Biology subjects

Jokela, M.

Publications and source records attributed to Jokela, M..

3 recordsLinked to original sources

bioRxiv2021

Comprehensive transcriptomic analysis shows disturbed calcium homeostasis and deregulation of T lymphocyte apoptosis in inclusion body myositis

ObjectiveInclusion body myositis (IBM) has an unclear molecular etiology due to the co-existence of characteristic cytotoxic T-cell activity and degeneration of muscle fibers. Using in-depth gene expression and splicing studies, we aimed at understanding the different components of the molecular pathomechanisms in IBM. MethodsWe performed RNA-seq on RNA extracted from skeletal muscle biopsies of clinically and histopathologically defined IBM (n=24), tibial muscular dystrophy (n=6), and histopathologically normal group (n=9). In a comprehensive transcriptomics analysis, we analyzed the differential gene expression, differential splicing and exon usage, downstream pathway analysis, and the interplay between coding and non-coding RNAs (micro RNAs and long non-coding RNAs). ResultsWe observe dysregulation of genes involved in calcium homeostasis, particularly affecting the T-cell activity and regulation, causing disturbed Ca2+ induced apoptotic pathway of T cells in IBM muscles. Additionally, LCK/p56, which is an essential gene in regulating the fate of T-cell apoptosis, shows altered expression and splicing usage in IBM muscles InterpretationOur analysis provides a novel understanding of the molecular mechanisms in IBM by showing a detailed dysregulation of genes involved in calcium homeostasis and its effect on T-cell functioning in IBM muscles. Loss of T-cell regulation is hypothesized to be involved in the consistent observation of no response to immune therapies in IBM patients. Our results show that loss of apoptotic control of cytotoxic T cells could indeed be one component of their abnormal cytolytic activity in IBM muscles.

neuroscience↗

bioRxiv2021

Biallelic loss-of-function OBSCN variants predispose individuals to severe, recurrent rhabdomyolysis

Rhabdomyolysis is the acute breakdown of skeletal myofibres in response to an initiating factor, most commonly toxins and over exertion. A variety of genetic disorders predispose to rhabdomyolysis through different pathogenic mechanisms, particularly in patients with recurrent episodes. However, the majority of cases remain without a genetic diagnosis. Here we present six patients who presented with severe and recurrent rhabdomyolysis, usually with onset in the teenage years; other features included a history of myalgia and muscle cramps. We identified ten bi-allelic loss-of-function variants in the gene encoding obscurin (OBSCN) co-segregating with disease. We show reduced expression of OBSCN and loss of obscurin protein in patient muscle. Obscurin is proposed to be involved in SR function and Ca2+ handling. Patient cultured myoblasts appear more susceptible to starvation as evidenced by a greater decreased in SR Ca2+ content compared to control myoblasts. This likely reflects a lower efficiency when pumping Ca2+ back into the SR and/or a decrease in Ca2+ SR storage ability when metabolism is diminished. OSBCN variants have previously been associated with cardiomyopathies. None of the patients presented with a cardiomyopathy and cardiac examinations were normal in all cases in which cardiac function was assessed. There was also no history of cardiomyopathy in first degree relatives, in particular in any of the carrier parents. This cohort is relatively young, thus follow-up studies and the identification of additional cases with bi-allelic null OBSCN variants will further delineate OBSCN-related disease and the clinical course of disease.

genetics↗

bioRxiv2020

Evidence for a behaviourally measurable perseverance trait

The aim of this exploratory study was to create a behavioural measure for trait(s) that reflect the ability and motivation to continue an unpleasant behaviour, i.e. perseverance or persistence, and to measure its correlates to several variables. We utilised six different tasks with 54 subjects to measure the perseverance-trait: cold pressor task, hand grip endurance task, impossible anagram task, impossible verbal reasoning task, thread and needle task and boring video task. According to our results, the task performances formed two perseverance factors that could be roughly described as "physical" and "mental" perseverance. Together, the two-factor solution is responsible for the common variance constituting 37.3 % of the total variance in the performances i.e. performance times. Excluding the impossible anagram task, the performance in any given task was better explained by performances in the other tasks (i.e. "trait", {eta}2 range = 0.131-0.253) than by rank order variable ("depletion", i.e. getting tired from the previous tasks, {eta}2 range = 0-0.096). HighlightsO_LIBehavioural perseverance of individuals can be measured behaviourally C_LIO_LIBehavioural perseverance forms a two-factor structure C_LIO_LIPerseverance trait is better predictor of performance than depletion of individuals personal resources in a task C_LI

physiology↗