Search Results (216)

In recent years, there has been increasing interest in new materials such as ceramic matrix composites (CMCs) for power generation and aerospace propulsion applications through hydrogen combustion. This study employed a deep artificial neural network (DANN) model to predict the ablation performance of CMCs in the hydrogen torch test (HTT). The study was conducted in three phases to increase the accuracy of the model’s predictions. Initially, to predict the thermal behavior of ceramic composites, two linear machine learning models were used known as Lasso and Ridge regression. In the second step, four decision tree-based ensemble machine learning models, namely random forest, gradient boosting regression, extreme gradient boosting regression, and extra tree regression, were used to improve the prediction accuracy metrics, including root mean square error (RMSE), mean absolute error (MAE), correlation coefficient (R² score), and mean absolute percentage error (MAPE), relative to the previously introduced linear models. Finally, to forecast the thermal stability of CMCs with time, an optimized DANN model with two hidden layers having rectified linear unit activation function was developed. The data collection procedure involved preparing CMCs with continuous Yttria-Stabilized Zirconia (YSZ) fibers and silicon carbide (SiC) matrix using a polymer infiltration and pyrolysis (PIP) technique. The samples were exposed to a hydrogen flame at a high heat flux of 183 W/cm² for a duration of 10 min. A good agreement between the DANN model’s predictions and experimental data with an R² score of 0.9671, RMSE of 16.45, an MAE of 14.07, and an MAPE of 3.92% confirmed the acceptability of the developed neural network model in this study. Full article

Money Art is a growing contemporary practice where artists transform banknotes into unique visual works. While conceptually powerful, these artworks present significant conservation challenges due to their fragile substrates and complex material compositions. This study investigates the degradation behaviour of UniPosca acrylic markers applied on zero-euro banknotes, drawing on the techniques of artist RichardHTT, and explores bio-based protective strategies suitable for their preservation. Laboratory samples were prepared to replicate the original artwork and subjected to accelerated ageing. A multi-analytical approach was employed, including multispectral imaging, Fourier trasform infrared (FTIR) and Raman spectroscopy, and scanning electron microscopy (SEM-EDS) colorimetric analysis. Thickness and adhesion properties were assessed with contact micrometry and peel tests, while wettability was evaluated through static contact angle measurements. Four biopolymer coatings, chitosan and chitosan–nanocellulose films with varying CNC concentrations, were evaluated for their transparency, mechanical stability, and compatibility with the substrate. Results showed that painted areas, especially those with blue and black pigments, experienced marked degradation, while, after coating application, samples demonstrated improved chromatic stability, hydrophobicity, and adhesion. Importantly, all coatings were fully removable via enzymatic cleaning with α-amylase, confirming their reversibility. This research highlights the potential of chitosan-based biocomposites as conservation materials for non-traditional artworks and contributes to developing tailored, reversible strategies for contemporary art preservation. Full article

Combined preimplantation genetic testing of aneuploidy (PGT-A) and monogenic disease (PGT-M) can be achieved through PCR-based whole genome amplification (WGA) and next-generation sequencing (NGS). However, pathogenic variant detection is usually achieved indirectly through single nucleotide polymorphism haplotyping, as direct detection of pathogenic variants is not always possible. We evaluated whether isothermal WGA was suitable for combined PGT-A and PGT-M that also permitted direct detection of repeat expansions and large deletions, in addition to indirect linkage analysis using microsatellite markers. Five-cell replicates from selected cell lines were subjected to isothermal or PCR-based WGA, followed by NGS-based PGT-A and direct and indirect PGT-M of Huntington’s disease and spinal muscular atrophy. Both WGA methods accurately detected aneuploidy and large (10 Mb) segmental imbalances. However, isothermal WGA produced higher genotyping accuracy compared with PCR-based WGA for all analysed microsatellite markers (93.5% vs. 75.6%), as well as at the HTT CAG repeat locus (100% vs. 7.7%) and the SMN1/2 locus (100% vs. 71.8%). These results demonstrate that isothermal WGA is potentially ideal for combined PGT-A and PGT-M that permits both direct and indirect detection of pathogenic variants including repeat expansions and gene deletions. Full article

Huntington disease’s (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine region (PolyQ) within the huntingtin protein (HTT). Mutated huntingtin (mHTT) is cytotoxic, particularly for striatal medium spiny neurons (MSNs), whose degeneration is the hallmark of HD. Autophagy inducers currently available promote the clearance of toxic proteins. However, due to their low selectivity and the possibility that prolonged autophagy hampers essential processes in unaffected cells, researchers have questioned their benefits in neurodegenerative diseases. Since MSNs express dopamine receptors D2 (DRD2) and D3 (DRD3) and DRD2/DRD3 agonists may activate autophagy, here, we explored how healthy and mHTT-challenged cells respond to prolonged DRD2/DRD3 agonist treatment. Autophagy activation and its effects on mHTT/polyQ clearance were studied in R6/1 mice (a genetic model of HD), their wild-type littermates, and DRD2- and DRD3-HEK cells expressing a pathogenic (Q74) and a non-pathogenic (Q23) polyQ fragment of mHTT treated with the DRD2/DRD3 agonist pramipexole. Two forms of DRD3-mediated autophagy were found: a transient mTORC1-dependent in WT mice and Q23-DRD3-HEK cells and a persistent AMPK-ULK1-activated in R6/1 mice and Q74-DRD3-HEK cells. This also promoted a robust clearance of soluble mHTT/polyQ and neuroprotection in striatal neurons and DRD3-HEK cells. The findings indicate that DRD3-induced autophagy may be a safe, disease-modifying intervention in HD patients. Full article

Importance: Genomic sequencing enables the rapid identification of a breadth of genetic variants. For clinical purposes, sequencing for small genetic variations is considered a solved problem, while challenges remain for structural variants, given the lower sensitivity and specificity. Interest has recently risen among governing bodies in developing protocols for population-wide genetic screening. However, usefulness is constrained when the probability of being affected by a rare disease remains low, despite a positive genetic test. This is a common scenario in neurodegenerative disorders. The problem is recognised among statisticians and statistical geneticists but is less well-understood by clinicians and researchers who will act on these results, and by the general public who might access screening services directly without the appropriate support for interpretation. Observations: We explore the probability of subsequent disease following genetic screening of several variants, both single nucleotide variants (SNVs) and larger repeat expansions, for two neurological conditions, Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS), comparing these results with screening for phenylketonuria, which is well-established. The risk following a positive screening test was 0.5% for C9orf72 in ALS and 0.4% for HTT in HD when testing repeat expansions, for which the test had sub-optimal performance (sensitivity = 99% and specificity = 90%), and 12.7% for phenylketonuria and 10.9% for ALS SOD1 when testing pathogenic SNVs (sensitivity = 99.96% and specificity = 99.95%). Subsequent screening confirmation via PCR for C9orf72 led to a 2% risk of developing ALS as a result of the reduced penetrance (44%). Conclusions and Relevance: We show that risk following a positive screening test result can be strikingly low for rare neurological diseases, even for fully penetrant variants such as HTT, if the test has sub-optimal performance. Accordingly, to maximise the utility of screening, it is vital to prioritise protocols with very high sensitivity and specificity, and a careful selection of markers for screening, giving regard to clinical interpretability, actionability, high penetrance, and secondary testing to confirm positive findings. Full article

Huntington’s disease (HD) is a detrimental neurodegenerative disease caused by the expansion of a CAG triplet in the HTT gene. This mutation leads to the production of mutant Huntingtin (Htt) protein with toxic gain-of-function. The mHtt is responsible in several ways for the establishment of an intricate pathogenetic scenario in affected cells, particularly in HD neurons. Among the features of HD, oxidative stress plays a relevant role in the progression of the disease at the cellular level. Mitochondrial dysfunction, bioenergetic deficits, Reactive Oxygen Species (ROS) production, neuroinflammation, and general reduction of antioxidant levels are all involved in the promotion of a toxic oxidative environment, eventually causing cell death. Nonetheless, neuronal cells exert antioxidant molecules to build up defense mechanisms. Key components of these defensive mechanisms are the nuclear factor erythroid 2-related factor 2 (NRF2) and peroxisome proliferator-activated receptor gamma coactivator-1 α (PGC-1α). Thus, this review aims to describe the involvement of oxidative stress in HD by exploring the roles of NRF2 and PGC-1α, crucial actors in this play. Finally, antioxidant therapeutic strategies targeting such markers are discussed. Full article

Fragile X, Huntington disease, and myotonic dystrophy type 1 are prototypical examples of human disorders caused by short tandem repeat variation, repetitive nucleotide stretches that are highly mutable both in the germline and somatic tissue. As short tandem repeats are unstable, they can expand, contract, and acquire and lose epigenetic marks in somatic tissue. This means within an individual, the genotype and epigenetic state at these loci can vary considerably from cell to cell. This somatic mosaicism may play a key role in clinical pathogenesis, and yet, our understanding of mosaicism in driving clinical phenotypes in short tandem repeat disorders is only just emerging. This review focuses on these three relatively well-studied examples where, given the advent of new technologies and bioinformatic approaches, a critical role for mosaicism is coming into focus both with respect to cellular physiology and clinical phenotypes. Full article

Background/Objectives: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of the CAG nucleotide repeat in the first exon of the huntingtin (HTT) gene. The disease typically manifests between the second and third decades of life and progresses gradually. The pathogenesis of HD involves the dysregulation of gene expression, influenced by various molecular processes ranging from transcription to protein stability. Methods: To investigate potential variations in gene expression associated with HD, a transcriptome study was conducted using peripheral blood mononuclear cell samples from 15 HD patients and 15 controls, all of Sicilian origin. Results: The analysis identified 7179 statistically significant differentially expressed genes between the two groups. Gene Set Enrichment Analysis (GSEA) and Gene Ontology (GO) terms were applied to identify the pathways affected by these differentially expressed mRNAs. The GSEA results highlighted significant associations between HD and GO pathways related to ribosomal functions and structure. These pathways were predominantly characterized by negative expression, with a substantial number of genes showing dysregulation. This suggests that the molecular processes leading to protein translation via ribosomes may be impaired in HD. Furthermore, dysregulation was observed in genes and non-coding RNAs involved in regulatory roles across various transcriptional processes. Conclusions: These findings support the hypothesis that the entire process, from transcription to translation, is disrupted in HD patients carrying the CAG repeat expansion in the first exon of the HTT gene. Full article

Depositions of protein aggregates are typical pathological hallmarks of various neurodegenerative diseases (NDs). For example, amyloid-beta (Aβ) and tau aggregates are present in the brain and plasma of patients with Alzheimer’s disease (AD); α-synuclein in Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA); mutant huntingtin protein (Htt) in Huntington’s disease (HD); and DNA-binding protein 43 kD (TDP-43) in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). The same misfolded proteins can be present in multiple diseases in the form of mixed proteinopathies. Since there is no cure for all these diseases, understanding the mechanisms of protein aggregation becomes imperative in modern medicine, especially for developing diagnostics and therapeutics. A Multimer Detection System (MDS) was designed to distinguish and quantify the multimeric/oligomeric forms from the monomeric form of aggregated proteins. As the unique epitope of the monomer is already occupied by capturing or detecting antibodies, the aggregated proteins with multiple epitopes would be accessible to both capturing and detecting antibodies simultaneously, and signals will be generated from the oligomers rather than the monomers. Hence, MDS could present a simple solution for measuring various conformations of aggregated proteins with high sensitivity and specificity, which may help to explore diagnostic and treatment strategies for developing anti-aggregation therapeutics. Full article

Background/Objectives: Short tandem repeat expansions are the most common cause of inherited neurological diseases. These disorders are clinically and genetically heterogeneous, such as in myotonic dystrophy and spinocerebellar ataxia, and they are caused by different repeat motifs in different genomic locations. Major advances in bioinformatic tools used to detect repeat expansions from short read sequencing data in the last few years have led to the implementation of these workflows into next generation sequencing pipelines in healthcare. Here, we aimed to evaluate the clinical utility of analysing repeat expansions through exome sequencing in a large cohort of genetically undiagnosed patients with neurological disorders. Methods: We here analyse 27 disease-causing DNA repeats found in the coding, intronic and untranslated regions in 12,496 exomes in patients with a range of neurogenetic conditions. Results: We identified—and validated by polymerase chain reaction—29 repeat expansions across a range of loci, 48% (n = 14) of which were diagnostic. We then analysed the genotyping performance across all repeat loci and found that, despite high coverage in most repeats in coding regions, some loci had low genotyping rates, such as those that cause spinocerebellar ataxia 2 (ATXN2, 0.1–8.4%) and Huntington disease (HTT, 0.2–58.2%), depending on the capture kit. Conversely, while most intronic repeats were not genotyped, we found a high genotyping rate in the intronic locus that causes spinocerebellar ataxia 36 (NOP56, 30.1–98.3%) and in the one that causes myotonic dystrophy type 1 (DMPK, myotonic dystrophy type 1). Conclusions: We show that the key factors that influence the genotyping rate of repeat expansion loci analysis are the sequencing read length and exome capture kit. These results provide important information about the performance of exome sequencing as a genetic test for repeat expansion disorders. Full article

Neurodegenerative disorders (NDs) cause progressive neuronal loss and are a significant public health concern, with NDs projected to become the second leading global cause of death within two decades. Huntington’s disease (HD) is a rare, progressive ND caused by an autosomal-dominant mutation in the huntingtin (HTT) gene, leading to severe neuronal loss in the brain and resulting in debilitating motor, cognitive, and psychiatric symptoms. Given the complex pathology of HD, biomarkers are essential for performing early diagnosis, monitoring disease progression, and evaluating treatment efficacy. However, the identification of consistent HD biomarkers is challenging due to the prolonged premanifest HD stage, HD’s heterogeneous presentation, and its multiple underlying biological pathways. This study involves a 10-year bibliometric analysis of HD biomarker research, revealing key research trends and gaps. The study also features a comprehensive literature review of emerging HD biomarkers, concluding the need for better stratification of HD patients and well-designed longitudinal studies to validate HD biomarkers. Promising candidate wet HD biomarkers— including neurofilament light chain protein (NfL), microRNAs, the mutant HTT protein, and specific metabolic and inflammatory markers— are discussed, with emphasis on their potential utility in the premanifest HD stage. Additionally, biomarkers reflecting brain structural deficits and motor or behavioral impairments, such as neurophysiological (e.g., motor tapping, speech, EEG, and event-related potentials) and imaging (e.g., MRI, PET, and diffusion tensor imaging) biomarkers, are evaluated. The findings underscore that the discovery and validation of reliable HD biomarkers urgently require improved patient stratification and well-designed longitudinal studies. Reliable biomarkers, particularly in the premanifest HD stage, are crucial for optimizing HD clinical management strategies, enabling personalized treatment approaches, and advancing clinical trials of HD-modifying therapies. Full article

Background: Huntington’s disease (HD) is a multifaceted neurological disorder characterized by the progressive deterioration of motor, cognitive, and psychiatric functions. Despite a limited understanding of its pathogenesis, research has implicated abnormal trinucleotide cytosine-adenine-guanine CAG repeat expansion in the huntingtin gene (HTT) as a critical factor. The development of innovative strategies is imperative for the early detection of predictive biomarkers, enabling timely intervention and mitigating irreversible cellular damage. Lipidomics, a comprehensive analytical approach, has emerged as an indispensable tool for systematically characterizing lipid profiles and elucidating their role in disease pathology. Method: A MedLine search was performed to identify studies that use lipidomics for the characterization of HD. Search terms included “Huntington disease”; “lipidomics”; “biomarker discovery”; “NMR”; and “Mass spectrometry”. Results: This review highlights the significance of lipidomics in HD diagnosis and treatment, exploring changes in brain lipids and their functions. Recent breakthroughs in analytical techniques, particularly mass spectrometry and NMR spectroscopy, have revolutionized brain lipidomics research, enabling researchers to gain deeper insights into the complex lipidome of the brain. Conclusions: A comprehensive understanding of the broad spectrum of lipidomics alterations in HD is vital for precise diagnostic evaluation and effective disease management. The integration of lipidomics with artificial intelligence and interdisciplinary collaboration holds promise for addressing the clinical variability of HD. Full article

To elucidate the potential roles of presynaptic and postsynaptic serotonergic activity in impulsivity traits, we investigated the relationship between self-reported impulsiveness and serotonin transporter (5-HTT) and 5-HT2A receptors in healthy individuals. In this study, 26 participants completed 3-Tesla magnetic resonance imaging and positron emission tomography with [¹¹C]DASB and [¹¹C]MDL100907. To quantify 5-HTT and 5-HT2A receptor availability, the binding potential (BP_ND) of [¹¹C]DASB and [¹¹C]MDL100907 was derived using the simplified reference tissue model with cerebellar gray matter as the reference region. The participants’ impulsivity levels were assessed using the Barratt Impulsiveness Scale-11 (BIS-11). The region of interest (ROI)-based partial correlation analysis with age, sex, and temperament traits as covariates revealed a significant positive correlation between non-planning impulsiveness and [¹¹C]MDL100907 BP_ND in the caudate (CAU) at Bonferroni-corrected p < 0.0045. Non-planning impulsiveness was also positively correlated with [¹¹C]MDL100907 BP_ND in the prefrontal cortex (PFC), ventromedial PFC, orbitofrontal cortex (OFC), insula (INS), amygdala (AMYG), putamen, ventral striatum, and thalamus, and the total score of BIS-11 was positively correlated with [¹¹C]MDL100907 BP_ND in the OFC, INS, AMYG, and CAU at uncorrected p < 0.05. Motor impulsiveness had a positive correlation with [¹¹C]DASB BP_ND in the CAU at uncorrected p < 0.05. Our results suggest that impulsivity traits, characterized by focusing on the present moment without considering future consequences, may be involved in serotonergic neurotransmission, particularly 5-HT2A receptor-mediated postsynaptic signaling in the CAU, which plays an important role in cognitive processes related to executive function, judgment of alternative outcomes, and inhibitory control. Full article

The predominant neurodegenerative diseases, Alzheimer’s disease, Parkinson’s disease, dementia with Lewy Bodies, Huntington’s disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are rarely pure diseases but, instead, show a diversity of mixed pathologies. At some level, all of them share a combination of one or more different toxic biomarker proteins: amyloid beta (Aβ), phosphorylated Tau (pTau), alpha-synuclein (αSyn), mutant huntingtin (mHtt), fused in sarcoma, superoxide dismutase 1, and TAR DNA-binding protein 43. These toxic proteins share some common attributes, making them potentially universal and simultaneous targets for therapeutic intervention. First, they all form toxic aggregates prior to taking on their final forms as contributors to plaques, neurofibrillary tangles, Lewy bodies, and other protein deposits. Second, the primary enzyme that directs their aggregation is transglutaminase 2 (TGM2), a brain-localized enzyme involved in neurodegeneration. Third, TGM2 binds to calmodulin, a regulatory event that can increase the activity of this enzyme threefold. Fourth, the most common mixed pathology toxic biomarkers (Aβ, pTau, αSyn, nHtt) also bind calmodulin, which can affect their ability to aggregate. This review examines the potential therapeutic routes opened up by this knowledge. The end goal reveals multiple opportunities that are immediately available for universal therapeutic treatment of the most devastating neurodegenerative diseases facing humankind. Full article

Huntington’s disease is a genetic disorder characterized by progressive neuronal cell damage in some areas of the brain; symptoms are commonly associated with chorea, rigidity and dystonia. The symptoms in Huntington’s Disease are caused by a pathological increase in the number of Cytokine-Adenine-Guanine (CAG) repeats on the first exon of the Huntingtin gene, which causes a protein to have an excessive number of glutamine residues; this alteration leads to a change in the protein’s conformation and function. Therefore, the purpose of this work was to design, synthesize and evaluate an antisense oligonucleotide (ASO; 95 nucleotides) HTT 90-5 directed to the Huntingtin CAG repeats in primary leukocyte culture cells from a patient with Huntington’s Disease; approximately 500,000 leukocytes per well extracted from venous blood were used, to which 100 pMol of ASO were administered, and the expression of Huntingtin was subsequently evaluated at 72 h by RT-PCR. Our results showed that the administration of the HTT 90-5 antisense decreased the expression of Huntingtin mRNA in the primary culture leukocyte cells from our patient. These results suggest that the use of long antisense targeting the CAG Huntingtin cluster may be an option to decrease the expression of Huntingtin and probably could be adjusted depending on the number of CAG repeats in the cluster. Full article