Federated Learning: Breaking Down Barriers in Global Genomic Research.

Recent advancements in Next-Generation Sequencing (NGS) technologies have revolutionized genomic research, presenting unprecedented opportunities for personalized medicine and population genetics. However, issues such as data silos, privacy concerns, and regulatory challenges hinder large-scale data integration and collaboration. Federated Learning (FL) has emerged as a transformative solution, enabling decentralized data analysis while preserving privacy and complying with regulations such as the General Data Protection Regulation (GDPR).

Deciphering the Complexity of FSHD: A Multimodal Approach as a Model for Rare Disorders.

Rare diseases are heterogeneous diseases characterized by various symptoms and signs. Due to the low prevalence of such conditions (less than 1 in 2000 people), medical expertise is limited, knowledge is poor and patients' care provided by medical centers is inadequate. An accurate diagnosis is frequently challenging and ongoing research is also insufficient, thus complicating the understanding of the natural progression of the rarest disorders.

Variants and Autosomal Dominant Retinitis Pigmentosa: Insights from the Italian Genetic Landscape.

Autosomal dominant retinitis pigmentosa (AD-RP) is caused by several genes, among which is one of the most investigated. This article will be focused on and its role in explaining AD-RP cases in the Italian population, taking advantage of the experience of the Genomic Medicine Laboratory UILDM at the Santa Lucia Foundation IRCCS. The retrospective evaluation of the distribution of variants in the Italian patients with a clinical suspicion of RP pointed out eight variants.

Exploring the Aβ fibrillogenesis timeline by atomic force microscopy and surface enhanced Raman spectroscopy.

Alzheimer's disease (AD) is a progressive debilitating neurological disorder representing the most common neurodegenerative disease worldwide. Although the exact pathogenic mechanisms of AD remain unresolved, the presence of extracellular amyloid-β peptide 1-42 (Aβ) plaques in the parenchymal and cortical brain is considered one of the hallmarks of the disease. In this work, we investigated the Aβ fibrillogenesis timeline up to 48 h of incubation, providing morphological and chemo-structural characterization of the main assemblies formed during the aggregation process of Aβ, by atomic force microscopy (AFM) and surface enhanced Raman spectroscopy (SERS), respectively.

The impact of updates in headache quality measures on adherence to best practices in a neurology resident clinic: A quality improvement study.

Objective: To apply the 2019 joint American Academy of Neurology (AAN) and American Headache Society (AHS) quality measures for headache management to a cohort of neurology resident physicians and then assess outcomes related to guideline adherence.

Background: The optimization of headache management is essential to reduce both the individual and systemic impact of these disorders. In 2014, the AAN developed 10 quality measures for evidence-based management of patients with headache.

Innovations in Medicine: Exploring ChatGPT's Impact on Rare Disorder Management.

Artificial intelligence (AI) is rapidly transforming the field of medicine, announcing a new era of innovation and efficiency. Among AI programs designed for general use, ChatGPT holds a prominent position, using an innovative language model developed by OpenAI. Thanks to the use of deep learning techniques, ChatGPT stands out as an exceptionally viable tool, renowned for generating human-like responses to queries.

Structure-Toxicity Relationship in Intermediate Fibrils from α-Synuclein Condensates.

The aberrant aggregation of α-synuclein (αS) into amyloid fibrils is associated with a range of highly debilitating neurodegenerative conditions, including Parkinson's disease. Although the structural properties of mature amyloids of αS are currently understood, the nature of transient protofilaments and fibrils that appear during αS aggregation remains elusive. Using solid-state nuclear magnetic resonance (ssNMR), cryogenic electron microscopy (cryo-EM), and biophysical methods, we here characterized intermediate amyloid fibrils of αS forming during the aggregation from liquid-like spherical condensates to mature amyloids adopting the structure of pathologically observed aggregates.

A single-domain antibody detects and neutralises toxic Aβ oligomers in the Alzheimer's disease CSF.

Background: Amyloid-β (Aβ) aggregation consists of a complex chain of nucleation events producing soluble oligomeric intermediates, which are considered the major neurotoxic agents in Alzheimer's disease (AD). Cerebral lesions in the brain of AD patients start to develop 20 years before symptom onset; however, no preventive strategies, effective treatments, or specific and sensitive diagnostic tests to identify people with early-stage AD are currently available. In addition, the isolation and characterisation of neurotoxic Aβ oligomers are particularly difficult because of their transient and heterogeneous nature.

Characterization of D4Z4 alleles and assessment of de novo cases in Facioscapulohumeral dystrophy (FSHD) in a cohort of Italian families.

Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant disease, although 10%-30% of cases are sporadic. However, this percentage may include truly de novo patients (carrying a reduced D4Z4 allele that is not present in either of the parents) and patients with apparently sporadic disease resulting from mosaicism, non-penetrance, or complex genetic situations in either patients or parents. In this study, we characterized the D4Z4 Reduced Alleles (DRA) and evaluated the frequency of truly de novo cases in FSHD1 in a cohort of DNA samples received consecutively for FSHD-diagnostic from 100 Italian families.

Long-Term Structural and Functional Assessment of Doyne Honeycomb Retinal Dystrophy following Nanosecond 2RT Laser Treatment: A Case Series.

Introduction: Doyne honeycomb retinal dystrophy (DHRD), or autosomal dominant radial drusen, is a genetic disease caused by pathogenic variants of the epidermal growth factor (EGF)-containing fibulin-like extracellular matrix protein 1 gene and is characterized by the formation of subretinal drusenoid deposits. In a previous study, we reported the short-term beneficial effects of nanosecond laser treatment (2RT) on retinal function in DHRD. The aim of the present report was to describe the findings of a long-term follow-up of retinal structure/function in a small case series of patients with DHRD who underwent 2RT treatment.

A Splicing Variant in RDH8 Is Associated with Autosomal Recessive Stargardt Macular Dystrophy.

Stargardt macular dystrophy is a genetic disorder, but in many cases, the causative gene remains unrevealed. Through a combined approach (whole-exome sequencing and phenotype/family-driven filtering algorithm) and a multilevel validation (international database searching, prediction scores calculation, splicing analysis assay, segregation analyses), a biallelic mutation in the gene was identified to be responsible for Stargardt macular dystrophy in a consanguineous Italian family. This paper is a report on the first family in which a biallelic deleterious mutation in is detected.

Epigenetic profiling of the D4Z4 locus: Optimization of the protocol for studying DNA methylation at single CpG site level.

The alteration of epigenetic modifications, including DNA methylation, can contribute to the etiopathogenesis and progression of many diseases. Among them, facioscapulohumeral dystrophy (FSHD) is a muscular disorder characterized by the loss of repressive epigenetic features affecting the D4Z4 locus (4q35). As a consequence, these alterations are responsible for DNA hypomethylation and a transcriptional-active chromatin conformation change that, in turn, lead to the aberrant expression of DUX4 in muscle cells.

Quantitative Attribution of the Protective Effects of Aminosterols against Protein Aggregates to Their Chemical Structures and Ability to Modulate Biological Membranes.

Natural aminosterols are promising drug candidates against neurodegenerative diseases, like Alzheimer and Parkinson, and one relevant protective mechanism occurs via their binding to biological membranes and displacement or binding inhibition of amyloidogenic proteins and their cytotoxic oligomers. We compared three chemically different aminosterols, finding that they exhibited different (i) binding affinities, (ii) charge neutralizations, (iii) mechanical reinforcements, and (iv) key lipid redistributions within membranes of reconstituted liposomes. They also had different potencies (EC) in protecting cultured cell membranes against amyloid-β oligomers.

α-Synuclein oligomers and fibrils: partners in crime in synucleinopathies.

The misfolding and aggregation of α-synuclein is the general hallmark of a group of devastating neurodegenerative pathologies referred to as synucleinopathies, such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. In such conditions, a range of different misfolded aggregates, including oligomers, protofibrils, and fibrils, are present both in neurons and glial cells. Growing experimental evidence supports the proposition that soluble oligomeric assemblies, formed during the early phases of the aggregation process, are the major culprits of neuronal toxicity; at the same time, fibrillar conformers appear to be the most efficient at propagating among interconnected neurons, thus contributing to the spreading of α-synuclein pathology.

The Toxicity of Protein Aggregates: New Insights into the Mechanisms.

The aberrant aggregation of specific peptides and proteins is the common feature of a range of more than 50 human pathologies, collectively referred to as protein misfolding diseases [...

APP and Bace1: Differential effect of cholesterol enrichment on processing and plasma membrane mobility.

High cholesterol levels are a risk factor for the development of Alzheimer's disease. Experiments investigating the influence of cholesterol on the proteolytic processing of the amyloid precursor protein (APP) by the β-secretase Bace1 and on their proximity in cells have led to conflicting results. By using a fluorescence bioassay coupled with flow cytometry we found a direct correlation between the increase in membrane cholesterol amount and the degree of APP shedding in living human neuroblastoma cells.

Characterization of Pairs of Toxic and Nontoxic Misfolded Protein Oligomers Elucidates the Structural Determinants of Oligomer Toxicity in Protein Misfolding Diseases.

The aberrant misfolding and aggregation of peptides and proteins into amyloid aggregates occurs in over 50 largely incurable protein misfolding diseases. These pathologies include Alzheimer's and Parkinson's diseases, which are global medical emergencies owing to their prevalence in increasingly aging populations worldwide. Although the presence of mature amyloid aggregates is a hallmark of such neurodegenerative diseases, misfolded protein oligomers are increasingly recognized as of central importance in the pathogenesis of many of these maladies.

NIPAT as Non-Invasive Prenatal Paternity Testing Using a Panel of 861 SNVs.

In 1997, it was discovered that maternal plasma contains Cell-Free Fetal DNA (cffDNA). cffDNA has been investigated as a source of DNA for non-invasive prenatal testing for fetal pathologies, as well as for non-invasive paternity testing. While the advent of Next Generation Sequencing (NGS) led to the routine use of Non-Invasive Prenatal Screening (NIPT or NIPS), few data are available regarding the reliability and reproducibility of Non-Invasive Prenatal Paternity Testing (NIPPT or NIPAT).

Longitudinal Structure-Function Evaluation in a Patient with -Associated Retinal Dystrophy: Progressive Visual Function Loss with Retinal Remodeling.

Background: Retinal dystrophies related to damaging variants in the cadherin-related family member 1 () gene are rare and phenotypically heterogeneous. Here, we report a longitudinal (three-year) structure-function evaluation of a patient with a -related retinal dystrophy.

Methods: A 14-year-old girl was evaluated between 2019 and 2022.

Analysis of Genetic Variants Associated with COVID-19 Outcome Highlights Different Distributions among Populations.

The clinical spectrum of SARS-CoV-2 infection ranges from asymptomatic status to mild infections, to severe disease and death. In this context, the identification of specific susceptibility factors is crucial to detect people at the higher risk of severe disease and improve the outcome of COVID-19 treatment. Several studies identified genetic variants conferring higher risk of SARS-CoV-2 infection and COVID-19 severity.