Somatic Instability Leading to Mosaicism in Fragile X Syndrome and Associated Disorders: Complex Mechanisms, Diagnostics, and Clinical Relevance.

Fragile X syndrome (FXS) is a genetic condition caused by the inheritance of alleles with >200 CGG repeats in the 5' UTR of the fragile X messenger ribonucleoprotein 1 () gene. These full mutation (FM) alleles are associated with DNA methylation and gene silencing, which result in intellectual disabilities, developmental delays, and social and behavioral issues. Mosaicism for both the size of the CGG repeat tract and the extent of its methylation is commonly observed in individuals with the FM.

Multimorbidity is associated with myocardial DNA damage, nucleolar stress, dysregulated energy metabolism, and senescence in cardiovascular disease.

This study investigates why individuals with multimorbidity-two or more chronic conditions-are more prone to adverse outcomes after surgery. In our cohort, ninety-eight of 144 participants had multimorbidity. The myocardial transcriptome and metabolites involved in energy production were measured in 53 and 57 sequential participants, respectively.

Exogenous Volatile Organic Compound (EVOC) Breath Testing Maximizes Classification Performance for Subjects with Cirrhosis and Reveals Signs of Portal Hypertension.

Cirrhosis detection in primary care relies on low-performing biomarkers. Consequently, up to 75% of subjects with cirrhosis receive their first diagnosis with decompensation when causal treatments are less effective at preserving liver function. We investigated an unprecedented approach to cirrhosis detection based on dynamic breath testing.

Carotid Plaque-RADS: A Novel Stroke Risk Classification System.

Background: Carotid artery atherosclerosis is highly prevalent in the general population and is a well-established risk factor for acute ischemic stroke. Although the morphological characteristics of vulnerable plaques are well recognized, there is a lack of consensus in reporting and interpreting carotid plaque features.

Objectives: The aim of this paper is to establish a consistent and comprehensive approach for imaging and reporting carotid plaque by introducing the Plaque-RADS (Reporting and Data System) score.

Organising the self-employed: combining community unionism, coworking and cooperativism across contexts.

The growing insecurity, flexibilisation and fragmentation of labour markets goes hand-in-hand with the decrease of social protection levels and collective representation for workers in non-standard employment relationships, such as the hybrid category of 'solo self-employed workers'. In response, on the one hand, trade unions attempt to approach and organise this heterogenous category of workers. On the other, new freelancer organisations are emerging to improve worker rights and safety, and overcome their social and professional isolation.

Elbow joint loads during simulated activities of daily living: implications for formulating recommendations after total elbow arthroplasty.

Background: Overloading of the elbow joint prosthesis following total elbow arthroplasty can lead to implant failure. Joint moments during daily activities are not well contextualized for a prosthesis's failure limits, and the effect of the current postoperative instruction on elbow joint loading is unclear. This study investigates the difference in elbow joint moments between simulated daily tasks and between flexion-extension, pronation-supination, and varus-valgus movement directions.

Activation Ratio Correlates with IQ in Female Carriers of the Premutation.

Carriers of the premutation (PM) allele are at risk of one or more clinical conditions referred to as FX premutation-associated conditions (FXPAC). Since the gene is on the X chromosome, the activation ratio (AR) may impact the risk, age of onset, progression, and severity of these conditions. The aim of this study was to evaluate the reliability of AR measured using different approaches and to investigate potential correlations with clinical outcomes.

DNA methylation episignatures are sensitive and specific biomarkers for detection of patients with / variants.

Accurate diagnosis for patients living with neurodevelopmental disorders is often met with numerous challenges, related to the ambiguity of findings and lack of specificity in genetic variants leading to pathology. Genome-wide DNA methylation analysis has been used to develop highly sensitive and specific 'episignatures' as biomarkers capable of differentiating and classifying complex neurodevelopmental disorders. In this study we describe distinct episignatures for KAT6A syndrome, caused by pathogenic variants in the lysine acetyltransferase A gene (), and for the two neurodevelopmental disorders associated with lysine acetyl transferase B ().

N-arachidonylglycine is a caloric state-dependent circulating metabolite which regulates human CD4T cell responsiveness.

Caloric deprivation interventions such as intermittent fasting and caloric restriction ameliorate metabolic and inflammatory disease. As a human model of caloric deprivation, a 24-h fast blunts innate and adaptive immune cell responsiveness relative to the refed state. Isolated serum at these time points confers these same immunomodulatory effects on transformed cell lines.

Non-alcoholic fatty liver disease is characterised by a reduced polyunsaturated fatty acid transport via free fatty acids and high-density lipoproteins (HDL).

Background And Objectives: Non-alcoholic fatty liver disease (NAFLD) develops due to impaired hepatic lipid fluxes and is a risk factor for chronic liver disease and atherosclerosis. Lipidomic studies consistently reported characteristic hepatic/VLDL "lipid signatures" in NAFLD; whole plasma traits are more debated. Surprisingly, the HDL lipid composition by mass spectrometry has not been characterised across the NAFLD spectrum, despite HDL being a possible source of hepatic lipids delivered from peripheral tissues alongside free fatty acids (FFA).

Impact of soluble tumor necrosis factor-related apoptosis-inducing ligand released by engineered adipose mesenchymal stromal cells on white blood cells.

Background Aims: The proapoptotic protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is physiologically expressed by immune cells and performs regulatory functions in infections, autoimmune diseases and cancer, where it acts as a tumor suppressor. Adipose-derived mesenchymal stromal cells (AD-MSCs) also may play immunomodulatory roles in both primary and acquired immune responses. We have previously demonstrated the efficacy of an anticancer gene therapy based on AD-MSC engineered to secrete a soluble TRAIL variant (sTRAIL) against pancreatic cancer.

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis.

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1.

Breath Biopsy to Identify Exhaled Volatile Organic Compounds Biomarkers for Liver Cirrhosis Detection.

Background And Aims: The prevalence of chronic liver disease in adults exceeds 30% in some countries and there is significant interest in developing tests and treatments to help control disease progression and reduce healthcare burden. Breath is a rich sampling matrix that offers non-invasive solutions suitable for early-stage detection and disease monitoring. Having previously investigated targeted analysis of a single biomarker, here we investigated a multiparametric approach to breath testing that would provide more robust and reliable results for clinical use.

Untargeted Lipidomics of Erythrocytes under Simulated Microgravity Conditions.

Lipidomics and metabolomics are nowadays widely used to provide promising insights into the pathophysiology of cellular stress disorders. Our study expands, with the use of a hyphenated ion mobility mass spectrometric platform, the understanding of the cellular processes and stress due to microgravity. By lipid profiling of human erythrocytes, we annotated complex lipids such as oxidized phosphocholines, phosphocholines bearing arachidonic in their moiety, as well as sphingomyelins and hexosyl ceramides associated with microgravity conditions.

Elbow joint biomechanics during ADL focusing on total elbow arthroplasty - a scoping review.

Background: Overloading is hypothesized to be one of the failure mechanisms following total elbow arthroplasty (TEA). It is unclear whether the current post-operative loading instruction is compliant with reported failure mechanisms. Aim is therefore to evaluate the elbow joint load during activities of daily living (ADL) and compare these loads with reported failure limits from retrieval and finite element studies.

The effects of facioscapulohumeral dystrophy and dynamic arm support on upper extremity muscle coordination in functional tasks.

This study's objective is to understand the effect of muscular weakness in persons with facioscapulohumeral dystrophy as well as the effect of a dynamic arm support on muscle coordination and activity performance, during activities of daily living. People with facioscapulohumeral dystrophy (n=12, 56.0±14.

Sphingolipids and acylcarnitines are altered in placentas from women with gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is the most common medical complication of pregnancy and a severe threat to pregnant people and offspring health. The molecular origins of GDM, and in particular the placental responses, are not fully known. The present study aimed to perform a comprehensive characterisation of the lipid species in placentas from pregnancies complicated with GDM using high-resolution MS lipidomics, with a particular focus on sphingolipids and acylcarnitines in a semi-targeted approach.

Expanding the genetics and phenotypic spectrum of Lysine-specific demethylase 5C (KDM5C): a report of 13 novel variants.

Lysine-specific demethylase 5C (KDM5C) has been identified as an important chromatin remodeling gene, contributing to X-linked neurodevelopmental disorders (NDDs). The KDM5C gene, located in the Xp22 chromosomal region, encodes the H3K4me3-me2 eraser involved in neuronal plasticity and dendritic growth. Here we report 30 individuals carrying 13 novel and one previously identified KDM5C variants.

Autologous Marrow Mesenchymal Stem Cell Driving Bone Regeneration in a Rabbit Model of Femoral Head Osteonecrosis.

Osteonecrosis of the femoral head (ONFH) is a progressive degenerative disease that ultimately requires a total hip replacement. Mesenchymal stromal/stem cells (MSCs), particularly the ones isolated from bone marrow (BM), could be promising tools to restore bone tissue in ONFH. Here, we established a rabbit model to mimic the pathogenic features of human ONFH and to challenge an autologous MSC-based treatment.

Human Adipose Mesenchymal Stromal/Stem Cells Improve Fat Transplantation Performance.

The resorption rate of autologous fat transfer (AFT) is 40-60% of the implanted tissue, requiring new surgical strategies for tissue reconstruction. We previously demonstrated in a rabbit model that AFT may be empowered by adipose-derived mesenchymal stromal/stem cells (AD-MSCs), which improve graft persistence by exerting proangiogenic/anti-inflammatory effects. However, their fate after implantation requires more investigation.

Understanding the Behaviour of Human Cell Types under Simulated Microgravity Conditions: The Case of Erythrocytes.

Erythrocytes are highly specialized cells in human body, and their main function is to ensure the gas exchanges, O and CO, within the body. The exposure to microgravity environment leads to several health risks such as those affecting red blood cells. In this work, we investigated the changes that occur in the structure and function of red blood cells under simulated microgravity, compared to terrestrial conditions, at different time points using biochemical and biophysical techniques.