Citations

Abstract Aggregation and nuclear depletion of the RNA binding protein TDP-43 are the crucial pathological features of amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM), two degenerative diseases of the CNS and muscle. The loss of TDP-43 nuclear function results in the aberrant inclusion of cryptic exons in mRNA transcripts, leading to the expression of de novo proteins. Clonally expanded and highly differentiated CD8 + T cells have been observed in individuals with TDP-43 proteinopathies and therapeutics modulating the T cell response have recently been found to extend survival. However, the target antigens mediating T cell activation have remained elusive. Here, we investigate whether the de novo proteins induced by aberrant cryptic splicing due to TDP-43 nuclear loss can act as neo-antigens. We detect the HDGFL2 cryptic peptide and multiple other TDP-43 cryptic exons in IBM skeletal muscle, where their presence correlates with enrichment of T cells and class I antigen presentation pathways. Furthermore, we identify epitopes deriving from HDGFL2 and IGLON5 cryptic peptides which are recognized by clonally expanded and functionally differentiated populations of CD8 + T cells in ALS and IBM Patients. Finally, we demonstrate that T cells engineered to express the identified TCRs can bind and activate in response to the cryptic peptide derived epitopes (cryptic epitopes) and are able to kill TDP-43 deficient astrocytes. This work identifies for the first time specific T cell antigens in ALS and IBM, directly linking adaptive immune response to TDP-43 pathology.

Sleep quality and its association with cognition has been widely studied in some neurodegenerative diseases, but less is known about this association in spinal muscular atrophy (SMA). In adult SMA ( n = 21) patients and age-matched controls ( n = 23), we assessed subjectively measured sleep quality and daytime somnolence. Cognition was assessed with a multi-domain neuropsychological battery. Further, we investigated the association between clinical functional scores and sleep questionnaire scores. Among SMA patients, better motor and limb function was associated with better subjective sleep quality ( p’s< 0.05). Clinicians should consider sleep quality in patient care and future studies are needed to better understand these relationships.

The purpose of this study was to determine whether the longitudinal progression of decline in left ventricular ejection fraction (LVEF) in Duchenne muscular dystrophy (DMD) patients is moderated by ADRB1 genotype and whether the efficacy of ß-blocker therapy is influenced by genotype status. About 147 DMD patients (6-34 years.) were analyzed with a focus on β 1 adrenergic receptor (ADRB1) genotype variants. Patients were grouped by ADRB1 genotype resulting in Gly389 patients and Arg389 patients. A generalized additive mixed effects model was used to examine differences in the nonlinear trend of LVEF across patient ages between genotype groups and for ß-blocker use. Both genotype groups displayed a progressive decline in LVEF starting around the mean age of ambulation loss (~12 years). However, there was no difference between genotype groups in the progression of decline in LVEF. There was a significant effect of ß-blocker use on longitudinal LVEF, wherein patients on ß-blockers had systematically lower LVEF when compared to patients not on ß-blockers. However, the effect of ß-blocker therapy on LVEF was not affected by ADRB1 genotype. The current study did not demonstrate an influence of patient ADRB1 genotype on longitudinal LVEF in our cohort. Despite previous literature suggesting a positive influence of ß-blocker use on cardiac function in DMD patients and of an ADRB1 genotypic difference in responsiveness to ß-blocker use, we did not observe this in our cohort. Interestingly, our cohort did not demonstrate a positive influence of ß-blocker use on LVEF measures.

Abstract Aims/Hypothesis The need for understanding obesity as a chronic disease, its stigmatization, and the lack of actionability related to it demands a new approach. The adiposity‐based chronic disease (ABCD) model is based on adiposity amount, distribution, and function, with a three stage complication‐centric rather than a body mass index (BMI)‐centric approach. The prevalence rates and associated risk factors are presented. Methods In total, 2159 participants were randomly selected from Czechia. ABCD was established as BMI ≥ 25 kg/m 2 or high body fat percent, or abdominal obesity and then categorized by their adiposity‐based complications: Stage 0: none; Stage 1: mild/moderate; Stage 2: severe. Results ABCD prevalence was 62.8%. Stage 0 was 2.3%; Stage 1 was 31.4%; Stage 2 was 29.1%. Comparing with other classifiers, participants in Stage 2 were more likely to have diabetes, hypertension, and metabolic syndrome than those with overweight, obesity, abdominal obesity, and increased fat mass. ABCD showed the highest sensitivity and specificity to detect participants with peripheral artery disease, increased intima media, and vascular disease. Conclusion/Interpretation The ABCD model provides a more sensitive approach that facilitates the early detection and stratification of participants at risk compared to traditional classifiers.

Abstract The extracellular matrix is a highly reactive scaffold formed by a wide array of multifunctional molecules, encompassing collagens and noncollagenous glycoproteins, proteoglycans, glycosaminoglycans, and polysaccharides. Besides outlining the tissue borders, the extracellular matrix profoundly regulates the behavior of resident cells by transducing mechanical signals, and by integrating multiple cues derived from the microenvironment. Evidence is mounting that changes in the biostructure of the extracellular matrix are instrumental for biliary repair. Following biliary damage and eventually, malignant transformation, the extracellular matrix undergoes several quantitative and qualitative modifications, which direct interactions among hepatic progenitor cells, reactive ductular cells, activated myofibroblasts and macrophages, to generate the ductular reaction. Herein, we will give an overview of the main molecular factors contributing to extracellular matrix remodeling in cholangiopathies. Then, we will discuss the structural alterations in terms of biochemical composition and physical stiffness featuring the “desmoplastic matrix” of cholangiocarcinoma along with their pro-oncogenic effects.

An Italian version of the Disability of the Arm, Shoulder and Hand (DASH) questionnaire has been devised and its reliability and validity have been assessed in a cross-sectional study of 108 consecutive patients with upper extremity pathologies. A sub-sample of 30 patients was used to assess re-test reliability. The principal DASH scale showed a high correlation with other patient-oriented measures and demonstrated good reproducibility, consistency and validity, which were similar to those for other languages’ versions of DASH. These findings suggest that the evaluation capacities of the Italian DASH are equivalent to those of other language versions of the DASH.