Search results for "COMPUTATION"

CHI3L1 - a novel myokine

2015

Emerging Roles of RNA 3′-end Cleavage and Polyadenylation in Pathogenesis, Diagnosis and Therapy of Human Disorders

2020

A crucial feature of gene expression involves RNA processing to produce 3′ ends through a process termed 3′ end cleavage and polyadenylation (CPA). This ensures the nascent RNA molecule can exit the nucleus and be translated to ultimately give rise to a protein which can execute a function. Further, alternative polyadenylation (APA) can produce distinct transcript isoforms, profoundly expanding the complexity of the transcriptome. CPA is carried out by multi-component protein complexes interacting with multiple RNA motifs and is tightly coupled to transcription, other steps of RNA processing, and even epigenetic modifications. CPA and APA contribute to the maintenance of a multitude of dive…

KnotGenome: a server to analyze entanglements of chromosomes.

2018

Abstract The KnotGenome server enables the topological analysis of chromosome model data using three-dimensional coordinate files of chromosomes as input. In particular, it detects prime and composite knots in single chromosomes, and links between chromosomes. The knotting complexity of the chromosome is presented in the form of a matrix diagram that reveals the knot type of the entire polynucleotide chain and of each of its subchains. Links are determined by means of the Gaussian linking integral and the HOMFLY-PT polynomial. Entangled chromosomes are presented graphically in an intuitive way. It is also possible to relax structure with short molecular dynamics runs before the analysis. Kn…

MetProc: Separating Measurement Artifacts from True Metabolites in an Untargeted Metabolomics Experiment

2019

High-throughput metabolomics using liquid chromatography and mass spectrometry (LC/MS) provides a useful method to identify biomarkers of disease and explore biological systems. However, the majority of metabolic features detected from untargeted metabolomics experiments have unknown ion signatures, making it critical that data should be thoroughly quality controlled to avoid analyzing false signals. Here, we present a postalignment method relying on intermittent pooled study samples to separate genuine metabolic features from potential measurement artifacts. We apply the method to lipid metabolite data from the PREDIMED (PREvención con DIeta MEDi-terránea) study to demonstrate clear remova…

Parsimonious Scenario for the Emergence of Viroid-Like Replicons De Novo

2019

This article belongs to the Special Issue Viroid-2018: International Conference on Viroids and Viroid-Like RNAs. Viroids are small, non-coding, circular RNA molecules that infect plants. Different hypotheses for their evolutionary origin have been put forward, such as an early emergence in a precellular RNA World or several de novo independent evolutionary origins in plants. Here, we discuss the plausibility of de novo emergence of viroid-like replicons by giving theoretical support to the likelihood of different steps along a parsimonious evolutionary pathway. While Avsunviroidae-like structures are relatively easy to obtain through evolution of a population of random RNA sequences of fixe…

Engineered Functional Redundancy Relaxes Selective Constraints upon Endogenous Genes in Viral RNA Genomes

2018

Functional redundancy, understood as the functional overlap of different genes, is a double-edge sword. At the one side, it is thought to serve as a robustness mechanism that buffers the deleterious effect of mutations hitting one of the redundant copies, thus resulting in pseudogenization. At the other side, it is considered as a source of genetic and functional innovation. In any case, genetically redundant genes are expected to show an acceleration in the rate of molecular evolution. Here, we tackle the role of functional redundancy in viral RNA genomes. To this end, we have evaluated the rates of compensatory evolution for deleterious mutations affecting an essential function, the suppr…

Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors.

2017

Improving the binding affinity of a chemical series by systematically probing one of its exit vectors is a medicinal chemistry activity that can benefit from molecular modeling input. Herein, we compare the effectiveness of four approaches in prioritizing building blocks with better potency: selection by a medicinal chemist, manual modeling, docking followed by manual filtering, and free energy calculations (FEP). Our study focused on identifying novel substituents for the apolar S2 pocket of cathepsin L and was conducted entirely in a prospective manner with synthesis and activity determination of 36 novel compounds. We found that FEP selected compounds with improved affinity for 8 out of …

Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes

2017

Targeted resequencing gene panels are used in the diagnostic setting to identify gene defects in epilepsy. We performed targeted resequencing using a 30-genes panel and a 95-genes panel in 349 patients with drug-resistant epilepsies beginning in the first years of life. We identified 71 pathogenic variants, 42 of which novel, in 30 genes, corresponding to 20.3% of the probands. In 66% of mutation positive patients seizures onset occurred before age 6 months. The 95-genes panel allowed a genetic diagnosis in 22 (6.3%) patients that would have otherwise been missed using the 30-gene panel. About 50% of mutations were identified in genes coding for sodium and potassium channel components. SCN2…

On the structural connectivity of large-scale models of brain networks at cellular level

2021

AbstractThe brain’s structural connectivity plays a fundamental role in determining how neuron networks generate, process, and transfer information within and between brain regions. The underlying mechanisms are extremely difficult to study experimentally and, in many cases, large-scale model networks are of great help. However, the implementation of these models relies on experimental findings that are often sparse and limited. Their predicting power ultimately depends on how closely a model’s connectivity represents the real system. Here we argue that the data-driven probabilistic rules, widely used to build neuronal network models, may not be appropriate to represent the dynamics of the …

How Can Interleukin-1 Receptor Antagonist Modulate Distinct Cell Death Pathways?

2018

Multiple mechanisms of cell death exist (apoptosis, necroptosis, pyroptosis) and the subtle balance of several distinct proteins and inhibitors tightly regulates the cell fate toward one or the other pathway. Here, by combining coimmunoprecipitation, enzyme assays, and molecular simulations, we ascribe a new role, within this entangled regulatory network, to the interleukin-1 receptor antagonist (IL-1Ra). Our study enlightens that IL-1Ra, which usually inhibits the inflammatory effects of IL-1α/β by binding to IL-1 receptor, under advanced pathological states prevents apoptosis and/or necroptosis by noncompetitively inhibiting the activity of caspase-8 and -9. Consensus docking, followed by…