Search results for "norm"

rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences

2018

Myotonic dystrophy type 1 and type 2 (DM1, DM2) are caused by expansions of CTG and CCTG repeats, respectively. RNAs containing expanded CUG or CCUG repeats interfere with the metabolism of other RNAs through titration of the Muscleblind-like (MBNL) RNA binding proteins. DM2 follows a more favorable clinical course than DM1, suggesting that specific modifiers may modulate DM severity. Here, we report that the rbFOX1 RNA binding protein binds to expanded CCUG RNA repeats, but not to expanded CUG RNA repeats. Interestingly, rbFOX1 competes with MBNL1 for binding to CCUG expanded repeats and overexpression of rbFOX1 partly releases MBNL1 from sequestration within CCUG RNA foci in DM2 muscle ce…

Total Hemi-overgrowth in Pigmentary Mosaicism of the (Hypomelanosis of) Ito Type: Eight Case Reports.

2016

Abstract Pigmentary mosaicism of the (hypomelanosis of) Ito type is an umbrella term, which includes phenotypes characterized by mosaic hypopigmentation in the form of streaks, whorls, patchy, or more bizarre skin configurations (running along the lines of Blaschko): these cutaneous patterns can manifest as an isolated skin disorder (pigmentary mosaicism of the Ito type) or as a complex malformation syndrome in association with extracutaneous anomalies (most often of the musculoskeletal and/or nervous systems) (hypomelanosis of Ito). Affected individuals are anecdotally reported to have also partial or total body hemi-overgrowth (HOG), which often causes moderate to severe complications. We…

In silico discovery of substituted pyrido[2,3-d]pyrimidines and pentamidine-like compounds with biological activity in myotonic dystrophy models

2016

Myotonic dystrophy type 1 (DM1) is a rare multisystemic disorder associated with an expansion of CUG repeats in mutant DMPK (dystrophia myotonica protein kinase) transcripts; the main effect of these expansions is the induction of pre-mRNA splicing defects by sequestering muscleblind-like family proteins (e.g. MBNL1). Disruption of the CUG repeats and the MBNL1 protein complex has been established as the best therapeutic approach for DM1, hence two main strategies have been proposed: targeted degradation of mutant DMPK transcripts and the development of CUG-binding molecules that prevent MBNL1 sequestration. Herein, suitable CUG-binding small molecules were selected using in silico approach…

The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution

2020

The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. Here, we develop a tool to quantify frameshift mutations in MSI colorectal and endometrial cancer. Our results show that frameshift mutation frequency is negatively correlated to the predicted immunogenicity of the resulting peptides, suggesting counterselection of cell clones with highly immunogenic frameshift peptid…

One NF1 Mutation may Conceal Another

2019

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with complete penetrance but high variable expressivity. NF1 is caused by loss-of-function mutations in the NF1 gene, a negative regulator of the RAS-MAPK pathway. The NF1 gene has one of the highest mutation rates in human disorders, which may explain the outbreak of independent de novo variants in the same family. Here, we report the co-occurrence of pathogenic variants in the NF1 and SPRED1 genes in six families with NF1 and Legius syndrome, using next-generation sequencing. In five of these families, we observed the co-occurrence of two independent NF1 variants. All NF1 variants were classified as pathogenic, according to t…

A Systematic Nomenclature for the Drosophila Ventral Nerve Cord.

2020

Drosophila melanogaster is an established model for neuroscience research with relevance in biology and medicine. Until recently, research on the Drosophila brain was hindered by the lack of a complete and uniform nomenclature. Recognizing this, Ito et al. (2014) produced an authoritative nomenclature for the adult insect brain, using Drosophila as the reference. Here, we extend this nomenclature to the adult thoracic and abdominal neuromeres, the ventral nerve cord (VNC), to provide an anatomical description of this major component of the Drosophila nervous system. The VNC is the locus for the reception and integration of sensory information and involved in generating most of the locomotor…

JNK pathway and heat shock response mediate the survival of C26 colon carcinoma bearing mice fed with the mushroom Pleurotus eryngii var. eryngii wit…

2021

In the last few years, there has been emerging interest in developing treatments against human diseases using natural bioactive content. Here, the powder of the edible mushroom Pleurotus eryngii var. eryngii was mixed with the normal diet of mice bearing C26 colon carcinoma. Interestingly, it was evidenced by a significant increase in the survival rate of C26 tumor-bearing mice accompanied by a significant increase in Hsp90 and Hsp27 protein levels in the tumors. These data were paralleled by a decrease in Hsp60 levels. The mushroom introduced in the diet induced the inhibition of the transcription of the pro-inflammatory cytokines IL-6 and IL-1 exerting an anti-inflammatory action. The eff…

2020

Human movements are characterized by highly non-linear and multi-dimensional interactions within the motor system. Recently, an increasing emphasis on machine-learning applications has led to a significant contribution to the field of gait analysis, e.g., in increasing the classification performance. In order to ensure the generalizability of the machine-learning models, different data preprocessing steps are usually carried out to process the measured raw data before the classifications. In the past, various methods have been used for each of these preprocessing steps. However, there are hardly any standard procedures or rather systematic comparisons of these different methods and their im…

Weakly coupled map lattice models for multicellular patterning and collective normalization of abnormal single-cell states

2017

We present a weakly coupled map lattice model for patterning that explores the effects exerted by weakening the local dynamic rules on model biological and artificial networks composed of two-state building blocks (cells). To this end, we use two cellular automata models based on: (i) a smooth majority rule (model I) and (ii) a set of rules similar to those of Conway's Game of Life (model II). The normal and abnormal cell states evolve according with local rules that are modulated by a parameter $\kappa$. This parameter quantifies the effective weakening of the prescribed rules due to the limited coupling of each cell to its neighborhood and can be experimentally controlled by appropriate e…

Genomic Amplifications and Distal 6q Loss: Novel Markers for Poor Survival in High-risk Neuroblastoma Patients.

2018

Abstract Background Neuroblastoma is characterized by substantial clinical heterogeneity. Despite intensive treatment, the survival rates of high-risk neuroblastoma patients are still disappointingly low. Somatic chromosomal copy number aberrations have been shown to be associated with patient outcome, particularly in low- and intermediate-risk neuroblastoma patients. To improve outcome prediction in high-risk neuroblastoma, we aimed to design a prognostic classification method based on copy number aberrations. Methods In an international collaboration, normalized high-resolution DNA copy number data (arrayCGH and SNP arrays) from 556 high-risk neuroblastomas obtained at diagnosis were coll…