363 research outputs found
Functional characterisation of the mammalian NDR1 and NDR2 protein kinases and their regulation by the mammalian Ste20-like kinase MST3
Protein modification is a common regulatory mechanism in order to transduce a signal from
one molecule to another. One of the best-studied protein modifications is phosphorylation.
The enzymes that are capable of transferring phosphate groups onto other proteins are called
protein kinases. Depending on the acceptor group, kinases can be distinguished into tyrosine,
serine/threonine and dual-specificity kinases. This work describes the characterisation of
human and mouse NDR1 and NDR2 kinases, members of the AGC group of serine/threonine
kinases. The NDR protein kinase family is highly conserved between yeast and human, and
several members have been shown to be involved in the regulation of cell morphology and the
control of cell cycle progression. For example, the yeast NDR kinases Sid2p
(Schizosaccharomyces pombe) and Dbf2p (Saccharomyces cerevisiae) are central
components of the septation-initiation network and the mitosis exit network, respectively. The
closest yeast relatives Cbk1p and Orb6p, members of the regulation of Ace2p transcription
and morphogenesis network and Orb6 signalling pathways, are implicated in the coordination
of cell cycle progression and cell morphology. This study, as well as studies using worms and
flies, provide evidence that not only NDR is conserved, but also the NDR signalling pathway
and regulation. Similar to yeast, NDR kinase activation is regulated by phosphorylation at the
activation segment phosphorylation site and the hydrophobic motif phosphorylation site. This
phosphorylation is regulated by a conserved signaling module consisting of MOB proteins
and a STE20âlike kinase. Here we show that the STE20-like kinase MST3 activates NDR by
phosphorylation specifically at the hydrophobic motif in vitro and in vivo. Furthermore,
MOB1A binding is important for the release of autoinhibition and full kinase activation. The
data also indicate that NDR is part of a feedback mechanism, which induces cleavage and
nuclear translocation of MST3. The data presented here also show that NDR1 and NDR2 are
differentially expressed, but regulated in a similar manner. Mouse Ndr1 mRNA is mainly
expressed in spleen, thymus and lung, whereas Ndr2 mRNA is more ubiquitously expressed,
with the highest levels in the gastrointestinal tract. Both, NDR1 and NDR2, are activated by
S100B protein and okadaic acid stimulated phosphorylation; NDR1 and NDR2 are also
indistinguishable in the biochemical assays used: membrane targetting, phosphorylation by
MST3, and activation by MOB. Further, this work describes the generation and initial
characterisation of a mouse model for NDR1 deficiency. Protein analysis using NDR1
knockout mouse embryonic fibroblasts suggest a compensation of the loss of NDR1 by
upregulation of NDR2 expression
Biological CO2-methanation: An approach to standardization
Power-to-Methane as one part of Power-to-Gas has been recognized globally as one of the key elements for the transition towards a sustainable energy system. While plants that produce methane catalytically have been in operation for a long time, biological methanation has just reached industrial pilot scale and near-term commercial application. The growing importance of the biological method is reflected by an increasing number of scientific articles describing novel approaches to improve this technology. However, these studies are diffcult to compare because they lack a coherent nomenclature. In this article, we present a comprehensive set of parameters allowing the characterization and comparison of various biological methanation processes. To identify relevant parameters needed for a proper description of this technology, we summarized existing literature and defined system boundaries for Power-to-Methane process steps. On this basis, we derive system parameters providing information on the methanation system, its performance, the biology and cost aspects. As a result, three different standards are provided as a blueprint matrix for use in academia and industry applicable to both, biological and catalytic methanation. Hence, this review attempts to set the standards for a comprehensive description of biological and chemical methanation processes
Treatment of Patients with the Hypereosinophilic Syndrome with Mepolizumab
BACKGROUND
The hypereosinophilic syndrome is a group of diseases characterized by persistent blood eosinophilia, defined as more than 1500 cells per microliter with end-organ involvement and no recognized secondary cause. Although most patients have a response to corticosteroids, side effects are common and can lead to considerable morbidity.
METHODS
We conducted an international, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of an antiâinterleukin-5 monoclonal antibody, mepolizumab, in patients with the hypereosinophilic syndrome. Patients were negative for the FIP1L1âPDGFRA fusion gene and required prednisone monotherapy, 20 to 60 mg per day, to maintain a stable clinical status and a blood eosinophil count of less than 1000 per microliter. Patients received either intravenous mepolizumab or placebo while the prednisone dose was tapered. The primary end point was the reduction of the prednisone dose to 10 mg or less per day for 8 or more consecutive weeks.
RESULTS
The primary end point was reached in 84% of patients in the mepolizumab group, as compared with 43% of patients in the placebo group (hazard ratio, 2.90; 95% confidence interval [CI], 1.59 to 5.26; P
CONCLUSIONS
Our study shows that treatment with mepolizumab, an agent designed to target eosinophils, can result in corticosteroid-sparing for patients negative for FIP1L1â PDGFRA who have the hypereosinophilic syndrome. (ClinicalTrials.gov number, NCT00086658.
The physics of spreading processes in multilayer networks
The study of networks plays a crucial role in investigating the structure,
dynamics, and function of a wide variety of complex systems in myriad
disciplines. Despite the success of traditional network analysis, standard
networks provide a limited representation of complex systems, which often
include different types of relationships (i.e., "multiplexity") among their
constituent components and/or multiple interacting subsystems. Such structural
complexity has a significant effect on both dynamics and function. Throwing
away or aggregating available structural information can generate misleading
results and be a major obstacle towards attempts to understand complex systems.
The recent "multilayer" approach for modeling networked systems explicitly
allows the incorporation of multiplexity and other features of realistic
systems. On one hand, it allows one to couple different structural
relationships by encoding them in a convenient mathematical object. On the
other hand, it also allows one to couple different dynamical processes on top
of such interconnected structures. The resulting framework plays a crucial role
in helping achieve a thorough, accurate understanding of complex systems. The
study of multilayer networks has also revealed new physical phenomena that
remain hidden when using ordinary graphs, the traditional network
representation. Here we survey progress towards attaining a deeper
understanding of spreading processes on multilayer networks, and we highlight
some of the physical phenomena related to spreading processes that emerge from
multilayer structure.Comment: 25 pages, 4 figure
Encoding of amplitude modulations by auditory neurons of the locust: influence of modulation frequency, rise time, and modulation depth
Using modulation transfer functions (MTF), we investigated how sound patterns are processed within the auditory pathway of grasshoppers. Spike rates of auditory receptors and primary-like local neurons did not depend on modulation frequencies while other local and ascending neurons had lowpass, bandpass or bandstop properties. Local neurons exhibited broader dynamic ranges of their rate MTF that extended to higher modulation frequencies than those of most ascending neurons. We found no indication that a filter bank for modulation frequencies may exist in grasshoppers as has been proposed for the auditory system of mammals. The filter properties of half of the neurons changed to an allpass type with a 50% reduction of modulation depths. Contrasting to reports for mammals, the sensitivity to small modulation depths was not enhanced at higher processing stages. In ascending neurons, a focus on the range of low modulation frequencies was visible in the temporal MTFs, which describe the temporal locking of spikes to the signal envelope. To investigate the influence of stimulus rise time, we used rectangularly modulated stimuli instead of sinusoidally modulated ones. Unexpectedly, steep stimulus onsets had only small influence on the shape of MTF curves of 70% of neurons in our sample
Community-Based Outbreaks in Vulnerable Populations of Invasive Infections Caused by Streptococcus pneumoniae Serotypes 5 and 8 in Calgary, Canada
BACKGROUND: Outbreaks of invasive pneumococcal disease (IPD) typically occur within institutions. Beginning in 2005, we detected an increase in serotype (ST) 5 and ST8 IPD cases, predominantly in homeless persons living in an open community. METHODOLOGY/PRINCIPAL FINDINGS: CASPER (Calgary Area S. pneumoniae Epidemiology Research) surveillance study of all IPD (sterile site isolates) in our region (pop ~1,100,000). Interviews and chart reviews of all cases and all isolates phenotypically analyzed and selected isolated tested by multi-locus sequence typing (MLST). CONCLUSIONS/SIGNIFICANCE: During 2005-2007, 162 cases of ST5 IPD and 45 cases of ST8 IPD were identified. The isolates demonstrated phenotypic and genotypic clonality. The ST5 isolates were sequence type (ST) 289 and demonstrated intermediate susceptibility to TMP-SMX. The ST8 isolates were predominantly ST1268, with a susceptible antimicrobial susceptibility profile. Individuals with ST5 IPD were more likely to be middle aged (OR 2.6), homeless (OR 4.4), using illicit drugs(OR 4.8), and asthmatic(OR 2.6). Those with ST8 were more likely to be male (OR 4.4), homeless (OR 2.6), aboriginal (OR7.3), and a current smoker (OR 2.5). Overlapping outbreaks of ST5 and ST8 IPD occurred in an open community in Calgary, Canada and homelessness was a predominant risk factor. Homelessness represents a unique community in which pneumococcal outbreaks can occur
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