Development of a Highly Potent Transthyretin Amyloidogenesis Inhibitor: Design, Synthesis, and Evaluation

Transthyretin amyloidosis (ATTR) is a group of fatal diseases described by the misfolding and amyloid deposition of transthyretin (TTR). Discovering small molecules that bind and stabilize the TTR tetramer, preventing its dissociation and subsequent aggregation, is a therapeutic strategy for these pathologies. Departing from the crystal structure of TTR in complex with tolcapone, a potent binder in clinical trials for ATTR, we combined rational design and molecular dynamics (MD) simulations to generate a series of novel halogenated kinetic stabilizers. Among them, M-23 displays one of the highest affinities for TTR described so far. The TTR/M-23 crystal structure confirmed the formation of unprecedented protein–ligand contacts, as predicted by MD simulations, leading to an enhanced tetramer stability both in vitro and in whole serum. We demonstrate that MD-assisted design of TTR ligands constitutes a new avenue for discovering molecules that, like M-23, hold the potential to become highly potent drugs to treat ATTR

Brain structural correlates of sensory phenomena in patients with obsessive-compulsive disorder

Background: sensory phenomena (SP) are uncomfortable feelings, including bodily sensations, sense of inner tension, 'just-right' perceptions, feelings of incompleteness, or 'urge-only' phenomena, which have been described to precede, trigger or accompany repetitive behaviours in individuals with obsessive-compulsive disorder (OCD). Sensory phenomena are also observed in individuals with tic disorders, and previous research suggests that sensorimotor cortex abnormalities underpin the presence of SP in such patients. However, to our knowledge, no studies have assessed the neural correlates of SP in patients with OCD. Methods: we assessed the presence of SP using the University of São Paulo Sensory Phenomena Scale in patients with OCD and healthy controls from specialized units in São Paulo, Brazil, and Barcelona. All participants underwent a structural magnetic resonance examination, and brain images were examined using DARTEL voxel-based morphometry. We evaluated grey matter volume differences between patients with and without SP and healthy controls within the sensorimotor and premotor cortices. Results: we included 106 patients with OCD and 87 controls in our study. Patients with SP (67% of the sample) showed grey matter volume increases in the left sensorimotor cortex in comparison to patients without SP and bilateral sensorimotor cortex grey matter volume increases in comparison to controls. No differences were observed between patients without SP and controls. Limitations: most patients were medicated. Participant recruitment and image acquisition were performed in 2 different centres. Conclusion: we have identified a structural correlate of SP in patients with OCD involving grey matter volume increases within the sensorimotor cortex; this finding is in agreement with those of tic disorder studies showing that abnormal activity and volume increases within this region are associated with the urges preceding tic onset

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration

Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency < 0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency < 0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology

Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer's disease

Altres ajuts: The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The research was funded in part by the European Commission Seventh Framework Programme for research, technological development, and demonstration under grant agreement 305299 (AgedBrainSYSBIO), the Belgian Science Policy Office Interuniversity Attraction Poles program, the Alzheimer Research Foundation (SAO-FRA), the Flemish government-initiated Flanders Impulse Program on Networks for Dementia Research (VIND), the Flemish government-initiated Methusalem Excellence Program, the Research Foundation Flanders (FWO), the VIB Technology Fund, the University of Antwerp Research Fund, Belgium; European Regional Development Fund, the Italian Ministry of Health (Ricerca Corrente and RF-2010-2319722), and the Fondazione Cassa di Risparmio di Pistoia e Pescia grant (2014.0365).Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD

IgE allergy diagnostics and other relevant tests in allergy, a World Allergy Organization position paper

Currently, testing for immunoglobulin E (IgE) sensitization is the cornerstone of diagnostic evaluation in suspected allergic conditions. This review provides a thorough and updated critical appraisal of the most frequently used diagnostic tests, both in vivo and in vitro. It discusses skin tests, challenges, and serological and cellular in vitro tests, and provides an overview of indications, advantages and disadvantages of each in conditions such as respiratory, food, venom, drug, and occupational allergy. Skin prick testing remains the first line approach in most instances; the added value of serum specific IgE to whole allergen extracts or components, as well as the role of basophil activation tests, is evaluated. Unproven, non-validated, diagnostic tests are also discussed. Throughout the review, the reader must bear in mind the relevance of differentiating between sensitization and allergy; the latter entails not only allergic sensitization, but also clinically relevant symptoms triggered by the culprit allergen.info:eu-repo/semantics/publishedVersio

Nanomicelles of Radium Dichloride [223Ra]RaCl2 Co-Loaded with Radioactive Gold [198Au]Au Nanoparticles for Targeted Alpha–Beta Radionuclide Therapy of Osteosarcoma

Alpha and beta particulate radiation are used for non-treated neoplasia, due to their ability to reach and remain in tumor sites. Radium-223 (223Ra), an alpha emitter, promotes localized cytotoxic effects, while radioactive gold (198Au), beta-type energy, reduces radiation in the surrounding tissues. Nanotechnology, including several radioactive nanoparticles, can be safely and effectively used in cancer treatment. In this context, this study aims to analyze the antitumoral effects of [223Ra]Ra nanomicelles co-loaded with radioactive gold nanoparticles ([198Au]AuNPs). For this, we synthesize and characterize nanomicelles, as well as analyze some parameters, such as particle size, radioactivity emission, dynamic light scattering, and microscopic atomic force. [223Ra]Ra nanomicelles co-loaded with [198Au]AuNPs, with simultaneous alpha and beta emission, showed no instability, a mean particle size of 296 nm, and a PDI of 0.201 (±0.096). Furthermore, nanomicelles were tested in an in vitro cytotoxicity assay. We observed a significant increase in tumor cell death using combined alpha and beta therapy in the same formulation, compared with these components used alone. Together, these results show, for the first time, an efficient association between alpha and beta therapies, which could become a promising tool in the control of tumor progression

IgE allergy diagnostics and other relevant tests in allergy, a World Allergy Organization position paper

Currently, testing for immunoglobulin E (IgE) sensitization is the cornerstone of diagnostic evaluation in suspected allergic conditions. This review provides a thorough and updated critical appraisal of the most frequently used diagnostic tests, both in vivo and in vitro. It discusses skin tests, challenges, and serological and cellular in vitro tests, and provides an overview of indications, advantages and disadvantages of each in conditions such as respiratory, food, venom, drug, and occupational allergy. Skin prick testing remains the first line approach in most instances; the added value of serum specific IgE to whole allergen extracts or components, as well as the role of basophil activation tests, is evaluated. Unproven, non-validated, diagnostic tests are also discussed. Throughout the review, the reader must bear in mind the relevance of differentiating between sensitization and allergy; the latter entails not only allergic sensitization, but also clinically relevant symptoms triggered by the culprit allergen

Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer’s disease

Abstract: Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD