharmacokinetic properties and its effect on microglial activation, Aβ deposition and hippocampal long-term potentiation (hLTP) in 5xFAD mice.ResultsWe found markedly enhanced microglial KCa3.1 expression/activity in brains of both 5xFAD mice and AD patients. In hippocampal slices, microglial KCa3.1 expression/activity was increased by AβO treatment, and its inhibition diminished the proinflammatory and hLTP-impairing activities of AβO. Senicapoc exhibited excellent brain penetrance and oral availability, and in 5xFAD mice, reduced neuroinflammation, decreased cerebral amyloid load, and enhanced hippocampal neuronal plasticity.InterpretationOur results prompt us to propose repurposing senicapoc for AD clinical trials, as senicapoc has excellent pharmacological properties and was safe and well-tolerated in a prior phase-3 clinical trial for sickle cell anemia. Such repurposing has the potential to expedite the urgently needed new drug discovery for AD

Loop level constraints on Seesaw neutrino mixing

Journal of High Energy Physics 2015.10 (2015): 130 reproduced by permission of Scuola Internazionale Superiore di Studi Avanzati (SISSA)We perform a detailed study of the importance of loop corrections when deriving bounds on heavy-active neutrino mixing in the context of general Seesaw mechanisms with extra heavy right-handed neutrinos. We find that, for low-scale Seesaws with an approximate B − L symmetry characterized by electroweak scale Majorana masses and large Yukawas, loop corrections could indeed become relevant in a small part of the parameter space. Previous results in the literature showed that a partial cancellation between these important loop corrections and the tree level contributions could relax some constraints and lead to qualitatively different results upon their inclusion. However, we find that this cancellation can only take place in presence of large violations of the B −L symmetry, that lead to acceptably large contributions to the light neutrino masses at loop level. Thus, when we restrict our analysis of the key observables to an approximate B − L symmetry so as to recover the correct values for neutrino masses, we always find loop corrections to be negligible in the regions of the parameter space preferred by dataWe are happy to acknowledge very illuminating discussions with Mattias Blennow, Belen Gavela, Stefano Rigolin and Alfredo Urbano. We also acknowledge financial support by the European Union through the ITN INVISIBLES (PITN-GA-2011-289442). EFM and JHG also acknowledge support from the EU through the FP7 Marie Curie Actions CIG NeuProbes (PCIG11-GA-2012-321582) and the Spanish MINECO through the “Ramon y Cajal” programme (RYC2011-07710), the project FPA2009-09017 and through the Centro de excelencia Severo Ochoa Program under grant SEV-2012-0249. This work was finalized during the stay of EFM at the Aspen Center for Physics, which is supported by the National Science Foundation grant PHY-1066293. This stay was also supported by a grant from the Simons Foundation. ML thanks the IFT UAM/CSIC for the kind hospitality during the early stages of this work. JLP also acknowledges support from the INFN program on Theoretical Astroparticle Physics (TASP) and the grant 2012CPPYP7 (Theoretical Astroparticle Physics) under the program PRIN 2012 funded by the Italian Ministry of Education, University and Research (MIUR

MeV-scale seesaw and leptogenesis

We study the type-I seesaw model with three right-handed neutrinos and Majorana masses below the pion mass. In this mass range, the model parameter space is not only strongly constrained by the requirement to explain the light neutrino masses, but also by experimental searches and cosmological considerations. In the existing literature, three disjoint regions of potentially viable parameter space have been identified. In one of them, all heavy neutrinos decay shortly before big bang nucleosynthesis. In the other two regions, one of the heavy neutrinos either decays between BBN and the CMB decoupling or is quasi-stable. We show that previously unaccounted constraints from photodisintegration of nuclei practically rule out all relevant decays that happen between BBN and the CMB decoupling. Quite remarkably, if all heavy neutrinos decay before BBN, the baryon asymmetry of the universe can be quite generically explained by low-scale leptogenesis, i.e. without further tuning in addition to what is needed to avoid experimental and cosmological constraints. This motivates searches for heavy neutrinos in pion decay experiments

OUTCOME OF A PILOT COURSE IN SCIENCE COMMUNICATION HIGHLIGHTS THE RELEVANCE OF STUDENT MOTIVATION

The authors devised a lecture series about the common principles making the core of Science Communication, irrespective of specialist disciplines. The aim of the initiative was to engage STEM students, curious about communication of science, into a mostly practical activity, evaluating their degree of satisfaction and the sustainability of the course schedule during the running semester. The course content was originally designed and advertised as an interactive living learning experience. It was then adapted last minute to remote teaching because of the Covid-19 semester, with a significant impact on both the actual interactions and the students’ satisfaction, with respect to expectations. Nonetheless, a follow-up analysis shows that 90% of students declared to have realized, in full or in part, their expected achievements. A high degree of global satisfaction (3.7/5) was acknowledged, despite 77% of students declared a Perceived Study Effort greater than expected. Final grades correlate positively with students Motivation, whereas they are not correlated with any specific Degree Course

New long-lived particle searches in heavy-ion collisions at the LHC

We show that heavy-ion collisions at the LHC provide a promising environment to search for signatures with displaced vertices in well-motivated new physics scenarios. Compared to proton collisions, they offer several advantages: (i) the number of parton level interactions per collision is larger, (ii) there is no pileup, (iii) the lower instantaneous luminosity compared to proton collisions allows one to operate the LHC experiments with very loose triggers, and (iv) there are new production mechanisms that are absent in proton collisions We focus on the third point and show that the modification of the triggers alone can increase the number of observable events by orders of magnitude if the long-lived particles are predominantly produced with low transverse momentum. Our results show that collisions of ions lighter than lead are well motivated from the viewpoint of searches for new physics. We illustrate this for the example of heavy neutrinos in the Neutrino Minimal Standard Model

Searching for dark radiation at the LHC

In this work we explore the intriguing connections between searches for long-lived particles (LLPs) at the LHC and early universe cosmology. We study the non-thermal production of ultra-relativistic particles (i.e. dark radiation) in the early universe via the decay of weak-scale LLPs and show that the cosmologically interesting range ∆Neff ~ 0.01–0.1 corresponds to LLP decay lengths in the mm to cm range. These decay lengths lie at the boundary between prompt and displaced signatures at the LHC and can be comprehensively explored by combining searches for both. To illustrate this point, we consider a scenario where the LLP decays into a charged lepton and a (nearly) massless invisible particle. By reinterpreting searches for promptly decaying sleptons and for displaced leptons at both ATLAS and CMS we can then directly compare LHC exclusions with cosmological observables. We find that the CMB-S4 target value of ∆Neff = 0.06 is already excluded by current LHC searches and even smaller values can be probed for LLP masses at the electroweak scale

Back analysis of the 2014 San Leo Landslide using combined terrestrial laser scanning and 3D distinct element modelling

This is the author accepted manuscript. The final version is available from Springer Verlag via http://dx.doi.org/10.1007/s00603-015-0763-5© 2015 Springer-Verlag Wien Landslides of the lateral spreading type, involving brittle geological units overlying ductile terrains, are a common occurrence in the sandstone and limestone plateaux of the northern Apennines of Italy. The edges of these plateaux are often the location of rapid landslide phenomena, such as rock slides, rock falls and topples. In this paper, we present a back analysis of a recent landslide (February 2014), involving the north-eastern sector of the San Leo rock slab (northern Apennines, Emilia-Romagna Region) which is a representative example of this type of phenomena. The aquifer hosted in the fractured slab, due to its relatively higher secondary permeability in comparison to the lower clayey units leads to the development of perennial and ephemeral springs at the contact between the two units. The related piping erosion phenomena, together with slope processes in the clay-shales have led to the progressive undermining of the slab, eventually predisposing large-scale landslides. Stability analyses were conducted coupling terrestrial laser scanning (TLS) and distinct element methods (DEMs). TLS point clouds were analysed to determine the pre- and post-failure geometry, the extension of the detachment area and the joint network characteristics. The block dimensions in the landslide deposit were mapped and used to infer the spacing of the discontinuities for insertion into the numerical model. Three-dimensional distinct element simulations were conducted, with and without undermining of the rock slab. The analyses allowed an assessment of the role of the undermining, together with the presence of an almost vertical joint set, striking sub-parallel to the cliff orientation, on the development of the slope instability processes. Based on the TLS and on the numerical simulation results, an interpretation of the landslide mechanism is proposed