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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. ispartof: Int J Environ Res Public Health vol:20 issue:2 pages:968- ispartof: location:Switzerland status: Published online

Fabry disease is caused by a deficiency of lysosomal alpha galactosidase and has a very large genotypic and phenotypic spectrum. Some patients who carry hypomorphic mutations can benefit from oral therapy with a pharmacological chaperone. The drug requires a very precise regimen because it is a reversible inhibitor of alpha-galactosidase. We looked for molecules that can potentiate this pharmacological chaperone, among drugs that have already been approved for other diseases. We tested candidate molecules in fibroblasts derived from a patient carrying a large deletion in the gene GLA, which were stably transfected with a plasmid expressing hypomorphic mutants. In our cell model, three drugs were able to potentiate the action of the pharmacological chaperone. We focused our attention on one of them, acetylsalicylic acid. We expect that acetylsalicylic acid can be used in synergy with the Fabry disease pharmacological chaperone and prolong its stabilizing effect on alpha-galactosidase.

The most common cause of human congenital disorders of glycosylation (CDG) are mutations in the phosphomannomutase gene PMM2, which affect protein N-linked glycosylation. The yeast gene SEC53 encodes a nearly-identical homolog of human PMM2. We evolved 384 populations of yeast harboring one of two human-disease-associated alleles, sec53-V238M and sec53-F126L, or wild-type SEC53. We find that after 1,000 generations, most populations compensate for the slow-growth phenotype associated with the sec53 human-disease-associated alleles. Through whole-genome sequencing we identify compensatory mutations, including known SEC53 genetic interactors. We observe an enrichment of compensatory mutations in other genes whose human homologs are associated with Type 1 CDG, including PGM1, which encodes the minor isoform of phosphoglucomutase in yeast. By genetic reconstruction, we show that evolved pgm1 mutations are dominant and allele-specific genetic interactors that restore both protein glycosylation and growth of yeast harboring the sec53-V238M allele. Finally, we characterize the enzymatic activity of purified Pgm1 mutant proteins. We find that reduction, but not elimination, of Pgm1 activity best compensates for the deleterious phenotypes associated with the sec53-V238M allele. Broadly, our results demonstrate the power of experimental evolution as a tool for identifying genes and pathways that compensate for human-disease associated alleles.

The 3,3&prime, 5,5&prime, tetrachloro-2-iodo-4,4&prime, bipyridine structure is proposed as a novel chemical scaffold for the design of new transthyretin (TTR) fibrillogenesis inhibitors. In the frame of a proof-of-principle exploration, four chiral 3,3&prime, tetrachloro-2-iodo-2&prime, substituted-4,4&prime, bipyridines were rationally designed and prepared from a simple trihalopyridine in three steps, including a Cu-catalysed Finkelstein reaction to introduce iodine atoms on the heteroaromatic scaffold, and a Pd-catalysed coupling reaction to install the 2&prime, substituent. The corresponding racemates, along with other five chiral 4,4&prime, bipyridines containing halogens as substituents, were enantioseparated by high-performance liquid chromatography in order to obtain pure enantiomer pairs. All stereoisomers were tested against the amyloid fibril formation (FF) of wild type (WT)-TTR and two mutant variants, V30M and Y78F, in acid mediated aggregation experiments. Among the 4,4&prime, bipyridine derivatives, interesting inhibition activity was obtained for both enantiomers of the 3,3&prime, tetrachloro-2&prime, (4-hydroxyphenyl)-2-iodo-4,4&prime, bipyridine. In silico docking studies were carried out in order to explore possible binding modes of the 4,4&prime, bipyridine derivatives into the TTR. The gained results point out the importance of the right combination of H-bond sites and the presence of iodine as halogen-bond donor. Both experimental and theoretical evidences pave the way for the utilization of the iodinated 4,4&prime, bipyridine core as template to design new promising inhibitors of TTR amyloidogenesis.

The term “pharmacological chaperone” was introduced 20 years ago. Since then the approach with this type of drug has been proposed for several diseases, lysosomal storage disorders representing the most popular targets. The hallmark of a pharmacological chaperone is its ability to bind a protein specifically and stabilize it. This property can be beneficial for curing diseases that are associated with protein mutants that are intrinsically active but unstable. The total activity of the affected proteins in the cell is lower than normal because they are cleared by the quality control system. Although most pharmacological chaperones are reversible competitive inhibitors or antagonists of their target proteins, the inhibitory activity is neither required nor desirable. This issue is well documented by specific examples among which those concerning Fabry disease. Direct specific binding is not the only mechanism by which small molecules can rescue mutant proteins in the cell. These drugs and the properly defined pharmacological chaperones can work together with different and possibly synergistic modes of action to revert a disease phenotype caused by an unstable protein.

Additional file 1. Student Satisfaction Questionnaire.docx

Indium phosphide quantum dots (QDs) have emerged as a new class of fluorescent nanocrystals for manifold applications, from biophotonics to nanomedicine. Recent efforts in improving the photoluminescence quantum yield, the chemical stability and the biocompatibility turned them into a valid alternative to well established Cd-based nanocrystals. In vitro studies provided first evidence for the lower toxicity of In-based QDs. Nonetheless, an urgent need exists for further assessment of the potential toxic effects in vivo. Here we use the freshwater polyp Hydra vulgaris, a well-established model previously adopted to assess the toxicity of CdSe/CdS nanorods and CdTe QDs. A systematic multilevel analysis was carried out in vivo, ex vivo, and in vitro comparing toxicity end points of CdSe- and InP-based QDs, passivated by ZnSe/ZnS shells and surface functionalized with penicillamine. Final results demonstrate that both the chemical composition of the QD core (InP vs CdSe) and the shell play a crucial role for final outcomes. Remarkably, in absence of in vivo alterations, cell and molecular alterations revealed hidden toxicity aspects, highlighting the biosafety of InP-based nanocrystals and outlining the importance of integrated multilevel analyses for proper QDs risk assessment., L.M. and P.R. acknowledge the French National Research Agency ANR (contracts NANOFRET, ANR-12-NANO-0007-03, NEUTRINOS, ANR-16-CE09-0015-03, and FLUO, ANR-18-CE09-0039-01). We thank Dr. Tim Senden, Dr. Christophe Lincheneau, and Dr. Karl David Wegner for QD synthesis and Fabio Agnese for TEM imaging. M.M. acknowledges financial support from the European Union′s Horizon 2020 research and innovation programme (Marie Skłodowska-Curie grant agreement No. 660228).

A large number of mutations causing PMM2-CDG, which is the most frequent disorder of glycosylation, destabilize phosphomannomutase2. We looked for a pharmacological chaperone to cure PMM2-CDG, starting from the structure of a natural ligand of phosphomannomutase2, &alpha, glucose-1,6-bisphosphate. The compound, &beta, glucose-1,6-bisphosphate, was synthesized and characterized via 31P-NMR. &beta, glucose-1,6-bisphosphate binds its target enzyme in silico. The binding induces a large conformational change that was predicted by the program PELE and validated in vitro by limited proteolysis. The ability of the compound to stabilize wild type phosphomannomutase2, as well as frequently encountered pathogenic mutants, was measured using thermal shift assay. &beta, glucose-1,6-bisphosphate is relatively resistant to the enzyme that specifically hydrolyses natural esose-bisphosphates.

Thyroid hormones are well known halogen bond (XB) donors as shown by short I···O contacts that underlie the selective binding of hormone thyroxine (T4) to transthyretin (TTR).[1] This protein is composed of four subunits, which are organized into a homotetrameric quaternary structure with two dimer-dimer interfaces.Dissociation of the native tetramer and subsequent aggregation to form insoluble amyloid fibrils are involved in several TTR amyloidosis (ATTR) diseases. Over the past decade, it was observed that T4 and other small molecules could inhibit the tetramer dissociation, and therefore be efficacious against ATTR diseases.[1] However, currently, these diseases still lack an effective therapy. On this basis, we describe herein the development of new atropisomeric iodinated 4,4'-bipyridines (IBPYs)[2] as TTR misfolding inhibitors. In particular, a docking study was performed in order to inspect interactions and binding modes of the IBPYs into the TTR. The (M)-2-iodo-4,4'-bipyridyl substructure has been identified as suitable for developing the new TTR stabilizers (Figure b). Interestingly, in this case, a XB was observed between the 2-iodine of IBPY and the side chain of Ser117' with distance and angle values in accord with what is defined as XB biomolecular contacts (penetration of the van der Waals atomic spheres -2.8%, angles: C-I···O = 149.34° and I···O-C = 111.85°).[3] References [1] Johnson, S. M., Wiseman, R. L., Sekijima, Y., Green, N. S., Adamski-Weiner, S. L., Kelly, J. W., Acc. Chem. Res. 2005, 38, 911-921. [2] (a) Mamane, V., Aubert, E., Peluso, P., Cossu, S., J. Org. Chem. 2013, 78, 7683-7689; (b) Mamane, V., Peluso, P., Aubert, E., Cossu, S., Pale, P., J. Org. Chem. 2016, 81, 4576-4587. [3] Ho, P. S., Top. Curr. Chem. 2015, 358, 241-276. Acknowledgement: This work has been supported by Università Ca' Foscari di Venezia, Italy (DSMN, ADIR funds). V. M. thanks the International Center Frontier Research in Chemistry (icFRC) and the Laboratory of Excellence for Complex System Chemistry (LabEx CSC).

Water ecosystems represent main targets of unintentional contamination of nanomaterials, due to industrial waste or other anthropogenic activities. Nanoparticle insult to living organisms may occur in a sequential way, first by chemical interactions of the material with the target membrane, then by progressive internalisation and interaction with cellular structures and organelles. These events trigger a signal transduction, through which cells modulate molecular pathway in order to respond and survive to the external elicitation. Therefore, the analysis of the global changes of the molecular machinery, possibly induced in an organism upon exposure to a given nanomaterial, may provide unique clues for proper and exhaustive risk assessment. Here, we tested the impact of core/shell CdSe/ZnS QDs coated by a positively charged polymer on two aquatic species, the polyp Hydra vulgaris and the coral S. pistillata, representative of freshwater and sea habitats, respectively. By using reliable approaches based on animal behaviour and physiology together with a whole transcriptomic profiling, we determined several toxicity endpoints. Despite the difference in the efficiency of uptake, both species were severely affected by QD treatment, resulting in dramatic morphological damages and tissue bleaching. Global transcriptional changes were also detected in both organisms, but presenting different temporal dynamics, suggesting both common and divergent functional responses in the two sentinel organisms. Due to the striking conservation of structure and genomic organisation among animals throughout evolution, our expression profiling offers new clues to identify novel molecular markers and pathways for comparative transcriptomics of nanotoxicity., This project was supported by Italy-Israel Joint Innovation Program for Scientific and Technological Cooperation in R&D to CT and by the European Commission (project FutureNanoNeeds to WJP).