111 research outputs found
Disruption of plasmepsin-4 and merozoites surface protein-7 genes in Plasmodium berghei induces combined virulence-attenuated phenotype
Blood stage malaria parasites causing a mild and self limited infection in mice have
been obtained with either radiation or chemical mutagenesis showing the possibility
of developing an attenuated malaria vaccine. Targeted disruption of plasmepsin-4
(pm4) or the merozoite surface protein-7 (msp7) genes also induces
a virulence-attenuated phenotype in terms of absence of experimental cerebral
malaria (ECM), delayed increase of parasitemia and reduced mortality rate. The
decrease in virulence in parasites lacking either pm4 or msp7 is
however incomplete and dependent on the parasite and mouse strain combination. The
sequential disruption of both genes induced remarkable virulence-attenuated
blood-stage parasites characterized by a self-resolving infection with low levels of
parasitemia and no ECM. Furthermore, convalescent mice were protected against the
challenge with P. berghei or P. yoelii parasites for several months.
These observations provide a proof-of-concept step for the development of human
malaria vaccines based on genetically attenuated blood-stage parasites
A Model of Late Long-Term Potentiation Simulates Aspects of Memory Maintenance
Late long-term potentiation (L-LTP) appears essential for the formation of
long-term memory, with memories at least partly encoded by patterns of
strengthened synapses. How memories are preserved for months or years, despite
molecular turnover, is not well understood. Ongoing recurrent neuronal
activity, during memory recall or during sleep, has been hypothesized to
preferentially potentiate strong synapses, preserving memories. This hypothesis
has not been evaluated in the context of a mathematical model representing
biochemical pathways important for L-LTP. I incorporated ongoing activity into
two such models: a reduced model that represents some of the essential
biochemical processes, and a more detailed published model. The reduced model
represents synaptic tagging and gene induction intuitively, and the detailed
model adds activation of essential kinases by Ca. Ongoing activity was modeled
as continual brief elevations of [Ca]. In each model, two stable states of
synaptic weight resulted. Positive feedback between synaptic weight and the
amplitude of ongoing Ca transients underlies this bistability. A tetanic or
theta-burst stimulus switches a model synapse from a low weight to a high
weight stabilized by ongoing activity. Bistability was robust to parameter
variations. Simulations illustrated that prolonged decreased activity reset
synapses to low weights, suggesting a plausible forgetting mechanism. However,
episodic activity with shorter inactive intervals maintained strong synapses.
Both models support experimental predictions. Tests of these predictions are
expected to further understanding of how neuronal activity is coupled to
maintenance of synaptic strength.Comment: Accepted to PLoS One. 8 figures at en
Host Genes Related to Paneth Cells and Xenobiotic Metabolism Are Associated with Shifts in Human Ileum-Associated Microbial Composition
The aim of this study was to integrate human clinical, genotype, mRNA microarray and 16 S rRNA sequence data collected on 84 subjects with ileal Crohn’s disease, ulcerative colitis or control patients without inflammatory bowel diseases in order to interrogate how host-microbial interactions are perturbed in inflammatory bowel diseases (IBD). Ex-vivo ileal mucosal biopsies were collected from the disease unaffected proximal margin of the ileum resected from patients who were undergoing initial intestinal surgery. Both RNA and DNA were extracted from the mucosal biopsy samples. Patients were genotyped for the three major NOD2 variants (Leufs1007, R702W, and G908R) and the ATG16L1T300A variant. Whole human genome mRNA expression profiles were generated using Agilent microarrays. Microbial composition profiles were determined by 454 pyrosequencing of the V3–V5 hypervariable region of the bacterial 16 S rRNA gene. The results of permutation based multivariate analysis of variance and covariance (MANCOVA) support the hypothesis that host mucosal Paneth cell and xenobiotic metabolism genes play an important role in host microbial interactions
Multilocus Phylogenetic Study of the Scheffersomyces Yeast Clade and Characterization of the N-Terminal Region of Xylose Reductase Gene
Many of the known xylose-fermenting (X-F) yeasts are placed in the Scheffersomyces clade, a group of ascomycete yeasts that have been isolated from plant tissues and in association with lignicolous insects. We formally recognize fourteen species in this clade based on a maximum likelihood (ML) phylogenetic analysis using a multilocus dataset. This clade is divided into three subclades, each of which exhibits the biochemical ability to ferment cellobiose or xylose. New combinations are made for seven species of Candida in the clade, and three X-F taxa associated with rotted hardwood are described: Scheffersomyces illinoinensis (type strain NRRL Y-48827T = CBS 12624), Scheffersomyces quercinus (type strain NRRL Y-48825T = CBS 12625), and Scheffersomyces virginianus (type strain NRRL Y-48822T = CBS 12626). The new X-F species are distinctive based on their position in the multilocus phylogenetic analysis and biochemical and morphological characters. The molecular characterization of xylose reductase (XR) indicates that the regions surrounding the conserved domain contain mutations that may enhance the performance of the enzyme in X-F yeasts. The phylogenetic reconstruction using XYL1 or RPB1 was identical to the multilocus analysis, and these loci have potential for rapid identification of cryptic species in this clade
The measurement of stress and phase fraction distributions in pre and post-transition Zircaloy oxides using nano-beam synchrotron X-ray diffraction
Zircaloy-4 oxide stress profiles and tetragonal:monoclinic oxide phase fraction distributions were studied using nano-beam transmission X-ray diffraction. Continuous stress relief and phase transformation during the first cycle of oxide growth was observed. The in-plane monoclinic stress was shown to relax strongly up to each transition, whereas in-plane tetragonal stress-relief (near the metal-oxide interface) was only observed post transition. The research demonstrates that plasticity in the metal and the development of a band of in-plane cracking both relax the monoclinic in-plane stress.The observations are consistent with a model of transition in which in-plane cracking becomes interlinked prior to transition. These cracks, combined with the development of cracks with a through-thickness component (driven primarily by plasticity in the metal) and/or a porous network of fine cracks (associated with phase transformation), form a percolation path through the oxide layer. The oxidising species can then percolate from the oxide surface to the metal/oxide interface, at which stage transition then ensues
The disruption of proteostasis in neurodegenerative diseases
Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio
Examining the Heterogeneous Genome Content of Multipartite Viruses BMV and CCMV by Native Mass Spectrometry
Since the concept was first introduced by Brian Chait and co-workers in 1991, mass spectrometry of proteins and protein complexes under non-denaturing conditions (native MS) has strongly developed, through parallel advances in instrumentation, sample preparation, and data analysis tools. However, the success rate of native MS analysis, particularly in heterogeneous mega-Dalton (MDa) protein complexes, still strongly depends on careful instrument modification. Here, we further explore these boundaries in native mass spectrometry, analyzing two related endogenous multipartite viruses: the Brome Mosaic Virus (BMV) and the Cowpea Chlorotic Mottle Virus (CCMV). Both CCMV and BMV are approximately 4.6 megadalton (MDa) in mass, of which approximately 1 MDA originates from the genomic content of the virion. Both viruses are produced as mixtures of three particles carrying different segments of the genome, varying by approximately 0.1 MDA in mass (~2%). This mixture of particles poses a challenging analytical problem for high-resolution native MS analysis, given the large mass scales involved. We attempt to unravel the particle heterogeneity using both Q-TOF and Orbitrap mass spectrometers extensively modified for analysis of very large assemblies. We show that manipulation of the charging behavior can provide assistance in assigning the correct charge states. Despite their challenging size and heterogeneity, we obtained native mass spectra with resolved series of charge states for both BMV and CCMV, demonstrating that native MS of endogenous multipartite virions is feasible. [Figure: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13361-016-1348-6) contains supplementary material, which is available to authorized users
Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases
The production of peroxide and superoxide is an inevitable consequence of
aerobic metabolism, and while these particular "reactive oxygen species" (ROSs)
can exhibit a number of biological effects, they are not of themselves
excessively reactive and thus they are not especially damaging at physiological
concentrations. However, their reactions with poorly liganded iron species can
lead to the catalytic production of the very reactive and dangerous hydroxyl
radical, which is exceptionally damaging, and a major cause of chronic
inflammation. We review the considerable and wide-ranging evidence for the
involvement of this combination of (su)peroxide and poorly liganded iron in a
large number of physiological and indeed pathological processes and
inflammatory disorders, especially those involving the progressive degradation
of cellular and organismal performance. These diseases share a great many
similarities and thus might be considered to have a common cause (i.e.
iron-catalysed free radical and especially hydroxyl radical generation). The
studies reviewed include those focused on a series of cardiovascular, metabolic
and neurological diseases, where iron can be found at the sites of plaques and
lesions, as well as studies showing the significance of iron to aging and
longevity. The effective chelation of iron by natural or synthetic ligands is
thus of major physiological (and potentially therapeutic) importance. As
systems properties, we need to recognise that physiological observables have
multiple molecular causes, and studying them in isolation leads to inconsistent
patterns of apparent causality when it is the simultaneous combination of
multiple factors that is responsible. This explains, for instance, the
decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference
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