Dysfunctional transcripts are formed by alternative polyadenylation in OPMD

Molecular Technology and Informatics for Personalised Medicine and HealthFunctional Genomics of Muscle, Nerve and Brain Disorder

Cytokine genes as potential biomarkers for muscle weakness in OPMD

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Robust nuclear lamina-based cell classification of aging and senescent cells

Changes in the shape of the nuclear lamina are exhibited in senescent cells, as well as in cells expressing mutations in lamina genes. To identify cells with defects in the nuclear lamina we developed an imaging method that quantifies the intensity and curvature of the nuclear lamina. We show that this method accurately describes changes in the nuclear lamina. Spatial changes in nuclear lamina coincide with redistribution of lamin A proteins and local reduction in protein mobility in senescent cell. We suggest that local accumulation of lamin A in the nuclear envelope leads to bending of the structure. A quantitative distinction of the nuclear lamina shape in cell populations was found between fresh and senescent cells, and between primary myoblasts from young and old donors. Moreover, with this method mutations in lamina genes were significantly distinct from cells with wild-type genes. We suggest that this method can be applied to identify abnormal cells during aging, in in vitro propagation, and in lamina disorders

Molecular Image Analysis: Quantitative Description and Classification of the Nuclear Lamina in Human Mesenchymal Stem Cells

The nuclear lamina is an intermediate filament network that provides a structural framework for the cell nucleus. Changes in lamina structure are found during changes in cell fate such as cell division or cell death and are associated with human diseases. An unbiased method that quantifies changes in lamina shape can provide information on cells undergoing changes in cellular functions. We have developed an image processing methodology that finds and quantifies the 3D structure of the nuclear lamina. We show that measurements on such images can be used for cell classification and provide information concerning protein spatial localization in this structure. To demonstrate the efficacy of this method, we compared the lamina of unmanipulated human mesenchymal stem cells (hMSCs) at passage 4 to cells activated for apoptosis. A statistically significant classification was found between the two populations

Regenerative potential of human muscle stem cells in chronic inflammation

International audienceABSTRACT: INTRODUCTION: Chronic inflammation is a profound systemic modification of the cellular microenvironment which could affect survival, repair and maintenance of muscle stem cells. The aim of this study was to define the role of chronic inflammation on the regenerative potential of satellite cells in human muscle. METHODS: As a model for chronic inflammation, 11 patients suffering from rheumatoid arthritis (RA) were included together with 16 patients with osteoarthritis (OA) as controls. The mean age of both groups was 64 years, with more females in the RA group compared to the OA group. During elective knee replacement surgery, a muscle biopsy was taken from the distal musculus vastus medialis. Cell populations from four RA and eight OA patients were used for extensive phenotyping because these cell populations showed no spontaneous differentiation and myogenic purity greater than 75% after explantation. RESULTS: After mononuclear cell explantation, myogenic purity, viability, proliferation index, number of colonies, myogenic colonies, growth speed, maximum number of population doublings and fusion index were not different between RA and OA patients. Furthermore, the expression of proteins involved in replicative and stress-induced premature senescence and apoptosis, including p16, p21, p53, hTERT and cleaved caspase-3, was not different between RA and OA patients. Mean telomere length was shorter in the RA group compared to the OA group. CONCLUSIONS: In the present study we found evidence that chronic inflammation in RA does not affect the in vitro regenerative potential of human satellite cells. Identification of mechanisms influencing muscle regeneration by modulation of its microenvironment may, therefore, be more appropriate

Differential Temporal and Spatial Progerin Expression during Closure of the Ductus Arteriosus in Neonates

Closure of the ductus arteriosus (DA) at birth is essential for the transition from fetal to postnatal life. Before birth the DA bypasses the uninflated lungs by shunting blood from the pulmonary trunk into the systemic circulation. The molecular mechanism underlying DA closure and degeneration has not been fully elucidated, but is associated with apoptosis and cytolytic necrosis in the inner media and intima. We detected features of histology during DA degeneration that are comparable to Hutchinson Gilford Progeria syndrome and ageing. Immunohistochemistry on human fetal and neonatal DA, and aorta showed that lamin A/C was expressed in all layers of the vessel wall. As a novel finding we report that progerin, a splicing variant of lamin A/C was expressed almost selectively in the normal closing neonatal DA, from which we hypothesized that progerin is involved in DA closure. Progerin was detected in 16.2%±7.2 cells of the DA. Progerin-expressing cells were predominantly located in intima and inner media where cytolytic necrosis accompanied by apoptosis will develop. Concomitantly we found loss of α-smooth muscle actin as well as reduced lamin A/C expression compared to the fetal and non-closing DA. In cells of the adjacent aorta, that remains patent, progerin expression was only sporadically detected in 2.5%±1.5 of the cells. Data were substantiated by the detection of mRNA of progerin in the neonatal DA but not in the aorta, by PCR and sequencing analysis. The fetal DA and the non-closing persistent DA did not present with progerin expressing cells. Our analysis revealed that the spatiotemporal expression of lamin A/C and progerin in the neonatal DA was mutually exclusive. We suggest that activation of LMNA alternative splicing is involved in vascular remodeling in the circulatory system during normal neonatal DA closure

Dietary Changes and Anxiety during the Coronavirus Pandemic: Differences between the Sexes

The SARS-CoV-2 (COVID-19) pandemic has been associated with both increased anxiety, deterioration in diet and weight gain. These associations may differ by sex. The present report examines differences by sex in diet quality in order to determine whether associations between diet and psychological stress during the initial phase of the COVID-19 pandemic differed by sex. This online study is available internationally in seven languages. The Mediterranean Diet Score was used to measure diet quality, while the General Anxiety Disorder 7-point scale (GAD-7) was used to measure anxiety. Findings were compared by self-reported sex (male vs. female). A total of 3797 respondents provided informed consent and met eligibility criteria, of whom 526 women were omitted due to being pregnant or six months or less post-partum, or due to reproductive status not being reported. Thus, 3271 individuals are included in the present report, of whom 71.2% were women. The median age of women was 30 (interquartile range (IQR) = 16) years vs. 31 (IQR = 19) years, p = 0.079. The median diet quality score was 9 (IQ = 3) in both women and men (p = 0.75). Despite the overall similarity in diet score, several components of the score differed significantly by sex. Women reported consuming significantly more olive oil, daily servings of vegetables, and weekly servings of sweet baked goods. Men reported consuming significantly more sweetened/carbonated drinks, red meat, alcohol, legumes, and hummus/tahini. Women reported a GAD-7 score of 6 (IQR = 8), while men reported 3 (6), p < 0.001. An inverse association was detected between the Mediterranean diet score and the GAD-7 score in both women (rho = −0.166, p < 0.001) and men (rho = −0.154, p < 0.001), and the correlation coefficients did not differ by sex (p = 0.76). Mediterranean diet score and age both reduced the odds of elevated anxiety (GAD-7 ≥ 10), while female sex, deterioration of diet quality during the outbreak, unemployment, and completing the survey in English increased the odds of this outcome. During the COVID-19 lockdowns, overall diet quality did not differ by sex; however, some differences by sex in components of the total score were detected. Moderate to severe anxiety was positively associated with female sex and poorer diet quality even after controlling for age, employment status, and the language in which the survey was performed