Drug Repositioning for Congenital Disorders of Glycosylation (CDG)

R.F. and acknowledge the funding from the Fundação para a Ciência e Tecnologia (FCT), Portugal. S.B. was supported by CDG & Allies—PAIN funding. M.A. acknowledges PhD program at the DISTABIF, Università degli Studi della Campania “Luigi Vanvitelli”, PhD fellowship POR Campania FSE 2014/2020 “Dottorati di Ricerca Con Caratterizzazione Industriale”.Advances in research have boosted therapy development for congenital disorders of glycosylation (CDG), a group of rare genetic disorders affecting protein and lipid glycosylation and glycosylphosphatidylinositol anchor biosynthesis. The (re)use of known drugs for novel medical purposes, known as drug repositioning, is growing for both common and rare disorders. The latest innovation concerns the rational search for repositioned molecules which also benefits from artificial intelligence (AI). Compared to traditional methods, drug repositioning accelerates the overall drug discovery process while saving costs. This is particularly valuable for rare diseases. AI tools have proven their worth in diagnosis, in disease classification and characterization, and ultimately in therapy discovery in rare diseases. The availability of biomarkers and reliable disease models is critical for research and development of new drugs, especially for rare and heterogeneous diseases such as CDG. This work reviews the literature related to repositioned drugs for CDG, discovered by serendipity or through a systemic approach. Recent advances in biomarkers and disease models are also outlined as well as stakeholders' views on AI for therapy discovery in CDG.publishersversionpublishe

Formability Limits, Fractography and Fracture Toughness in Sheet Metal Forming

This paper is focused on the utilisation of double edge notched tension, staggered and shear tests to determine fracture toughness and the formability limits by fracture in principal strain space. The experiments were performed in test specimens with different geometries and ligament angles, and the influence of strain hardening was taken into consideration by selecting two materials (aluminium AA1050-H111 and pure copper), with very different strain hardening exponents. Results are plotted in principal strain space, and the discussion is focused on the link between formability limits, fracture toughness and macroscopic fractography characteristics of the specimens that fail by mode I, mode II or mixed-mode

Formability limits in sheet-bulk forming

This paper is focused on the characterization of the fracture limits in sheet-bulk forming. The approach extends to crack opening in mode III (out-of-plane shearing), a digital image correlation-based methodology for determining the fracture forming limits in mode I (tension) and mode II (in-plane shearing). For this purpose, a sheet lengthwise compression test with different end constraints is developed and utilized to obtain the strain loading paths up to fracture in mode III, for the first time directly from sheets. The three fracture forming limits of sheet-bulk forming are first characterized in principal strain space and then transformed into the space of effective strain vs. stress triaxiality by means of an analytical procedure based on anisotropic plastic deformation under proportional loading. A new uncoupled ductile damage criterion is introduced and successfully implemented in an in-house finite element computer program to predict the location where the out-of-plane shearing cracks are triggered. The overall results point out to the difficulty in merging the three different fracture forming limits into a single-branched fracture locus covering the plane stress deformation conditions and the three-dimensional states of stress that are likely to be found in sheet-bulk forming processes.info:eu-repo/semantics/publishedVersio

A Community-Based Participatory Framework to Co-Develop Patient Education Materials (PEMs) for Rare Diseases: A Model Transferable across Diseases

At least 50% of chronic disease patients don’t follow their care plans, leading to lower health outcomes and higher medical costs. Providing Patient Education Materials (PEMs) to individuals living with a disease can help to overcome these problems. PEMs are especially beneficial for people suffering from multisystemic and underrecognized diseases, such as rare diseases. Congenital disorders of glycosylation (CDG) are ultra-rare diseases, where a need was identified for PEMs in plain language that can clearly explain complex information. Community involvement in the design of PEMs is extremely important for diseases whose needs are underserved, such as rare diseases; however, attempts to involve lay and professional stakeholders are lacking. This paper presents a community-based participatory framework to co-create PEMs for CDG, that is transferable to other diseases. A literature review and questionnaire were performed, and only four articles describing the development of PEMS for rare diseases have been found, which demonstrates a lack of standardized approaches. The framework and PEMs were co-developed with CDG families and will be crucial in increasing health literacy and empowering families. We will close a gap in the creation of PEMs for CDG by delivering these resources in lay language in several languages