Folding mechanisms steer the amyloid fibril formation propensity of highly homologous proteins

Significant advances in the understanding of the molecular determinants of fibrillogenesis can be expected from comparative studies of the aggregation propensities of proteins with highly homologous structures but different folding pathways. Here, we fully characterize, by means of stopped-flow, T-jump, CD and DSC experiments, the unfolding mechanisms of three highly homologous proteins, zinc binding Ros87 and Ml153-149 and zinc-lacking Ml452-151. The results indicate that the three proteins significantly differ in terms of stability and (un)folding mechanisms. Particularly, Ros87 and Ml153-149 appear to be much more stable to guanidine denaturation and are characterized by folding mechanisms including the presence of an intermediate. On the other hand, metal lacking Ml452-151 folds according to a classic two-state model. Successively, we have monitored the capabilities of Ros87, Ml452-151 and Ml153-149 to form amyloid fibrils under native conditions. Particularly, we show, by CD, fluorescence, DLS, TEM and SEM experiments, that after 168 hours, amyloid formation of Ros87 has started, while Ml153-149 has formed only amorphous aggregates and Ml452-151 is still monomeric in solution. This study shows how metal binding can influence protein folding pathways and thereby control conformational accessibility to aggregation-prone states, which in turn changes aggregation kinetics, shedding light on the role of metal ions in the development of protein deposition diseases

A perturbed MicroRNA expression pattern characterizes embryonic neural stem cells derived from a severe mouse model of spinal muscular atrophy (SMA)

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and the leading genetic cause of death in infants. Despite the disease-causing gene, survival motor neuron (SMN1), encodes a ubiquitous protein, SMN1 deficiency preferentially affects spinal motor neurons (MNs), leaving the basis of this selective cell damage still unexplained. As neural stem cells (NSCs) are multipotent self-renewing cells that can differentiate into neurons, they represent an in vitro model for elucidating the pathogenetic mechanism of neurodegenerative diseases such as SMA. Here we characterize for the first time neural stem cells (NSCs) derived from embryonic spinal cords of a severe SMNΔ7 SMA mouse model. SMNΔ7 NSCs behave as their wild type (WT) counterparts, when we consider neurosphere formation ability and the expression levels of specific regional and self-renewal markers. However, they show a perturbed cell cycle phase distribution and an increased proliferation rate compared to wild type cells. Moreover, SMNΔ7 NSCs are characterized by the differential expression of a limited number of miRNAs, among which miR-335-5p and miR-100-5p, reduced in SMNΔ7 NSCs compared to WT cells. We suggest that such miRNAs may be related to the proliferation differences characterizing SMNΔ7 NSCs, and may be potentially involved in the molecular mechanisms of SMA

Human vulnerability in the metaverse

Technology companies promise that it will bring about a newly empowered, just, and equitable society, by removing physical  barriers to social participation and enhancing human capabilities and experiences.  But there are many factors to consider  when discussing what  the metaverse should be, how significant it might become, and how it will affect both the individual and society. On the one hand, the report acknowledges the positive impact the metaverse could have in empowering individuals and enhancing human capabilities, particularly for those who experience vulnerability in the offline world. However, it also highlights the reinforcement of social inequalities due to the digital divide, limited access for certain groups, and the perpetuation of subordination and conformity within the virtual realm.The paper questions why the metaverse is being developed, how it will be created and accessed, who will be creating it, and how it is defined. It also explores the nuances and definitions of vulnerability and positions human vulnerability within the context of the metaverse to consider its impact.In light of these findings, the report presents a set of recommendations for governments and regulators. These include requiring businesses developing the metaverse to follow the UN Guiding Principles on Business and Human Rights, involving vulnerable groups in the design process, establishing guidelines for measuring the impact on human rights, and enacting new laws and policies to address gaps in the legal framework.As the metaverse continues to gain momentum and attract widespread interest, the potential risks and vulnerabilities must be acknowledged and mitigated. Effective Protection of Fundamental Rights in a pluralist worl

Licensing high-risk artificial intelligence: toward ex ante justification for a disruptive technology

Effective Protection of Fundamental Rights in a pluralist worl

Pricing privacy – the right to know the value of your personal data

Effective Protection of Fundamental Rights in a pluralist worl

Understanding first-year students’ curiosity and interest about physics : Lessons learned from the HOPE project

This paper focuses on results of an interview based survey of first-year university physics students, carried out within the EU Horizons in Physics Education (HOPE) project (http://hopenetwork.eu/). 94 interviews conducted in 13 universities have been analyzed to investigate the factors that inspire young people to study physics. In particular, the main motivational factor, which was proven to consist of personal interest and curiosity, was unfolded into different categories and detailed interest profiles were produced. The results are arguably useful to help academic curriculum developers and teaching personnel in physics departments to provide guidance to students in developing and focusing their interest towards specific sub-fields and/or to design targeted recruitment and outreach initiatives.Peer reviewe

Lumasiran treatment in pediatric patients with PH1: real-world data within a compassionate use program in Italy

Background Primary hyperoxaluria (PH) is a rare, severe genetic disorder, characterized by increased urinary excretion of calcium oxalate, which is responsible for kidney damage and systemic clinical manifestations. Since the year 2020, a new molecule, lumasiran, based on RNA interference (RNAi) technology, has been added to the traditional therapeutic approach. The aim of this analysis was to define the baseline characteristics of a PH1 pediatric population treated with lumasiran in a compassionate-use program setting, and to evaluate the medium-term efficacy of this drug in the routine clinical setting.Methods A retrospective observational analysis was conducted in nine pediatric patients (male:female 5:4; median age at lumasiran start 1.9 years, range 0-14.1). Data concerning oxalate concentration in plasma and urine, kidney stones events, ultrasound and kidney function were collected during the study period (follow-up, mean +/- standard deviation: 15.3 +/- 5 months).Results In this analysis, a reduction in the urinary oxalate to creatinine ratio (reduction range within the sixth month of treatment from 25.8% to 69.6%, median 51.2%) as well as plasma oxalate concentration under the limit of supersaturation of oxalate in all the patients. Only one patient presented new stone events; kidney ultrasonographic findings related to nephrocalcinosis remained stable in eight out of nine patients. Glomerular filtration rate remained stable during treatment. No adverse events related to lumasiran were noted.Conclusion Data from this analysis support the efficacy and safety of lumasiran in a pediatric clinical setting, especially if administrated in early life

What inspires young people to study physics? Results from the WG1 interviews survey

The talk will focus on the main results of an Interview based Survey of 1st Year University Physics Students, carried out within Working Group 1 (WG1) of the HOPE project. Among the HOPE activities, 112 interviews have been conducted in 16 universities, in order to investigate in some depth the factors that inspire young people to study physics and to identify possible critical factors which can produce the dropping out.The individual interviews have been carried out on a selection of students who had previously answered the WG1 Questionnaire on the inspirational factors, led by Gareth Jones from the Imperial College, London. In the talk, we will show how the interviews helped us to unpack the main results achieved with the questionnaire survey. In particular, we will present a comprehensive picture of \u201ccuriosity\u201d which turned out to be the predominant motivating factor and we will show how the interviews can throw extra light on reasons for comparatively low scores for factors like (i) enhancing employment prospects, (ii) effect of physics teacher, (iii) scientists in the family

Probing the Residual Structure in Avian Prion Hexarepeats by CD, NMR and MD Techniques

Many proteins perform essential biological functions by means of regions that lacking specific organized structure exist as an ensemble of interconverting transient conformers. The characterization of such regions, including the description of their structural propensities, number of conformations and relative populations can provide useful insights. Prion diseases result from the conversion of a normal glycoprotein into a misfolded pathogenic isoform. The structures of mammal and chicken prion proteins show a similar fold with a globular domain and a flexible N-terminal portion that contains different repeated regions: octarepeats (PHGGGWGQ) in mammals and hexarepeats (PHNPGY) in chickens. The higher number of prolines in the hexarepeat region suggests that this region may retain a significant amount of residual secondary structure. Here, we report the CD, NMR and MD characterization of a peptide (2-HexaPY) composed of two hexarepeats. We combine experimental NMR data and MD to investigate at atomic level its ensemble-averaged structural properties, demonstrating how each residue of both repeats has a different quantified PPII propensity that shows a periodicity along the sequence. This feature explains the absence of cooperativity to stabilize a PPII conformation. Nonetheless, such residual structure can play a role in nucleating local structural transitions as well as modulating intra-molecular or inter-molecular interactions