Trimmed likelihood estimators for stochastic differential equations with an application to crack growth analysis from photos

We introduce trimmed likelihood estimators for processes given by a stochastic differential equation for which a transition density is known or can be approximated and present an algorithm to calculate them. To measure the fit of the observations to a given stochastic process, two performance measures based on the trimmed likelihood estimator are proposed. The approach is applied to crack growth data which are obtained from a series of photos by backtracking large cracks which were detected in the last photo. Such crack growth data are contaminated by several outliers caused by errors in the automatic image analysis. We show that trimming 20% of the data of a growth curve leads to good results when 100 obtained crack growth curves are fitted with the Ornstein-Uhlenbeck process and the Cox-Ingersoll-Ross processes while the fit of the Geometric Brownian Motion is significantly worse. The method is sensitive in the sense that crack curves obtained under different stress conditions provide significantly different parameter estimates

CTG-Repeat Detection in Primary Human Myoblasts of Myotonic Dystrophy Type 1

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder caused by unstable CTG-repeat expansions in the DMPK gene. Tissue mosaicism has been described for the length of these repeat expansions. The most obvious affected tissue is skeletal muscle, making it the first target for therapy development. To date there is no approved therapy despite some existing approaches. Thus, there is the demand to further advance therapeutic developments, which will in return require several well-characterized preclinical tools and model systems. Here we describe a modified method to identify the CTG-repeat length in primary human myoblasts isolated from DM1 patients that requires less genomic DNA and avoids radioactive labeling. Using this method, we show that primary human DM1 myoblast cultures represent a population of cells with different CTG-repeat length. Comparing DNA from the identical muscle biopsy specimen, the range of CTG-repeat length in the myoblast culture is within the same range of the muscle biopsy specimen. In conclusion, primary human DM1 myoblast cultures are a well-suited model to investigate certain aspects of the DM1 pathology. They are a useful platform to perform first-line investigations of preclinical therapies

Trimmed likelihood estimators for stochastic differential equations with an application to crack growth analysis from photos

We introduce trimmed likelihood estimators for processes given by a stochastic differential equation for which a transition density is known or can be approximated and present an algorithm to calculate them. To measure the fit of the observations to a given stochastic process, two performance measures based on the trimmed likelihood estimator are proposed. The approach is applied to crack growth data which are obtained from a series of photos by backtracking large cracks which were detected in the last photo. Such crack growth data are contaminated by several outliers caused by errors in the automatic image analysis. We show that trimming 20% of the data of a growth curve leads to good results when 100 obtained crack growth curves are fitted with the Ornstein- Uhlenbeck process and the Cox-Ingersoll-Ross processes while the fit of the Geometric Brownian Motion is significantly worse. The method is sensitive in the sense that crack curves obtained under different stress conditions provide significantly different parameter estimates

Myotonic Dystrophy-A Progeroid Disease?

Myotonic dystrophies (DM) are slowly progressing multisystemic disorders caused by repeat expansions in the DMPK or CNBP genes. The multisystemic involvement in DM patients often reflects the appearance of accelerated aging. This is partly due to visible features such as cataracts, muscle weakness, and frontal baldness, but there are also less obvious features like cardiac arrhythmia, diabetes or hypogammaglobulinemia. These aging features suggest the hypothesis that DM could be a segmental progeroid disease. To identify the molecular cause of this characteristic appearance of accelerated aging we compare clinical features of DM to "typical" segmental progeroid disorders caused by mutations in DNA repair or nuclear envelope proteins. Furthermore, we characterize if this premature aging effect is also reflected on the cellular level in DM and investigate overlaps with "classical" progeroid disorders. To investigate the molecular similarities at the cellular level we use primary DM and control cell lines. This analysis reveals many similarities to progeroid syndromes linked to the nuclear envelope. Our comparison on both clinical and molecular levels argues for qualification of DM as a segmental progeroid disorder

Alternative splicing coupled mRNA decay shapes the temperature‐dependent transcriptome

Mammalian body temperature oscillates with the time of the day and is altered in diverse pathological conditions. We recently identified a body temperature‐sensitive thermometer‐like kinase, which alters SR protein phosphorylation and thereby globally controls alternative splicing (AS). AS can generate unproductive variants which are recognized and degraded by diverse mRNA decay pathways—including nonsense‐mediated decay (NMD). Here we show extensive coupling of body temperature‐controlled AS to mRNA decay, leading to global control of temperature‐dependent gene expression (GE). Temperature‐controlled, decay‐inducing splicing events are evolutionarily conserved and pervasively found within RNA‐binding proteins, including most SR proteins. AS‐coupled poison exon inclusion is essential for rhythmic GE of SR proteins and has a global role in establishing temperature‐dependent rhythmic GE profiles, both in mammals under circadian body temperature cycles and in plants in response to ambient temperature changes. Together, these data identify body temperature‐driven AS‐coupled mRNA decay as an evolutionary ancient, core clock‐independent mechanism to generate rhythmic GE

Late-onset neuromuscular disorders in the differential diagnosis of sarcopenia

BACKGROUND Sarcopenia is the age-related loss of muscle mass and strength. Undiagnosed late-onset neuromuscular disorders need to be considered in the differential diagnosis of sarcopenia. AIM Based on emblematic case reports and current neuromuscular diagnostic guidelines for three common late-onset neuromuscular disorders, a differential diagnostic approach for geriatric patients presenting with a sarcopenic phenotype is given. METHODS Patients over 65~years of age with sarcopenia, amyotrophic lateral sclerosis, inclusion body myositis and myotonic dystrophy type 2 were recruited. All patients were assessed for sarcopenia based on the revised European consensus definition. Patients with neuromuscular diseases were diagnosed according to the revised El Escorial criteria and the European neuromuscular centre criteria. Phenotypes and diagnostic criteria for all patients were summarized including their specific histopathological findings. RESULTS All patients with neuromuscular diseases were positively screened for sarcopenia and classified as severe sarcopenic by means of assessment. The clinical phenotype, the evolution pattern of weakness and muscle atrophy combined with laboratory finding including electromyography could unquestionably distinguish the diseases. DISCUSSION Neuromuscular disorders can manifest beyond the age of 65~years and misdiagnosed as sarcopenia. The most common diseases are inclusion body myositis, amyotrophic lateral sclerosis and myotonic dystrophy type 2. A diagnostic work-up for neuromuscular diseases ensures their correct diagnosis by clinical-, electrophysiological, histopathological, and genetic work-up. CONCLUSIONS In geriatric patients with a focal or asymmetrical muscular weakness and atrophy, sarcopenia assessment should be extended with patient's history of disease course. Furthermore, concomitant diseases, analysis of serum creatine kinase, electrophysiological examination, and in selected patients muscle biopsy and gene analysis is needed to rule out a late-onset neuromuscular disorder

Influence of IGF-I serum concentration on muscular regeneration capacity in patients with sarcopenia

BACKGROUND Previous research has described a neuroprotective effect of IGF-I, supporting neuronal survival, axon growth and proliferation of muscle cells. Therefore, the association between IGF-I concentration, muscle histology and electrophysiological markers in a cohort of patients with sarcopenia dares investigation. METHODS Measurement of serum concentrations of IGF-I and binding partners, electromyographic measurements with the MUNIX (Motor Unit Number Index) method and muscle biopsies were performed in 31 patients with acute hip fracture older age 60 years. Molecular markers for denervation (neural cell adhesion molecule NCAM) and proliferation markers (Ki67) were assessed by immunofluorescence staining of muscle biopsy tissue. Skeletal muscle mass by bioelectrical impedance analysis and hand-grip strength were measured to assess sarcopenia status according to EWGSOP2 criteria. RESULTS Thirty-one patients (20 women) with a mean age of 80.6 ± 7.4 years were included. Concentrations of IGF-I and its binding partners were significantly associated with sarcopenia (ß = - 0.360; p = 0.047) and MUNIX (ß = 0.512; p = 0.005). Further, expression of NCAM (ß = 0.380; p = 0.039) and Ki67 (ß = 0.424; p = 0.022) showed significant associations to IGF-I concentrations. CONCLUSIONS The findings suggest a pathogenetic role of IGF-I in sarcopenia based on muscle denervation

Nuclear Envelope Transmembrane Proteins in Myotonic Dystrophy Type 1

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder with predominant myotonia and muscular dystrophy which is caused by CTG-repeat expansions in the DMPK gene. These repeat expansions are transcribed and the resulting mRNA accumulates RNA-binding proteins involved in splicing, resulting in a general splicing defect. We observed nuclear envelope (NE) alterations in DM1 primary myoblasts. These included invaginations of the NE as well as an altered composition of the nuclear lamina. Specifically, we investigated NE transmembrane proteins (NETs) in DM1 primary myoblasts, staining to determine if their distribution was altered compared to controls and if this could contribute to these structural defects. We also tested the expression of these NETs in muscle and how localization changes in the DM1 primary myoblasts undergoing differentiation in vitro to myotubes. We found no changes in the localization of the tested NETs, but most tended to exhibit reduced expression with increasing DMPK-repeat length. Nonetheless, the DM1 patient expression range was within the expression range of the controls. Additionally, we found a down-regulation of the possible nesprin 1 giant isoform in DM1 primary myoblasts which could contribute to the increased NE invaginations. Thus, nesprin 1 may be an interesting target for further investigation in DM1 disease pathology

RBM6 splicing factor promotes homologous recombination repair of double-strand breaks and modulates sensitivity to chemotherapeutic drugs

RNA-binding proteins regulate mRNA processing and translation and are often aberrantly expressed in cancer. The RNA-binding motif protein 6, RBM6, is a known alternative splicing factor that harbors tumor suppressor activity and is frequently mutated in human cancer. Here, we identify RBM6 as a novel regulator of homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Mechanistically, we show that RBM6 regulates alternative splicing-coupled nonstop-decay of a positive HR regulator, Fe65/APBB1. RBM6 knockdown leads to a severe reduction in Fe65 protein levels and consequently impairs HR of DSBs. Accordingly, RBM6-deficient cancer cells are vulnerable to ATM and PARP inhibition and show remarkable sensitivity to cisplatin. Concordantly, cisplatin administration inhibits the growth of breast tumor devoid of RBM6 in mouse xenograft model. Furthermore, we observe that RBM6 protein is significantly lost in metastatic breast tumors compared with primary tumors, thus suggesting RBM6 as a potential therapeutic target of advanced breast cancer. Collectively, our results elucidate the link between the multifaceted roles of RBM6 in regulating alternative splicing and HR of DSBs that may contribute to tumorigenesis, and pave the way for new avenues of therapy for RBM6-deficient tumors