Biomedical subjects

Adam Arkin

Publications and source records attributed to Adam Arkin.

12 recordsLinked to original sources

PubMed2026

Phage therapy in oncology: opportunities for cancer prevention and treatment.

Bacteriophages (phages) are emerging as programmable biological therapeutics in oncology, extending beyond their traditional antimicrobial applications. This review proposes a phage-microbiome-immune-oncology axis that links microbial dynamics, immune modulation, and engineered phages to guide precision cancer prevention and therapy. Phages can eliminate cancer-associated bacteria, remodel the tumor microenvironment, enhance antitumor immunity, and deliver targeted therapeutic payloads. However, several critical challenges must be addressed to realize this therapeutic potential, particularly host immune responses that limit repeat dosing, inefficient tumor penetration, and the need for rigorous clinical validation. By examining phage-host-tumor interactions through robust model systems and highlighting translational opportunities, this review establishes phage therapy as a promising frontier in precision oncology that warrants accelerated clinical development.

Humans↗

PubMed2006

RegTransBase--a database of regulatory sequences and interactions in a wide range of prokaryotic genomes.

RegTransBase is a manually curated database of regulatory interactions in prokaryotes that captures the knowledge in public scientific literature using a controlled vocabulary. Although several databases describing interactions between regulatory proteins and their binding sites are already being maintained, they either focus mostly on the model organisms Escherichia coli and Bacillus subtilis or are entirely computationally derived. RegTransBase describes a large number of regulatory interactions reported in many organisms and contains the following types of experimental data: the activation or repression of transcription by an identified direct regulator, determining the transcriptional regulatory function of a protein (or RNA) directly binding to DNA (RNA), mapping or prediction of a binding site for a regulatory protein and characterization of regulatory mutations. Currently, RegTransBase content is derived from about 3000 relevant articles describing over 7000 experiments in relation to 128 microbes. It contains data on the regulation of about 7500 genes and evidence for 6500 interactions with 650 regulators. RegTransBase also contains manually created position weight matrices (PWM) that can be used to identify candidate regulatory sites in over 60 species. RegTransBase is available at http://regtransbase.lbl.gov.

Bacterial Proteins↗

PubMed2006

The evolution of two-component systems in bacteria reveals different strategies for niche adaptation.

Two-component systems including histidine protein kinases represent the primary signal transduction paradigm in prokaryotic organisms. To understand how these systems adapt to allow organisms to detect niche-specific signals, we analyzed the phylogenetic distribution of nearly 5,000 histidine protein kinases from 207 sequenced prokaryotic genomes. We found that many genomes carry a large repertoire of recently evolved signaling genes, which may reflect selective pressure to adapt to new environmental conditions. Both lineage-specific gene family expansion and horizontal gene transfer play major roles in the introduction of new histidine kinases into genomes; however, there are differences in how these two evolutionary forces act. Genes imported via horizontal transfer are more likely to retain their original functionality as inferred from a similar complement of signaling domains, while gene family expansion accompanied by domain shuffling appears to be a major source of novel genetic diversity. Family expansion is the dominant source of new histidine kinase genes in the genomes most enriched in signaling proteins, and detailed analysis reveals that divergence in domain structure and changes in expression patterns are hallmarks of recent expansions. Finally, while these two modes of gene acquisition are widespread across bacterial taxa, there are clear species-specific preferences for which mode is used.

Adaptation, Physiological↗

PubMed2006

Model discrimination using data collaboration.

This paper introduces a practical data-driven method to discriminate among large-scale kinetic reaction models. The approach centers around a computable measure of model/data mismatch. We introduce two provably convergent algorithms that were developed to accommodate large ranges of uncertainty in the model parameters. The algorithms are demonstrated on a simple toy example and a methane combustion model with more than 100 uncertain parameters. They are subsequently used to discriminate between two models for a contemporarily studied biological signaling network.

Algorithms↗

PubMed2006

Cellular response of Shewanella oneidensis to strontium stress.

The physiology and transcriptome dynamics of the metal ion-reducing bacterium Shewanella oneidensis strain MR-1 in response to nonradioactive strontium (Sr) exposure were investigated. Studies indicated that MR-1 was able to grow aerobically in complex medium in the presence of 180 mM SrCl2 but showed severe growth inhibition at levels above that concentration. Temporal gene expression profiles were generated from aerobically grown, mid-exponential-phase MR-1 cells shocked with 180 mM SrCl2 and analyzed for significant differences in mRNA abundance with reference to data for nonstressed MR-1 cells. Genes with annotated functions in siderophore biosynthesis and iron transport were among the most highly induced (>100-fold [P < 0.05]) open reading frames in response to acute Sr stress, and a mutant (SO3032::pKNOCK) defective in siderophore production was found to be hypersensitive to SrCl2 exposure, compared to parental and wild-type strains. Transcripts encoding multidrug and heavy metal efflux pumps, proteins involved in osmotic adaptation, sulfate ABC transporters, and assimilative sulfur metabolism enzymes also were differentially expressed following Sr exposure but at levels that were several orders of magnitude lower than those for iron transport genes. Precipitate formation was observed during aerobic growth of MR-1 in broth cultures amended with 50, 100, or 150 mM SrCl2 but not in cultures of the SO3032::pKNOCK mutant or in the abiotic control. Chemical analysis of this precipitate using laser-induced breakdown spectroscopy and static secondary ion mass spectrometry indicated extracellular solid-phase sequestration of Sr, with at least a portion of the heavy metal associated with carbonate phases.

Bacterial Proteins↗

PubMed2006

Transcriptome profiling of Shewanella oneidensis gene expression following exposure to acidic and alkaline pH.

The molecular response of Shewanella oneidensis MR-1 to variations in extracellular pH was investigated based on genomewide gene expression profiling. Microarray analysis revealed that cells elicited both general and specific transcriptome responses when challenged with environmental acid (pH 4) or base (pH 10) conditions over a 60-min period. Global responses included the differential expression of genes functionally linked to amino acid metabolism, transcriptional regulation and signal transduction, transport, cell membrane structure, and oxidative stress protection. Response to acid stress included the elevated expression of genes encoding glycogen biosynthetic enzymes, phosphate transporters, and the RNA polymerase sigma-38 factor (rpoS), whereas the molecular response to alkaline pH was characterized by upregulation of nhaA and nhaR, which are predicted to encode an Na+/H+ antiporter and transcriptional activator, respectively, as well as sulfate transport and sulfur metabolism genes. Collectively, these results suggest that S. oneidensis modulates multiple transporters, cell envelope components, and pathways of amino acid consumption and central intermediary metabolism as part of its transcriptome response to changing external pH conditions.

Acids↗

PubMed2005

Transcriptome analysis of Shewanella oneidensis MR-1 in response to elevated salt conditions.

Whole-genomic expression patterns were examined in Shewanella oneidensis cells exposed to elevated sodium chloride. Genes involved in Na(+) extrusion and glutamate biosynthesis were significantly up-regulated, and the majority of chemotaxis/motility-related genes were significantly down-regulated. The data also suggested an important role for metabolic adjustment in salt stress adaptation in S. oneidensis.

Adaptation, Physiological↗

PubMed2004

Reconstruction of regulatory and metabolic pathways in metal-reducing delta-proteobacteria.

BACKGROUND: Relatively little is known about the genetic basis for the unique physiology of metal-reducing genera in the delta subgroup of the proteobacteria. The recent availability of complete finished or draft-quality genome sequences for seven representatives allowed us to investigate the genetic and regulatory factors in a number of key pathways involved in the biosynthesis of building blocks and cofactors, metal-ion homeostasis, stress response, and energy metabolism using a combination of regulatory sequence detection and analysis of genomic context. RESULTS: In the genomes of delta-proteobacteria, we identified candidate binding sites for four regulators of known specificity (BirA, CooA, HrcA, sigma-32), four types of metabolite-binding riboswitches (RFN-, THI-, B12-elements and S-box), and new binding sites for the FUR, ModE, NikR, PerR, and ZUR transcription factors, as well as for the previously uncharacterized factors HcpR and LysX. After reconstruction of the corresponding metabolic pathways and regulatory interactions, we identified possible functions for a large number of previously uncharacterized genes covering a wide range of cellular functions. CONCLUSIONS: Phylogenetically diverse delta-proteobacteria appear to have homologous regulatory components. This study for the first time demonstrates the adaptability of the comparative genomic approach to de novo reconstruction of a regulatory network in a poorly studied taxonomic group of bacteria. Recent efforts in large-scale functional genomic characterization of Desulfovibrio species will provide a unique opportunity to test and expand our predictions.

Bacterial Proteins↗

PubMed2004

Response experiments for nonlinear systems with application to reaction kinetics and genetics.

A unified type of response experiment is suggested for complex systems made up of individual species (atoms, molecules, quasi-particles, biological organisms, etc.). We make the following assumptions: (i) some of the species may exist in two forms, labeled and unlabeled, respectively; (ii) the kinetic and transport properties of the labeled and unlabeled species are the same, respectively (neutrality assumption); (iii) the experiment preserves the total input and output fluxes; only the fractions of the labeled compounds in the input and output fluxes are varied. Under these circumstances a linear integral superposition law connects the fractions of labeled species in the input and output fluxes. This linear superposition law is valid for homogeneous and inhomogeneous systems and for systems with intrinsic (hidden) state variables; it arises from the neutrality condition and holds even though the underlying dynamics of the process may be highly nonlinear. Because this response law does not involve the linearization of the evolution equations it has great potential for the analysis of complex physical, chemical, and biological systems. We compare our approach with the linearization techniques used in biochemistry and genetics. We consider a simple reaction network involving replication, transformation, and disappearance steps and study the influence of experimental (measurement) and linearization errors on the evaluated values of rate coefficients. We show that the method involving the linearization of the kinetic equations leads to unpredictable results; because of the interference between measurement and linearization errors, either error compensation or error amplification occurs. Although our approach does not eliminate the effects of measurement errors, it leads to more consistent results. For a broad range of input fractions no error amplification or compensation occurs, and the error range for the rate coefficients is about the same as the error range of the measurements.

Genetics, Medical↗

PubMed2004

Global transcriptome analysis of the heat shock response of Shewanella oneidensis.

Shewanella oneidensis is an important model organism for bioremediation studies because of its diverse respiratory capabilities. However, the genetic basis and regulatory mechanisms underlying the ability of S. oneidensis to survive and adapt to various environmentally relevant stresses is poorly understood. To define this organism's molecular response to elevated growth temperatures, temporal gene expression profiles were examined in cells subjected to heat stress by using whole-genome DNA microarrays for S. oneidensis. Approximately 15% (n = 711) of the total predicted S. oneidensis genes (n = 4,648) represented on the microarray were significantly up- or downregulated (P < 0.05) over a 25-min period after shift to the heat shock temperature. As expected, the majority of the genes that showed homology to known chaperones and heat shock proteins in other organisms were highly induced. In addition, a number of predicted genes, including those encoding enzymes in glycolysis and the pentose cycle, serine proteases, transcriptional regulators (MerR, LysR, and TetR families), histidine kinases, and hypothetical proteins were induced. Genes encoding membrane proteins were differentially expressed, suggesting that cells possibly alter their membrane composition or structure in response to variations in growth temperature. A substantial number of the genes encoding ribosomal proteins displayed downregulated coexpression patterns in response to heat stress, as did genes encoding prophage and flagellar proteins. Finally, a putative regulatory site with high conservation to the Escherichia coli sigma32-binding consensus sequence was identified upstream of a number of heat-inducible genes.

Bacterial Proteins↗

PubMed2002

Determination of causal connectivities of species in reaction networks.

We present an approach to the determination of causal connectivities and part of the kinetics of complex reaction systems. Our approach is based on analytical and computational methods for studying the effects of a pulse change of concentration of a chemical species in a reaction network, either at equilibrium or in a nonequilibrium stationary state. Such disturbances generally propagate through a few species, depending on the values of the kinetic coefficients, before being broadened and dissipated. This short range gives a local probe of the kinetics and connectivity of the reaction network. The range of propagation also indicates species to perturb in further experiments. From piecing together these local connectivities, the global structure of the network can be constructed. The experimental design allows deduction of both reaction orders and rate constants in many cases. An example of the usefulness of the approach is illustrated on a model of a part of glycolysis.

Adenosine Triphosphate↗

PubMed2001

On the deduction of chemical reaction pathways from measurements of time series of concentrations.

We discuss the deduction of reaction pathways in complex chemical systems from measurements of time series of chemical concentrations of reacting species. First we review a technique called correlation metric construction (CMC) and show the construction of a reaction pathway from measurements on a part of glycolysis. Then we present two new improved methods for the analysis of time series of concentrations, entropy metric construction (EMC), and entropy reduction method (ERM), and illustrate (EMC) with calculations on a model reaction system. (c) 2001 American Institute of Physics.

Journal Article↗