Search results for "mutant"

Viral replication modes in single-peak fitness landscapes: A dynamical systems analysis

2017

Positive-sense, single-stranded RNA viruses are important pathogens infecting almost all types of organisms. Experimental evidence from distributions of mutations and from viral RNA amplification suggest that these pathogens may follow different RNA replication modes, ranging from the stamping machine replication (SMR) to the geometric replication (GR) mode. Although previous theoretical work has focused on the evolutionary dynamics of RNA viruses amplifying their genomes with different strategies, little is known in terms of the bifurcations and transitions involving the so-called error threshold (mutation-induced dominance of mutants) and lethal mutagenesis (extinction of all sequences du…

Fluorinated Chaperone−β-Cyclodextrin Formulations for β-Glucocerebrosidase Activity Enhancement in Neuronopathic Gaucher Disease

2017

Amphiphilic glycomimetics encompassing a rigid, undistortable nor-tropane skeleton based on 1,6-anhydro-L-idonojirimycin and a polyfluorinated antenna, when formulated as the corresponding inclusion complexes with β-cyclodextrin (βCD), have been shown to behave as pharmacological chaperones (PCs) that efficiently rescue lysosomal β- glucocerebrosidase mutants associated to the neuronopathic variants of Gaucher disease (GD), including the highly refractory L444P/L444P and L444P/P415R single nucleotide polymorphs, in patient fibroblasts. The body of work here presented includes the design criteria for the PC prototype, the synthesis of a series of candidates, the characterization of the PC:βC…

Rett Syndrome Mutant Neural Cells Lacks MeCP2 Immunoreactive Bands.

2016

Dysfunctions of MeCP2 protein lead to various neurological disorders such as Rett syndrome and Autism. The exact functions of MeCP2 protein is still far from clear. At a molecular level, there exist contradictory data. MeCP2 protein is considered a single immunoreactive band around 75 kDa by western-blot analysis but several reports have revealed the existence of multiple MeCP2 immunoreactive bands above and below the level where MeCP2 is expected. MeCP2 immunoreactive bands have been interpreted in different ways. Some researchers suggest that multiple MeCP2 immunoreactive bands are unidentified proteins that cross-react with the MeCP2 antibody or degradation product of MeCP2, while others…

2020

Interactome maps are valuable resources to elucidate protein function and disease mechanisms. Here, we report on an interactome map that focuses on neurodegenerative disease (ND), connects ∼5,000 human proteins via ∼30,000 candidate interactions and is generated by systematic yeast two-hybrid interaction screening of ∼500 ND-related proteins and integration of literature interactions. This network reveals interconnectivity across diseases and links many known ND-causing proteins, such as α-synuclein, TDP-43, and ATXN1, to a host of proteins previously unrelated to NDs. It facilitates the identification of interacting proteins that significantly influence mutant TDP-43 and HTT toxicity in tr…

A giant type I polyketide synthase participates in zygospore maturation in Chlamydomonas reinhardtii

2017

Polyketide synthases (PKSs) occur in many bacteria, fungi and plants. They are highly versatile enzymes involved in the biosynthesis of a large variety of compounds including antimicrobial agents, polymers associated with bacterial cell walls and plant pigments. While harmful algae are known to produce polyketide toxins, sequences of the genomes of non-toxic algae, including those of many green algal species, have surprisingly revealed the presence of genes encoding type I PKSs. The genome of the model alga Chlamydomonas reinhardtii (Chlorophyta) contains a single type I PKS gene, designated PKS1 (Cre10.g449750), which encodes a giant PKS with a predicted mass of 2.3 MDa. Here, we show that…

Results of COLUMBUS Part 2: A phase 3 trial of encorafenib (ENCO) plus binimetinib (BINI) versus ENCO in BRAF-mutant melanoma

2017

IVAC MUTANOME: A first-in-human phase I clinical trial targeting individual mutant neoantigens for the treatment of melanoma

2017

Erwinia amylovoracatalases KatA and KatG are virulence factors and delay the starvation-induced viable but non-culturable (VBNC) response

2017

The life cycle of the plant pathogen Erwinia amylovora comprises periods inside and outside the host in which it faces oxidative stress caused by hydrogen peroxide (H2 O2 ) and other compounds. The sources of this stress are plant defences, other microorganisms and/or exposure to starvation or other environmental challenges. However, the functional roles of H2 O2 -neutralizing enzymes, such as catalases, during plant-pathogen interactions and/or under starvation conditions in phytopathogens of the family Erwiniaceae or closely related families have not yet been investigated. In this work, the contribution of E. amylovora catalases KatA and KatG to virulence and survival in non-host environm…

Pharmacological disruption of the MID1/α4 interaction reduces mutant Huntingtin levels in primary neuronal cultures.

2017

Expression of mutant Huntingtin (HTT) protein is central to the pathophysiology of Huntington's Disease (HD). The E3 ubiquitin ligase MID1 appears to have a key role in facilitating translation of the mutant HTT mRNA suggesting that interference with the function of this complex could be an attractive therapeutic approach. Here we describe a peptide that is able to disrupt the interaction between MID1 and the α4 protein, a regulatory subunit of protein phosphatase 2A (PP2A). By fusing this peptide to a sequence from the HIV-TAT protein we demonstrate that the peptide can disrupt the interaction within cells and show that this results in a decrease in levels of ribosomal S6 phosphorylation a…

Dynamics of a Protein Interaction Network Associated to the Aggregation of polyQ-Expanded Ataxin-1

2020

Background: Several experimental models of polyglutamine (polyQ) diseases have been previously developed that are useful for studying disease progression in the primarily affected central nervous system. However, there is a missing link between cellular and animal models that would indicate the molecular defects occurring in neurons and are responsible for the disease phenotype in vivo. Methods: Here, we used a computational approach to identify dysregulated pathways shared by an in vitro and an in vivo model of ATXN1(Q82) protein aggregation, the mutant protein that causes the neurodegenerative polyQ disease spinocerebellar ataxia type-1 (SCA1). Results: A set of common dysregulated pathwa…