The integrated microbial genomes (IMG) system

The integrated microbial genomes (IMG) system is a new data management and analysis platform for microbial genomes provided by the Joint Genome Institute (JGI). IMG contains both draft and complete JGI genomes integrated with other publicly available microbial genomes of all three domains of life. IMG provides tools and viewers for analyzing genomes, genes and functions, individually or in a comparative context. IMG allows users to focus their analysis on subsets of genes and genomes of interest and to save the results of their analysis. IMG is available at

Energetics of Glucose Metabolism: A Phenomenological Approach to Metabolic Network Modeling

A new formalism to describe metabolic fluxes as well as membrane transport processes was developed. The new flux equations are comparable to other phenomenological laws. Michaelis-Menten like expressions, as well as flux equations of nonequilibrium thermodynamics, can be regarded as special cases of these new equations. For metabolic network modeling, variable conductances and driving forces are required to enable pathway control and to allow a rapid response to perturbations. When applied to oxidative phosphorylation, results of simulations show that whole oxidative phosphorylation cannot be described as a two-flux-system according to nonequilibrium thermodynamics, although all coupled reactions per se fulfill the equations of this theory. Simulations show that activation of ATP-coupled load reactions plus glucose oxidation is brought about by an increase of only two different conductances: a [Ca2+] dependent increase of cytosolic load conductances, and an increase of phosphofructokinase conductance by [AMP], which in turn becomes increased through [ADP] generation by those load reactions. In ventricular myocytes, this feedback mechanism is sufficient to increase cellular power output and O2 consumption several fold, without any appreciable impairment of energetic parameters. Glucose oxidation proceeds near maximal power output, since transformed input and output conductances are nearly equal, yielding an efficiency of about 0.5. This conductance matching is fulfilled also by glucose oxidation of β-cells. But, as a price for the metabolic mechanism of glucose recognition, β-cells have only a limited capability to increase their power output

Application of the Principles of Systems Biology and Wiener’s Cybernetics for Analysis of Regulation of Energy Fluxes in Muscle Cells in Vivo

The mechanisms of regulation of respiration and energy fluxes in the cells are analyzed based on the concepts of systems biology, non-equilibrium steady state kinetics and applications of Wiener’s cybernetic principles of feedback regulation. Under physiological conditions cardiac function is governed by the Frank-Starling law and the main metabolic characteristic of cardiac muscle cells is metabolic homeostasis, when both workload and respiration rate can be changed manifold at constant intracellular level of phosphocreatine and ATP in the cells. This is not observed in skeletal muscles. Controversies in theoretical explanations of these observations are analyzed. Experimental studies of permeabilized fibers from human skeletal muscle vastus lateralis and adult rat cardiomyocytes showed that the respiration rate is always an apparent hyperbolic but not a sigmoid function of ADP concentration. It is our conclusion that realistic explanations of regulation of energy fluxes in muscle cells require systemic approaches including application of the feedback theory of Wiener’s cybernetics in combination with detailed experimental research. Such an analysis reveals the importance of limited permeability of mitochondrial outer membrane for ADP due to interactions of mitochondria with cytoskeleton resulting in quasi-linear dependence of respiration rate on amplitude of cyclic changes in cytoplasmic ADP concentrations. The system of compartmentalized creatine kinase (CK) isoenzymes functionally coupled to ANT and ATPases, and mitochondrial-cytoskeletal interactions separate energy fluxes (mass and energy transfer) from signalling (information transfer) within dissipative metabolic structures – intracellular energetic units (ICEU). Due to the non-equilibrium state of CK reactions, intracellular ATP utilization and mitochondrial ATP regeneration are interconnected by the PCr flux from mitochondria. The feedback regulation of respiration occurring via cyclic fluctuations of cytosolic ADP, Pi and Cr/PCr ensures metabolic stability necessary for normal function of cardiac cells

Mitochondria and Energetic Depression in Cell Pathophysiology

Mitochondrial dysfunction is a hallmark of almost all diseases. Acquired or inherited mutations of the mitochondrial genome DNA may give rise to mitochondrial diseases. Another class of disorders, in which mitochondrial impairments are initiated by extramitochondrial factors, includes neurodegenerative diseases and syndromes resulting from typical pathological processes, such as hypoxia/ischemia, inflammation, intoxications, and carcinogenesis. Both classes of diseases lead to cellular energetic depression (CED), which is characterized by decreased cytosolic phosphorylation potential that suppresses the cell’s ability to do work and control the intracellular Ca2+ homeostasis and its redox state. If progressing, CED leads to cell death, whose type is linked to the functional status of the mitochondria. In the case of limited deterioration, when some amounts of ATP can still be generated due to oxidative phosphorylation (OXPHOS), mitochondria launch the apoptotic cell death program by release of cytochrome c. Following pronounced CED, cytoplasmic ATP levels fall below the thresholds required for processing the ATP-dependent apoptotic cascade and the cell dies from necrosis. Both types of death can be grouped together as a mitochondrial cell death (MCD). However, there exist multiple adaptive reactions aimed at protecting cells against CED. In this context, a metabolic shift characterized by suppression of OXPHOS combined with activation of aerobic glycolysis as the main pathway for ATP synthesis (Warburg effect) is of central importance. Whereas this type of adaptation is sufficiently effective to avoid CED and to control the cellular redox state, thereby ensuring the cell survival, it also favors the avoidance of apoptotic cell death. This scenario may underlie uncontrolled cellular proliferation and growth, eventually resulting in carcinogenesis

The Integrated Microbial Genomes (IMG) System: A Case Study

Biological data management includes the traditional areas of data generation, acquisition, modelling, integration, and analysis. Although numerous academic biological data management systems are currently available, employing them effectively remains a significant challenge. We discuss how this challenge was addressed in the course of developing the Integrated Microbial Genomes (IMG) system for comparative analysis of microbial genome data. 1

Eukaryotic Genome Annotation and Analysis @ JGI

Over 40 eukaryotic genomes have been annotated using JGI Annotation Pipeline, which combines several gene prediction and annotation tools. Predicted genes and annotations are accessible via interactive visualization tools integrated into JGI Genome Portal. The diverse set of annotated genomes represents the major branches of the tree of life and provides basis for comparative genomics analysis. This comparative analysis as well as analysis of available experimental data (ESTs, microarrays, proteomics) enable validation of predicted genes. In addition, community-driven manual curation of predicted genes and functions in annotated genomes further improves their quality

Annotation of Eukaryotic Genomes

We annotated over 60 eukaryotic genomes increasing annotation throughput ~;10 fold in the last 5 years with improved annotation process, automated annotation pipeline, and further developed genome analysis tools integrated in the Eukaryotic Genome Portal. We developed a Community Annotation model, unique across sequencing centers, to achieve higher quality of annotations, teach and train new users, and build stronger genome user communities. These tools will serve as a platform for programmatic approach to scaling up sequencing and analysis of microbial eukaryotic, for example, JGI Fungal Program, along the directions of (i) sequencing phylogenetic breadth, (ii) deeper sampling DOE mission relevant organisms, and (iii) exploring ecological diversity. A diverse portfolio of microbial eukaryotes (68 fungal and 21 algal projects at different stages in JGI pipeline) and DOE mission positions the JGI to sequence a broad range of microbial eukaryotes