253 research outputs found
Targeted Disruption of the PME-1 Gene Causes Loss of Demethylated PP2A and Perinatal Lethality in Mice
Phosphoprotein phosphatase 2A (PP2A), a major serine-threonine protein phosphatase in eukaryotes, is an oligomeric protein comprised of structural (A) and catalytic (C) subunits to which a variable regulatory subunit (B) can associate. The C subunit contains a methyl ester post-translational modification on its C-terminal leucine residue, which is removed by a specific methylesterase (PME-1). Methylesterification is thought to control the binding of different B subunits to AC dimers, but little is known about its physiological significance in vivo.Here, we show that targeted disruption of the PME-1 gene causes perinatal lethality in mice, a phenotype that correlates with a virtually complete loss of the demethylated form of PP2A in the nervous system and peripheral tissues. Interestingly, PP2A catalytic activity over a peptide substrate was dramatically reduced in PME-1(-/-) tissues, which also displayed alterations in phosphoproteome content.These findings suggest a role for the demethylated form of PP2A in maintenance of enzyme function and phosphorylation networks in vivo
Overview of IFMIF-DONES diagnostics: Requirements and techniques
The IFMIF-DONES Facility is a unique first-class scientific infrastructure whose construction is foreseen in Granada, Spain, in the coming years. Strong integration efforts are being made at the current project phase aiming at harmonizing the ongoing design of the different and complex Systems of the facility. The consolidation of the Diagnostics and Instrumentation, transversal across many of them, is a key element of this purpose. A top-down strategy is proposed for a systematic Diagnostics Review and Requirement definition, putting emphasis in the one-of-a-kind instruments necessary by the operational particularities of some of the Systems, as well as to the harsh environment that they shall survive. In addition, other transversal aspects such as the ones related to Safety and Machine Protection and their respective requirements shall be also considered. The goal is therefore to advance further and solidly in the respective designs, identify problems in advance, and steer the Diagnostics development and validation campaigns that will be required. The present work provides an overview of this integration strategy as well as a description of some of the most challenging Diagnostics and Instruments within the facility, including several proposed techniques currently under study
Abundance of the Quorum-Sensing Factor Ax21 in Four Strains of Stenotrophomonas maltophilia Correlates with Mortality Rate in a New Zebrafish Model of Infection
Stenotrophomonas maltophilia is a Gram-negative pathogen with emerging nosocomial incidence. Little is known about its pathogenesis and the genomic diversity exhibited by clinical isolates complicates the study of pathogenicity and virulence factors. Here, we present a strategy to identify such factors in new clinical isolates of S. maltophilia, incorporating an adult-zebrafish model of S. maltophilia infection to evaluate relative virulence coupled to 2D difference gel electrophoresis to explore underlying differences in protein expression. In this study we report upon three recent clinical isolates and use the collection strain ATCC13637 as a reference. The adult-zebrafish model shows discrimination capacity, i.e. from very low to very high mortality rates, with clinical symptoms very similar to those observed in natural S. maltophilia infections in fish. Strain virulence correlates with resistance to human serum, in agreement with previous studies in mouse and rat and therefore supporting zebrafish as a replacement model. Despite its clinical origin, the collection strain ATCC13637 showed obvious signs of attenuation in zebrafish, with null mortality. Multilocus-sequence-typing analysis revealed that the most virulent strains, UV74 and M30, exhibit the strongest genetic similitude. Differential proteomic analysis led to the identification of 38 proteins with significantly different abundance in the three clinical strains relative to the reference strain. Orthologs of several of these proteins have been already reported to have a role in pathogenesis, virulence or resistance mechanisms thus supporting our strategy. Proof of concept is further provided by protein Ax21, whose abundance is shown here to be directly proportional to mortality in the zebrafish infection model. Indeed, recent studies have demonstrated that this protein is a quorum-sensing-related virulence factor
Effects of Aging on Endotoxin Tolerance Induced by Lipopolysaccharides Derived from Porphyromonas gingivalis and Escherichia coli
Background: Periodontitis is a bacterially induced chronic inflammatory disease. Exposure of the host to periodontal pathogens and their virulence factors induces a state of hyporesponsiveness to subsequent stimulations, termed endotoxin tolerance. Aging has a profound effect on immune response to bacteria challenge. The aim of this study was to explore the effects of aging on endotoxin tolerance induced by Porphyromonas gingivalis (P. gingivalis) lipopolysaccharide (LPS) and Escherichia coli (E. coli) LPS in murine peritoneal macrophages. Methodology/Principal Findings: We studied the cytokine production (TNF-aand IL-10) and Toll-like receptor 2, 4 (TLR2, 4) gene and protein expressions in peritoneal macrophages from young (2-month-old) and middle-aged (12-month-old) ICR mice following single or repeated P. gingivalis LPS or E. coli LPS stimulation. Pretreatment of peritoneal macrophages with P. gingivalis LPS or E. coli LPS resulted in a reduction in TNF-a production and an increase in IL-10 production upon secondary stimulation (p,0.05), and the markedly lower levels of TNF-a and higher levels of IL-10 were observed in macrophages from young mice compared with those from middle-aged mice (p,0.05). In addition, LPS restimulations also led to the significantly lower expression levels of TLR2, 4 mRNA and protein in macrophages from young mice (p,0.05). Conclusions/Significance: Repeated LPS stimulations triggered endotoxin tolerance in peritoneal macrophages and the ability to develop tolerance in young mice was more excellent. The impaired ability to develop endotoxin tolerance resulte
Productâprocess matrix and complementarity approach
The relationship between different types of innovation is analysed from three different approaches. On the one hand, the distinctive view assumes that the determinants of each type of innovation are different and therefore there is no relationship between them. On the other hand, the integrative view considers that the different types of innovation are complementary. Finally, the productâprocess matrix framework suggests that the relationship between product innovation and process innovation is substitutive. Using data from Spain belonging to the Technological Innovation Panel (PITEC) for the years 2008, 2009, 2010, 2011 and 2012, we tested which of the three approaches is predominant. To perform the hypothesis test, we used the so-called complementarity approach. We find that there is no unique relation. The nature of the relationship depends on the types of innovation that interact. Our most significant finding is that the relationship between product innovation and process innovation is complementary. This finding contradicts the proposal of the productâprocess matrix framework. Consequently, the joint implementation of both types of innovation generates a greater impact on the performance of a company than the sum of their separate implementation
Disposable sensors in diagnostics, food and environmental monitoring
Disposable sensors are lowâcost and easyâtoâuse sensing devices intended for shortâterm or rapid singleâpoint measurements. The growing demand for fast, accessible, and reliable information in a vastly connected world makes disposable sensors increasingly important. The areas of application for such devices are numerous, ranging from pharmaceutical, agricultural, environmental, forensic, and food sciences to wearables and clinical diagnostics, especially in resourceâlimited settings. The capabilities of disposable sensors can extend beyond measuring traditional physical quantities (for example, temperature or pressure); they can provide critical chemical and biological information (chemoâ and biosensors) that can be digitized and made available to users and centralized/decentralized facilities for data storage, remotely. These features could pave the way for new classes of lowâcost systems for health, food, and environmental monitoring that can democratize sensing across the globe. Here, a brief insight into the materials and basics of sensors (methods of transduction, molecular recognition, and amplification) is provided followed by a comprehensive and critical overview of the disposable sensors currently used for medical diagnostics, food, and environmental analysis. Finally, views on how the field of disposable sensing devices will continue its evolution are discussed, including the future trends, challenges, and opportunities
Embedded Software of the KM3NeT Central Logic Board
The KM3NeT Collaboration is building and operating two deep sea neutrino
telescopes at the bottom of the Mediterranean Sea. The telescopes consist of
latices of photomultiplier tubes housed in pressure-resistant glass spheres,
called digital optical modules and arranged in vertical detection units. The
two main scientific goals are the determination of the neutrino mass ordering
and the discovery and observation of high-energy neutrino sources in the
Universe. Neutrinos are detected via the Cherenkov light, which is induced by
charged particles originated in neutrino interactions. The photomultiplier
tubes convert the Cherenkov light into electrical signals that are acquired and
timestamped by the acquisition electronics. Each optical module houses the
acquisition electronics for collecting and timestamping the photomultiplier
signals with one nanosecond accuracy. Once finished, the two telescopes will
have installed more than six thousand optical acquisition nodes, completing one
of the more complex networks in the world in terms of operation and
synchronization. The embedded software running in the acquisition nodes has
been designed to provide a framework that will operate with different hardware
versions and functionalities. The hardware will not be accessible once in
operation, which complicates the embedded software architecture. The embedded
software provides a set of tools to facilitate remote manageability of the
deployed hardware, including safe reconfiguration of the firmware. This paper
presents the architecture and the techniques, methods and implementation of the
embedded software running in the acquisition nodes of the KM3NeT neutrino
telescopes
Spread of a SARS-CoV-2 variant through Europe in the summer of 2020.
Following its emergence in late 2019, the spread of SARS-CoV-21,2 has been tracked by phylogenetic analysis of viral genome sequences in unprecedented detail3â5. Although the virus spread globally in early 2020 before borders closed, intercontinental travel has since been greatly reduced. However, travel within Europe resumed in the summer of 2020. Here we report on a SARS-CoV-2 variant, 20E (EU1), that was identified in Spain in early summer 2020 and subsequently spread across Europe. We find no evidence that this variant has increased transmissibility, but instead demonstrate how rising incidence in Spain, resumption of travel, and lack of effective screening and containment may explain the variantâs success. Despite travel restrictions, we estimate that 20E (EU1) was introduced hundreds of times to European countries by summertime travellers, which is likely to have undermined local efforts to minimize infection with SARS-CoV-2. Our results illustrate how a variant can rapidly become dominant even in the absence of a substantial transmission advantage in favourable epidemiological settings. Genomic surveillance is critical for understanding how travel can affect transmission of SARS-CoV-2, and thus for informing future containment strategies as travel resumes. © 2021, The Author(s), under exclusive licence to Springer Nature Limited
Prospects for combined analyses of hadronic emission from -ray sources in the Milky Way with CTA and KM3NeT
The Cherenkov Telescope Array and the KM3NeT neutrino telescopes are major
upcoming facilities in the fields of -ray and neutrino astronomy,
respectively. Possible simultaneous production of rays and neutrinos
in astrophysical accelerators of cosmic-ray nuclei motivates a combination of
their data. We assess the potential of a combined analysis of CTA and KM3NeT
data to determine the contribution of hadronic emission processes in known
Galactic -ray emitters, comparing this result to the cases of two
separate analyses. In doing so, we demonstrate the capability of Gammapy, an
open-source software package for the analysis of -ray data, to also
process data from neutrino telescopes. For a selection of prototypical
-ray sources within our Galaxy, we obtain models for primary proton and
electron spectra in the hadronic and leptonic emission scenario, respectively,
by fitting published -ray spectra. Using these models and instrument
response functions for both detectors, we employ the Gammapy package to
generate pseudo data sets, where we assume 200 hours of CTA observations and 10
years of KM3NeT detector operation. We then apply a three-dimensional binned
likelihood analysis to these data sets, separately for each instrument and
jointly for both. We find that the largest benefit of the combined analysis
lies in the possibility of a consistent modelling of the -ray and
neutrino emission. Assuming a purely leptonic scenario as input, we obtain, for
the most favourable source, an average expected 68% credible interval that
constrains the contribution of hadronic processes to the observed -ray
emission to below 15%.Comment: 18 pages, 15 figures. Submitted to journa
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