Search results for "pathogen"
showing 10 items of 1657 documents
Impact of Safety-Related Dose Reductions or Discontinuations on Sustained Virologic Response in HCV-Infected Patients: Results from the GUARD-C Cohor…
2015
Background: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. Methods: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the i…
In silico identification and experimental validation of hits active against KPC-2 β-lactamase
2018
Bacterial resistance has become a worldwide concern, particularly after the emergence of resistant strains overproducing carbapenemases. Among these, the KPC-2 carbapenemase represents a significant clinical challenge, being characterized by a broad substrate spectrum that includes aminothiazoleoxime and cephalosporins such as cefotaxime. Moreover, strains harboring KPC-type β-lactamases are often reported as resistant to available β-lactamase inhibitors (clavulanic acid, tazobactam and sulbactam). Therefore, the identification of novel non β-lactam KPC-2 inhibitors is strongly necessary to maintain treatment options. This study explored novel, non-covalent inhibitors active against KPC-2, …
Recent advances in the expression, evolution, and dynamics of prokaryotic genomes
2007
Work on the molecular and cellular biology of prokaryotic microorganisms and their phage continues to be at the cutting edge in many areas of fundamental research in the life sciences. An important stimulus has been the large number of complete bacterial and archaeal genome sequences that have appeared over the past decade and that now are being produced at a rate of several hundred per year. This information is the foundation for all of the “-omics” leading to a global evaluation of the state of the cell under various conditions of growth or stress. An overview of the sequenced prokaryotic genomes has also greatly influenced our thinking about the evolution of life on earth. The EMBO Confe…
Friedreich Ataxia: An Update on Animal Models, Frataxin Function and Therapies
2009
Friedreich ataxia (FRDA) is an autosomal recessive progressively debilitating degenerative disease that principally affects the nervous system and the heart. Although FRDA is considered a rare disease, is the most common inherited ataxia. It is caused by loss-of-function mutations in the FXN gene, mainly an expanded GAA triplet repeat in the intron 1. The genetic defect results in the reduction of frataxin levels, a protein targeted to the mitochondria. Frataxin deficiency leads to mitochondrial dysfunction, oxidative damage and iron accumulation. Studies of the yeast and animal models of the disease have led to propose several different roles for frataxin. Animal models have also been impo…
Desmin‐related Myopathies
2006
Outstanding progress in elucidating the pathology of muscular disorders at light and electron microscopic levels has allowed the identification of proteins involved in pathological alterations. This, in turn, has led to discoveries of multiple genes and mutations associated with previously poorly understood conditions. An unexpected result is that phenotypically similar and pathogenetically related neuromuscular disorders are associated with mutations in one or the other of several interacting proteins. Keywords: desmin-related myopathy; distal myopathy; cardiomyopathy; desmin and alpha-B crystallin gene mutations; functional analysis; molecular pathogenesis; genotype–phenotype correlations
DNASE1L3 Deficiency, New Phenotypes and Evidence for a Transient Type I Interferon Signaling
2021
Introduction: Deoxyribonuclease 1 like 3 (DNASE1L3) is a secreted enzyme that has been shown to digest the extracellular chromatin derived from apoptotic bodies, and DNASE1L3 pathogenic variants have been associated to a lupus phenotype. It is unclear whether interferon signaling is sustained in DNASE1L3 deficiency in humans. Objectives: Here, we report on four patients with pathogenic variations in DNASE1L3, including 2 previously undescribed causal variants, and expand the phenotype from SLE to vasculitis with gut involvement. To explore whether or not the interferon cascade was strongly and sustainably induced, Interferon stimulated genes (ISGs) expression was assessed for each patient. …
A genetic background with low mutational robustness is associated with increased adaptability to a novel host in an RNA virus.
2009
Although mutational robustness is central to many evolutionary processes, its relationship to evolvability remains poorly understood and has been very rarely tested experimentally. Here, we measure the evolvability of Vesicular stomatitis virus in two genetic backgrounds with different levels of mutational robustness. We passaged the viruses into a novel cell type to model a host-jump episode, quantified changes in infectivity and fitness in the new host, evaluated the cost of adaptation in the original host and analyzed the genetic basis of this adaptation. Lineages evolved from the less robust genetic background demonstrated increased adaptability, paid similar costs of adaptation to the …
Innate immune pathways act synergistically to constrain RNA virus evolution in Drosophila melanogaster
2021
AbstractHost-pathogen interactions impose recurrent selective pressures that lead to constant adaptation and counter-adaptation in both competing species. Here, we sought to study this evolutionary arms-race and assessed the impact of the innate immune system on viral population diversity and evolution, using D. melanogaster as model host and its natural pathogen Drosophila C virus (DCV). We first isogenized eight fly genotypes generating animals defective for RNAi, Imd and Toll innate immune pathways and also pathogen sensing and gut renewal pathways. Wild-type or mutant flies were then orally infected and DCV was serially passaged ten times. Viral population diversity was studied after ea…
Phylogeny and life cycle of the zoonotic pathogen Vibrio vulnificus
2020
Vibrio vulnificus is a zoonotic pathogen able to cause diseases in humans and fish that occasionally result in sepsis and death. Most reviews about this pathogen (including those related to its ecology) are clearly biased towards its role as a human pathogen, emphasizing its relationship with oysters as its main reservoir, the role of the known virulence factors as well as the clinic and the epidemiology of the human disease. This review tries to give to the reader a wider vision of the biology of this pathogen covering aspects related to its phylogeny and evolution and filling the gaps in our understanding of the general strategies that V. vulnificus uses to survive outside and inside its …
Multiple infection dynamics has pronounced effects on the fitness of RNA viruses
2001
Several factors play a role during the replication and transmission of RNA viruses. First, as a consequence of their enormous mutation rate, complex mixtures of genomes are generated immediately after infection of a new host. Secondly, differences in growth and competition rates drive the selection of certain genetic variants within an infected host. Thirdly, but not less important, a random sampling occurs at the moment of viral infectious passage from an infected to a healthy host. In addition, the availability of hosts also influences the fate of a given viral genotype. When new hosts are scarce, different viral genotypes might infect the same host, adding an extra complexity to the comp…