MidA is a putative methyltransferase that is required for mitochondrial complex I function

10 páginas, 6 figuras.-- et al.Dictyostelium and human MidA are homologous proteins that belong to a family of proteins of unknown function called DUF185. Using yeast two-hybrid screening and pull-down experiments, we showed that both proteins interact with the mitochondrial complex I subunit NDUFS2. Consistent with this, Dictyostelium cells lacking MidA showed a specific defect in complex I activity, and knockdown of human MidA in HEK293T cells resulted in reduced levels of assembled complex I. These results indicate a role for MidA in complex I assembly or stability. A structural bioinformatics analysis suggested the presence of a methyltransferase domain; this was further supported by site-directed mutagenesis of specific residues from the putative catalytic site. Interestingly, this complex I deficiency in a Dictyostelium midA- mutant causes a complex phenotypic outcome, which includes phototaxis and thermotaxis defects. We found that these aspects of the phenotype are mediated by a chronic activation of AMPK, revealing a possible role of AMPK signaling in complex I cytopathology.This work was supported by grants BMC2006-00394 and BMC2009-09050 to R.E. from the Spanish Ministerio de Ciencia e Innovación; to P.R.F. from the Thyne Reid Memorial Trusts and the Australian Research Council; to A.V. and O.G. from the Spanish National Bioinformatics Institute (www.inab.org), a platform of Genome Spain; to R.G. from the Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI070167) and from the Comunidad de Madrid (GEN-0269/2006). S.C. is supported by a research contract from Consejería de Educación de la Comunidad de Madrid y del Fondo Social Europeo (FSE).Peer Reviewe

Two unequally redundant "helper" immune receptor families mediate Arabidopsis thaliana intracellular "sensor" immune receptor functions

Plant nucleotide-binding (NB) leucine-rich repeat (LRR) receptor (NLR) proteins function as intracellular immune receptors that perceive the presence of pathogen-derived virulence proteins (effectors) to induce immune responses. The 2 major types of plant NLRs that "sense"pathogen effectors differ in their N-terminal domains: these are Toll/interleukin-1 receptor resistance (TIR) domain-containing NLRs (TNLs) and coiled-coil (CC) domain-containing NLRs (CNLs). In many angiosperms, the RESISTANCE TO POWDERY MILDEW 8 (RPW8)-CC domain containing NLR (RNL) subclass of CNLs is encoded by 2 gene families, ACTIVATED DISEASE RESISTANCE 1 (ADR1) and N REQUIREMENT GENE 1 (NRG1), that act as "helper"NLRs during multiple sensor NLR-mediated immune responses. Despite their important role in sensor NLR-mediated immunity, knowledge of the specific, redundant, and synergistic functions of helper RNLs is limited. We demonstrate that the ADR1 and NRG1 families act in an unequally redundant manner in basal resistance, effector-triggered immunity (ETI) and regulation of defense gene expression. We define RNL redundancy in ETI conferred by some TNLs and in basal resistance against virulent pathogens. We demonstrate that, in Arabidopsis thaliana, the 2 RNL families contribute specific functions in ETI initiated by specific CNLs and TNLs. Time-resolved whole genome expression profiling revealed that RNLs and "classical"CNLs trigger similar transcriptome changes, suggesting that RNLs act like other CNLs to mediate ETI downstream of sensor NLR activation. Together, our genetic data confirm that RNLs contribute to basal resistance, are fully required for TNL signaling, and can also support defense activation during CNL-mediated ETI

Endothelin-1 enhances fibrogenic gene expression, but does not promote DNA synthesis or apoptosis in hepatic stellate cells

BACKGROUND: In liver injury, the pool of hepatic stellate cell (HSC) increases and produces extracellular matrix proteins, decreasing during the resolution of fibrosis. The profibrogenic role of endothelin-1 (ET-1) in liver fibrosis remains disputed. We therefore studied the effect of ET-1 on proliferation, apoptosis and profibrogenic gene expression of HSCs. RESULTS: First passage HSC predominantly expressed endothelin A receptor (ETAR) mRNA and 4th passage HSC predominantly expressed the endothelin B receptor (ETBR) mRNA. ET-1 had no effect on DNA synthesis in 1st passage HSC, but reduced DNA synthesis in 4th passage HSC by more than 50%. Inhibition of proliferation by endothelin-1 was abrogated by ETBR specific antagonist BQ788, indicating a prominent role of ETBR in growth inhibition. ET-1 did not prevent apoptosis induced by serum deprivation or Fas ligand in 1st or 4th passage HSC. However, ET-1 increased procollagen α1(I), transforming growth factor β-1 and matrix metalloproteinase (MMP)-2 mRNA transcripts in a concentration-dependent manner in 1st, but not in 4th passage HSC. Profibrogenic gene expression was abrogated by ETAR antagonist BQ123. Both BQ123 and BQ788 attenuated the increase of MMP-2 expression by ET-1. CONCLUSION: We show that ET-1 stimulates fibrogenic gene expression for 1st passage HSC and it inhibits HSC proliferation for 4th passage HSC. These data indicate the profibrogenic and antifibrogenic action of ET-1 for HSC are involved in the process of liver fibrosis

Integrated Medical Model (IMM) 4.0 Enhanced Functionalities

The Integrated Medical Model is a probabilistic simulation model that uses input data on 100 medical conditions to simulate expected medical events, the resources required to treat, and the resulting impact to the mission for specific crew and mission characteristics. The newest development version of IMM, IMM v4.0, adds capabilities that remove some of the conservative assumptions that underlie the current operational version, IMM v3. While IMM v3 provides the framework to simulate whether a medical event occurred, IMMv4 also simulates when the event occurred during a mission timeline. This allows for more accurate estimation of mission time lost and resource utilization. In addition to the mission timeline, IMMv4.0 features two enhancements that address IMM v3 assumptions regarding medical event treatment. Medical events in IMMv3 are assigned the untreated outcome if any resource required to treat the event was unavailable. IMMv4 allows for partially treated outcomes that are proportional to the amount of required resources available, thus removing the dichotomous treatment assumption. An additional capability IMMv4 is to use an alternative medical resource when the primary resource assigned to the condition is depleted, more accurately reflecting the real-world system. The additional capabilities defining IMM v4.0the mission timeline, partial treatment, and alternate drug result in more realistic predicted mission outcomes. The primary model outcomes of IMM v4.0 for the ISS6 mission, including mission time lost, probability of evacuation, and probability of loss of crew life, are be compared to those produced by the current operational version of IMM to showcase enhanced prediction capabilities

Дослідження місцезнаходжень культури лінійно-стрічкової кераміки на Волині

Українсько-німецько-польська експедиція проводила дослідження пам’яток культури лінійно-стрічкової кераміки на Волині в межах підготовки проекту їх планового вивчення

Integrated Medical Model Project - Overview and Summary of Historical Application

Introduction: The Integrated Medical Model (IMM) Project represents one aspect of NASA's Human Research Program (HRP) to quantitatively assess medical risks to astronauts for existing operational missions as well as missions associated with future exploration and commercial space flight ventures. The IMM takes a probabilistic approach to assessing the likelihood and specific outcomes of one hundred medical conditions within the envelope of accepted space flight standards of care over a selectable range of mission capabilities. A specially developed Integrated Medical Evidence Database (iMED) maintains evidence-based, organizational knowledge across a variety of data sources. Since becoming operational in 2011, version 3.0 of the IMM, the supporting iMED, and the expertise of the IMM project team have contributed to a wide range of decision and informational processes for the space medical and human research community. This presentation provides an overview of the IMM conceptual architecture and range of application through examples of actual space flight community questions posed to the IMM project. Methods: Figure 1 [see document] illustrates the IMM modeling system and scenario process. As illustrated, the IMM computational architecture is based on Probabilistic Risk Assessment techniques. Nineteen assumptions and limitations define the IMM application domain. Scenario definitions include crew medical attributes and mission specific details. The IMM forecasts probabilities of loss of crew life (LOCL), evacuation (EVAC), quality time lost during the mission, number of medical resources utilized and the number and type of medical events by combining scenario information with in-flight, analog, and terrestrial medical information stored in the iMED. In addition, the metrics provide the integrated information necessary to estimate optimized in-flight medical kit contents under constraints of mass and volume or acceptable level of mission risk. Results and Conclusions: Historically, IMM simulations support Science and Technology planning, Exploration mission planning, and ISS program operations by supplying simulation support, iMED data information, and subject matter expertise to Crew Health and Safety and the HRP. Upcoming release of IMM version 4.0 seeks to provide enhanced functionality to increase the quality of risk decisions made using the IMM through a more accurate representation of the real world system

Integrated Medical Model Overview

The Integrated Medical Model (IMM) Project represents one aspect of NASA's Human Research Program (HRP) to quantitatively assess medical risks to astronauts for existing operational missions as well as missions associated with future exploration and commercial space flight ventures. The IMM takes a probabilistic approach to assessing the likelihood and specific outcomes of one hundred medical conditions within the envelope of accepted space flight standards of care over a selectable range of mission capabilities. A specially developed Integrated Medical Evidence Database (iMED) maintains evidence-based, organizational knowledge across a variety of data sources. Since becoming operational in 2011, version 3.0 of the IMM, the supporting iMED, and the expertise of the IMM project team have contributed to a wide range of decision and informational processes for the space medical and human research community. This presentation provides an overview of the IMM conceptual architecture and range of application through examples of actual space flight community questions posed to the IMM project

Knowledge-based matrix factorization temporally resolves the cellular responses to IL-6 stimulation

<p>Abstract</p> <p>Background</p> <p>External stimulations of cells by hormones, cytokines or growth factors activate signal transduction pathways that subsequently induce a re-arrangement of cellular gene expression. The analysis of such changes is complicated, as they consist of multi-layered temporal responses. While classical analyses based on clustering or gene set enrichment only partly reveal this information, matrix factorization techniques are well suited for a detailed temporal analysis. In signal processing, factorization techniques incorporating data properties like spatial and temporal correlation structure have shown to be robust and computationally efficient. However, such correlation-based methods have so far not be applied in bioinformatics, because large scale biological data rarely imply a natural order that allows the definition of a delayed correlation function.</p> <p>Results</p> <p>We therefore develop the concept of graph-decorrelation. We encode prior knowledge like transcriptional regulation, protein interactions or metabolic pathways in a weighted directed graph. By linking features along this underlying graph, we introduce a partial ordering of the features (e.g. genes) and are thus able to define a graph-delayed correlation function. Using this framework as constraint to the matrix factorization task allows us to set up the fast and robust graph-decorrelation algorithm (GraDe). To analyze alterations in the gene response in <it>IL-6 </it>stimulated primary mouse hepatocytes, we performed a time-course microarray experiment and applied GraDe. In contrast to standard techniques, the extracted time-resolved gene expression profiles showed that <it>IL-6 </it>activates genes involved in cell cycle progression and cell division. Genes linked to metabolic and apoptotic processes are down-regulated indicating that <it>IL-6 </it>mediated priming renders hepatocytes more responsive towards cell proliferation and reduces expenditures for the energy metabolism.</p> <p>Conclusions</p> <p>GraDe provides a novel framework for the decomposition of large-scale 'omics' data. We were able to show that including prior knowledge into the separation task leads to a much more structured and detailed separation of the time-dependent responses upon <it>IL-6 </it>stimulation compared to standard methods. A Matlab implementation of the GraDe algorithm is freely available at <url>http://cmb.helmholtz-muenchen.de/grade</url>.</p

Evaluation of patients with a recent clinical fracture and osteoporosis, a multidisciplinary approach

The aetiology of osteoporotic fractures is multifactorial, but little is known about the way to evaluate patients with a recent clinical fracture for the presence of secondary osteoporosis