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PubMed2004

New technologies for nutrition research.

The Experimental Biology 2003 symposium entitled "New Technologies for Nutrition Research" was organized to highlight new and emerging technologies, including nanotechnology and proteomics, and to suggest ways for their integration into nutrition research. Speakers focused on topics that included accelerator mass spectrometry for ultra-low level radiolabel tracing, nanodevices for real-time optical intracellular sensing, mass spectrometric techniques for examining protein expression, as well as potential applications for nanotechnology in the food sciences. These technologies may be particularly useful in obtaining accurate spatial information and low-level detection of essential and nonessential bioactive food components (nutrients) and their metabolites, and in enhancing the understanding of the impact of nutrient/metabolite and biomolecular interactions. Highlights from this symposium are presented briefly herein.

Animals↗

PubMed2002

Hemoglobin switching and modulation: genes, cells, and signals.

A detailed understanding of hemoglobin production in erythroid cells is of fundamental clinical importance for the treatment of hemoglobinopathies. Several hundred scientific reports and dozens of reviews describe this intriguing topic of research. Early studies demonstrated the temporal nature of a hemoglobin-switching phenomenon during development in the circulating erythrocytes of humans. The focus then shifted from descriptive to experimental analyses and model systems in an effort to define the switching mechanisms. The application of molecular biology in those experimental models has been a primary focus for the last two decades. Today, advances in the fields of stem cell biology and signal transduction are being integrated with those genetic studies. Genomic and proteomic approaches are also being developed to provide a more robust description of the biologic variables involved. This review highlights recent advances in erythroid genetics and cellular biology with an emphasis upon the modulation of fetal hemoglobin expression during the maturation of adult human erythrocytes.

Erythropoiesis↗

PubMed2005

Mast cell-specific genes--new drug targets/pathogenesis.

It has become possible to see all the expressed genes present in a cell (transcriptome) at once using microarray. We have applied microarray technology in various studies involving allergic diseases. Although we and others have discovered various novel molecules crucially involved in the pathogenesis of the disease, transcriptome assay is now expected as a tool for understanding the whole molecule balancing, i.e., system biology. Here I introduce examples of our trials for understanding the whole functional roles of mast cells as has been published in the web database for transcriptomes expressed by several mast cell types and various cell types. In the near future, we will be able to construct human mast cell models in silico (in a computer) by analyzing integrative information regarding the genome, transcriptome and proteome of mast cells, and will be able to test our hypotheses without having to perform in vitro tests.

Animals↗

PubMed2006

Knock-out of SO1377 gene, which encodes the member of a conserved hypothetical bacterial protein family COG2268, results in alteration of iron metabolism, increased spontaneous mutation and hydrogen peroxide sensitivity in Shewanella oneidensis MR-1.

BACKGROUND: Shewanella oneidensis MR-1 is a facultative, gram-negative bacterium capable of coupling the oxidation of organic carbon to a wide range of electron acceptors such as oxygen, nitrate and metals, and has potential for bioremediation of heavy metal contaminated sites. The complete 5-Mb genome of S. oneidensis MR-1 was sequenced and standard sequence-comparison methods revealed approximately 42% of the MR-1 genome encodes proteins of unknown function. Defining the functions of hypothetical proteins is a great challenge and may need a systems approach. In this study, by using integrated approaches including whole genomic microarray and proteomics, we examined knockout effects of the gene encoding SO1377 (gi24372955), a member of the conserved, hypothetical, bacterial protein family COG2268 (Clusters of Orthologous Group) in bacterium Shewanella oneidensis MR-1, under various physiological conditions. RESULTS: Compared with the wild-type strain, growth assays showed that the deletion mutant had a decreased growth rate when cultured aerobically, but not affected under anaerobic conditions. Whole-genome expression (RNA and protein) profiles revealed numerous gene and protein expression changes relative to the wild-type control, including some involved in iron metabolism, oxidative damage protection and respiratory electron transfer, e. g. complex IV of the respiration chain. Although total intracellular iron levels remained unchanged, whole-cell electron paramagnetic resonance (EPR) demonstrated that the level of free iron in mutant cells was 3 times less than that of the wild-type strain. Siderophore excretion in the mutant also decreased in iron-depleted medium. The mutant was more sensitive to hydrogen peroxide and gave rise to 100 times more colonies resistant to gentamicin or kanamycin. CONCLUSION: Our results showed that the knock-out of SO1377 gene had pleiotropic effects and suggested that SO1377 may play a role in iron homeostasis and oxidative damage protection in S. oneidensis MR-1.

Bacterial Proteins↗

PubMed2005

Cognate peptide-receptor ligand mapping by directed phage display.

BACKGROUND: A rapid phage display method for the elucidation of cognate peptide specific ligand for receptors is described. The approach may be readily integrated into the interface of genomic and proteomic studies to identify biologically relevant ligands. METHODS: A gene fragment library from influenza coat protein haemagglutinin (HA) gene was constructed by treating HA cDNA with DNAse I to create 50-100 bp fragments. These fragments were cloned into plasmid pORFES IV and in-frame inserts were selected. These in-frame fragment inserts were subsequently cloned into a filamentous phage display vector JC-M13-88 for surface display as fusions to a synthetic copy of gene VIII. Two well characterized antibodies, mAb 12CA5 and pAb 07431, directed against distinct known regions of HA were used to pan the library. RESULTS: Two linear epitopes, HA peptide 112-126 and 162-173, recognized by mAb 12CA5 and pAb 07431, respectively, were identified as the cognate epitopes. CONCLUSION: This approach is a useful alternative to conventional methods such as screening of overlapping synthetic peptide libraries or gene fragment expression libraries when searching for precise peptide protein interactions, and may be applied to functional proteomics.

Journal Article↗

PubMed2005

Molecular pain, a new era of pain research and medicine.

Molecular pain is a relatively new and rapidly expanding research field that represents an advanced step from conventional pain research. Molecular pain research addresses physiological and pathological pain at the cellular, subcellular and molecular levels. These studies integrate pain research with molecular biology, genomics, proteomics, modern electrophysiology and neurobiology. The field of molecular pain research has been rapidly expanding in the recent years, and has great promise for the identification of highly specific and effective targets for the treatment of intractable pain. Although several existing journals publish articles on classical pain research, none are specifically dedicated to molecular pain research. Therefore, a new journal focused on molecular pain research is needed. Molecular Pain, an Open Access, peer-reviewed, online journal, will provide a forum for molecular pain scientists to communicate their research findings in a targeted manner to others in this important and growing field.

Biomedical Research↗

PubMed2006

Metabolic labeling of plant cell cultures with K(15)NO3 as a tool for quantitative analysis of proteins and metabolites.

Strategies for robust quantitative comparison between different biological samples are of high importance in experiments that address biological questions beyond the establishment of protein lists. Here, we propose the use of 15N-KNO3 as the only nitrogen source in Arabidopsis cell cultures in order to achieve a metabolically fully labeled cell population. Proteins from such metabolically labeled culture are distinguishable from unlabeled protein populations by a characteristic mass shift that depends on the amino acid composition of the tryptic peptide analyzed. In addition, the metabolically labeled cell extracts are also suitable for comparative quantitative analysis of nitrogen-containing cellular metabolic complement. Protein extracts from unlabeled and from standardized 15N-labeled cells were combined into one sample for joined analytical processing. This has the advantage of (i) reduced experimental variability and (ii) immediate relative quantitation at the level of single extracted peptide and metabolite spectra. Together ease and accuracy of relative quantitation for profiling experiments is substantially improved. The metabolic labeling strategy has been validated by mixtures of protein extracts and metabolite extracts from the same cell cultures in known ratios of labeled to unlabeled extracts (1:1, 1:4, and 4:1). We conclude that saturating metabolic 15N-labeling provides a robust and affordable integrative strategy to answer questions in quantitative proteomics and nitrogen focused metabolomics.

Journal Article↗

PubMed2006

Proteomics: a new diagnostic frontier.

BACKGROUND: Analysis of proteins has been an integral part of the field of clinical chemistry for decades. Recent advances in technology and complete identification of the human genome sequence have opened up new opportunities for analysis of proteins for clinical diagnostic purposes. METHODS: Content of a recent conference of proteomics is summarized. RESULTS: New analytical methods allow the simultaneous analysis of a large number of proteins in biological fluids such as serum and plasma, offering partial views of the complete set of proteins or proteome. Plasma presents many analytical challenges, such as the complexity of components, predominance of a few major components, and the large concentration range of components, but the number of proteins that can be detected in plasma has expanded dramatically from hundreds to thousands. At the same time, there is increased capability to detect structural variations of proteins. Recent studies also identified the presence of complex sets of small protein fragments in plasma. This set of protein fragments, the fragmentome or peptidome, is potentially a rich source of information about physiologic and disease processes. CONCLUSIONS: Advances in proteomics offer great promise for the discovery of markers that might serve as the basis for new clinical laboratory tests. There are many challenges, however, in the translation of newly discovered markers into clinical laboratory tests.

Biomarkers↗

PubMed2006

Isolation of transcription factor complexes by in vivo biotinylation tagging and direct binding to streptavidin beads.

Efficient tagging methodologies are an integral aspect of protein complex characterization by proteomic approaches. Owing to the very high affinity of biotin for avidin and streptavidin, biotinylation tagging offers an attractive approach for the efficient purification of protein complexes. The very high affinity of the biotin/(strept)avidin system also offers the potential for the single-step capture of lower abundance protein complexes, such as transcription factor complexes. The identification of short peptide tags that are efficiently biotinylated by the bacterial BirA biotin ligase led to an approach for the single-step purification of transcription factor complexes by specific in vivo biotinylation tagging. A short sequence tag fused N-terminally to the transcription factor of interest is very efficiently biotinylated by BirA coexpressed in the same cells, as was demonstrated by the tagging of the essential hematopoietic transcription factor GATA-1. The direct binding to streptavidin of biotinylated GATA-1 in nuclear extracts resulted in the single-step capture of the tagged factor and associated proteins, which were eluted and identified by mass spectrometry. This led to the characterization of several distinct GATA-1 complexes with other transcription factors and chromatin remodeling cofactors, which are involved in activation and repression of gene targets. Thus, BirA-mediated tagging is an efficient approach for the direct capture and characterization of transcription factor complexes.

Amino Acid Sequence↗

PubMed2026

Multi-omics Investigations of Immune Microenvironment of Human Colorectal Cancer.

BACKGROUND/AIM: Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. Although immunotherapy has improved outcomes for a subset of patients, its limited efficacy in many cases highlights the need for a more comprehensive understanding of the CRC immune microenvironment. This study aimed to characterize the molecular landscape of the CRC immune microenvironment using an integrated multi-omics approach and to identify candidate regulatory molecules associated with immune remodelling. MATERIALS AND METHODS: We integrated structural variation, DNA methylation, chromatin accessibility, proteomic, and phosphoproteomic data generated from an in-house CRC cohort with transcriptomic data from The Cancer Genome Atlas (TCGA). Analyses focused on 1,539 immune-related genes (IRGs) associated with CD4+ T cells, B cells, and natural killer (NK) cells. Multi-layered genomic and proteomic analyses were performed to identify altered immune-related pathways, hub genes, candidate transcription factors, and upstream kinases. RESULTS: Higher infiltration of CD4+ T cells, B cells, and NK cells was associated with CRC. IRGs exhibited widespread alterations across genomic, epigenomic, transcriptomic, proteomic, and phosphoproteomic levels. IL10, LEP, ITGAM, and EGFR emerged as candidate hub genes. EGFR phosphorylation at S991 and T693 was significantly decreased in CRC. STAT2 and HSF1 were identified as candidate upstream transcription factors, while CDK2 emerged as a candidate upstream kinase associated with immune infiltration and immune checkpoint expression. CONCLUSION: This study provides a systematic multi-omics characterization of immune microenvironment remodelling in CRC and identifies candidate molecular regulators that may serve as potential targets for future immunotherapy research.

Humans↗

PubMed2006

Major advances in fundamental dairy cattle nutrition.

Fundamental nutrition seeks to describe the complex biochemical reactions involved in assimilation and processing of nutrients by various tissues and organs, and to quantify nutrient movement (flux) through those processes. Over the last 25 yr, considerable progress has been made in increasing our understanding of metabolism in dairy cattle. Major advances have been made at all levels of biological organization, including the whole animal, organ systems, tissues, cells, and molecules. At the whole-animal level, progress has been made in delineating metabolism during late pregnancy and the transition to lactation, as well as in whole-body use of energy-yielding substrates and amino acids for growth in young calves. An explosion of research using multicatheterization techniques has led to better quantitative descriptions of nutrient use by tissues of the portal-drained viscera (digestive tract, pancreas, and associated adipose tissues) and liver. Isolated tissue preparations have provided important information on the interrelationships among glucose, fatty acid, and amino acid metabolism in liver, adipose tissue, and mammary gland, as well as the regulation of these pathways during different physiological states. Finally, the last 25 yr has witnessed the birth of "molecular biology" approaches to understanding fundamental nutrition. Although measurements of mRNA abundance for proteins of interest already have provided new insights into regulation of metabolism, the next 25 yr will likely see remarkable advances as these techniques continue to be applied to problems of dairy cattle biology. Integration of the "omics" technologies (functional genomics, proteomics, and metabolomics) with measurements of tissue metabolism obtained by other methods is a particularly exciting prospect for the future. The result should be improved animal health and well being, more efficient dairy production, and better models to predict nutritional requirements and provide rations to meet those requirements.

Absorption↗

PubMed2006

[Microarray as a standard laboratory technique and as an unprecedented tool for understanding systems biology].

It is now possible to examine all the expressed genes present in a cell (transcriptome) simultaneously using microarray. Thus, microarrays have attracted tremendous interest among biologists. We have applied microarray technology to various studies regarding allergic diseases. Although we and others have discovered various novel molecules crucially involved in the pathogenesis of the disease, transcriptome assay is now expected as a tool for understanding overall molecule balancing, i.e., systems biology. Here we introduce examples of our trials to understand the functional roles of a certain cell type related to allergy as has been published in the web database. In the near future, we will be able to construct human inflammatory cell models in silico (in a computer) by analyzing integrative information regarding the genome, transcriptome and proteome of mast cells and can test our hypothesis without performing in vitro testing.

Animals↗

PubMed2026

Emerging Principles in Spatial Functional Genomics.

Spatial transcriptomic and proteomic atlases have enabled mapping of gene programs within intact tissues, but these measurements remain largely descriptive and do not define the mechanisms controlling tissue biology. Pooled CRISPR screening provides scalable causal interrogation of gene function but remains largely confined to dissociated systems that lack spatial context. In vivo spatial functional genomics (SFG) bridges these approaches by integrating genetic perturbations with in situ transcriptomic and proteomic readouts to measure gene function within intact tissue ecosystems. By preserving spatial organization, SFG enables interpretation of perturbations through effects on cell-cell interactions, diffusible signals, multicellular niches, and tissue architecture. Here, we outline key design axes of SFG: perturbation strategy, barcoding strategy, and phenotypic readout. We discuss computational challenges, including spatial autocorrelation, neighborhood dependence, and context-aware null modeling, and highlight how SFG reveals non-cell-autonomous, architecture-dependent mechanisms of gene function, advancing toward predictive models of tissue organization and gene function.

Genomics↗

PubMed2026

Bifunctional covalent organic framework for rapid isolation of extracellular vesicles and proteomics-based biomarker discovery.

Extracellular vesicles (EVs), serving as crucial carriers of biomarkers for tumor diagnosis and prognostic evaluation, as well as drug delivery vehicles and therapeutic targets, making it a research hotspot. The isolation methods represent a key aspect of EV-associated research. In this work, an alkynyl-functionalized covalent organic framework (COF) was synthesized under acidic conditions at room temperature and further modified by photo-initiated thiol-yne click reaction, yielding a bifunctionalized COF material decorated with distearoyl phosphatidylethanolamine (DSPE) and Ti4+. This bifunctional COF material (COF-DSPE-Ti) can leverage the bifunctional synergistic effect between DSPE and Ti4+ sites, thereby facilitating the efficient isolation of EVs. This synergistic effect enables the efficient isolation of EVs within 3 min. Proteomic analysis reveals that this isolation method significantly outperforms ultracentrifugation, and an effective EV isolation and analysis can be completed using only 10 μL of plasma sample. For clinical liquid biopsy, the integration of the COF-DSPE-Ti method with proteomics lead to the identification of 64 upregulated proteins in plasma samples from colorectal cancer (CRC) patients, among which S100A9 emerged as a potential EV biomarker. In addition, KLK2, KLK3, and FOLH1, which have been established as diagnostic markers for prostate cancer (PCa), are successfully identified in EVs isolated from the urine of PCa patients. These findings demonstrate the reliability of this approach for screening EV-associated biomarkers and provide a novel strategy for the early diagnosis and prognostic assessment of CRC and PCa.

Proteomics↗

PubMed2006

The ToxCast program for prioritizing toxicity testing of environmental chemicals.

The U.S. Environmental Protection Agency (EPA) is developing methods for utilizing computational chemistry, high-throughput screening (HTS), and various toxicogenomic technologies to predict potential for toxicity and prioritize limited testing resources toward chemicals that likely represent the greatest hazard to human health and the environment. This chemical prioritization research program, entitled "ToxCast," is being initiated with the purpose of developing the ability to forecast toxicity based on bioactivity profiling. The proof-of-concept phase of ToxCast will focus upon chemicals with an existing, rich toxicological database in order to provide an interpretive context for the ToxCast data. This set of several hundred reference chemicals will represent numerous structural classes and phenotypic outcomes, including tumorigens, developmental and reproductive toxicants, neurotoxicants, and immunotoxicants. The ToxCast program will evaluate chemical properties and bioactivity profiles across a broad spectrum of data domains: physical-chemical, predicted biological activities based on existing structure-activity models, biochemical properties based on HTS assays, cell-based phenotypic assays, and genomic and metabolomic analyses of cells. These data will be generated through a series of external contracts, along with collaborations across EPA, with the National Toxicology Program, and with the National Institutes of Health Chemical Genomics Center. The resulting multidimensional data set provides an informatics challenge requiring appropriate computational methods for integrating various chemical, biological, and toxicological data into profiles and models predicting toxicity.

Animals↗

PubMed2026

Unlocking the Circulating Proteome: Toward Clinical Translation.

Blood-based proteomics is approaching a translational inflection point. Driven by advances in measurement technologies, rapid expansion of analytical capabilities, and growing adoption across research and medical communities, there is increasing demand for clinically actionable biomarkers. As the field transitions away from purely large-scale discovery-oriented studies toward more informed, targeted, application-driven analyses, the generation of proteomic data is no longer the bottleneck. Instead, the central challenge is to translate these measurements into robust, reproducible, and clinically meaningful insights. In this Review, we assess recent technological and methodological developments, evaluate persistent preanalytical and interpretative limitations, and outline the key steps required for clinical translation. We focus on three deeply interconnected dimensions: the capabilities and constraints of current measurement platforms, the role of computational and machine learning approaches in extracting biological and clinical signals, and the emergence of large-scale population studies that create new opportunities for validation and generalization. Finally, we discuss a forward-looking vision in which proteomics plays a central role in dynamic, multilayered omics frameworks, where integration with genomics, temporal profiling, and imaging can deepen our understanding of health, disease, and therapeutic response.

Humans↗

PubMed2006

Complete and integrated pyrene degradation pathway in Mycobacterium vanbaalenii PYR-1 based on systems biology.

Mycobacterium vanbaalenii PYR-1 was the first bacterium isolated by virtue of its ability to metabolize the high-molecular-weight polycyclic aromatic hydrocarbon (PAH) pyrene. We used metabolic, genomic, and proteomic approaches in this investigation to construct a complete and integrated pyrene degradation pathway for M. vanbaalenii PYR-1. Genome sequence analyses identified genes involved in the pyrene degradation pathway that we have proposed for this bacterium. To identify proteins involved in the degradation, we conducted a proteome analysis of cells exposed to pyrene using one-dimensional gel electrophoresis in combination with liquid chromatography-tandem mass spectrometry. Database searching performed with the M. vanbaalenii PYR-1 genome resulted in identification of 1,028 proteins with a protein false discovery rate of <1%. Based on both genomic and proteomic data, we identified 27 enzymes necessary for constructing a complete pathway for pyrene degradation. Our analyses indicate that this bacterium degrades pyrene to central intermediates through o-phthalate and the beta-ketoadipate pathway. Proteomic analysis also revealed that 18 enzymes in the pathway were upregulated more than twofold, as indicated by peptide counting when the organism was grown with pyrene; three copies of the terminal subunits of ring-hydroxylating oxygenase (NidAB2, MvanDraft_0817/0818, and PhtAaAb), dihydrodiol dehydrogenase (MvanDraft_0815), and ring cleavage dioxygenase (MvanDraft_3242) were detected only in pyrene-grown cells. The results presented here provide a comprehensive picture of pyrene metabolism in M. vanbaalenii PYR-1 and a useful framework for understanding cellular processes involved in PAH degradation.

Bacterial Proteins↗

PubMed2026

A Draft Map of E. coli Proteoforms.

Top-down proteomics (TDP) enables direct characterization of intact proteoforms, providing protein-level insights into molecular diversity arising from post-translational modifications and sequence variations. Despite this advantage, proteome coverage in TDP remains limited relative to bottom-up proteomics (BUP). To expand coverage, we developed an integrated multidimensional approach combining sequential protein extraction, size-exclusion chromatography (SEC) fractionation, and capillary zone electrophoresis (CZE)-tandem mass spectrometry (MS/MS) and reversed-phase liquid chromatography (RPLC)-MS/MS. This approach identified 743 proteoform families and 10,613 proteoforms from E. coli cells through hundreds of MS runs. By incorporating previous E. coli TDP data sets from our group, we identified 14,932 proteoforms from 985 proteoform families, covering 43% of the E. coli proteome. The data represent the highest proteome coverage of cells by MS-based TDP, creating a draft map of E. coli proteoforms. The results offer strong evidence that MS-based TDP can reach high proteome coverage.

Escherichia coli↗