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Symposium: New Technologies for Nutrition Research

New Technologies for Nutrition Research¹

Sharon A. Ross^*,2, Pothur R. Srinivas, Andrew J. Clifford^**, Stephen C. Lee, Martin A. Philbert and Robert L. Hettich

^* Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892; Vascular Biology Research Program, Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892; ^** Department of Nutrition, University of California-Davis, Davis, CA 95616; Ohio State University, College of Engineering, Biomedical Engineering Center, Ohio State University, Columbus, OH 43210; Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109; and Chemical Sciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831

²To whom correspondence should be addressed. E-mail: rosssha{at}mail.nih.gov.

	ABSTRACT

TOP ABSTRACT Nanotechnology in vivo: an... Nutrient metabolism at attomole... Nanotechnology: a tool for... Nanodevices for real-time... Mass spectrometric techniques... Concluding Remarks LITERATURE CITED

 
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.

KEY WORDS: • bioactive food components • food science • accelerator mass spectrometry • nanotechnology • proteomics

New and emerging technologies such as microarray technology and nanotechnology have the potential to advance the science of nutrition by assisting in the discovery, development, and delivery of several intervention strategies to improve health and to reduce the risk and complications of several diseases. Some of the areas that would benefit most from emerging technologies include identifying sites of action (molecular targets) for bioactive food components (including essential and nonessential bioactive food components); characterizing biomarkers that reflect exposure, response, and susceptibility to foods and their components; and perhaps the identification of new target delivery systems for optimizing health.

Microarray technology, for example, is a powerful tool that is increasingly being employed in nutrition research (1), and additional biological insights employing this methodology are certain to surface. Genome-wide monitoring of gene expression is now possible using DNA microarrays, which allow the simultaneous assessment of the transcription of tens of thousands of genes and of their relative expression between normal cells and pathological cells such as tumor cells. Microarray analysis of gene expression profiles is likely to be useful in identifying critical sites of action and in pinpointing molecular targets as potential biomarkers. For example, microarray analysis of gene expression profiles can be used to identify the similarities and differences between bioactive food components and to identify critical sites of action of the component in specific tissues (2). More recently, microarray technology has been used to probe protein expression or epigenetic events such as DNA methylation and histone acetylation (3,4). Such revolutionary technologies may lead to the discovery of new biomarkers for early disease detection and prognosis prediction, and of new tools for prevention and therapy of diseases.

"Nanotechnology" is defined as the creation of functional materials, devices, and systems through control of matter at the scale of 1 to 100 nm, and the exploitation of novel properties and phenomena at the same scale (5) (nano, derived from Greek, means dwarf). Such technology offers the possibility of examining biological processes when limited by sampling issues. This emerging field is likely to be critical for enabling breakthroughs of new and effective tools in the medical sciences (i.e., nanomedicine) (6). Medical uses for nanotechnology include development of nanoparticles for diagnostic and screening purposes (i.e., early detection of cancer), development of artificial receptors, DNA sequencing using nanopores, manufacture of unique drug (and perhaps nutrient) delivery systems, as well as gene therapy and tissue engineering applications (6,7). Nanomachines able to circulate through the bloodstream, kill microbes, or undo tissue damage could be delivered to the human body through medicines or even foods. Significant progress in the development of sensors for rapid detection of pathogens in foods or the environment has been made in part due to discoveries and tools of nanotechnology. For example, a real-time PCR-detection approach provided significant advancements to PCR-based methods for the rapid detection of food pathogens (8). Nanotechnology applications in nutrition research may assist with obtaining accurate spatial information of a nutrient or bioactive food component in tissue and low-level detection of essential and nonessential nutrients and metabolites, as well as increasing an understanding of nutrient and biomolecular interactions in specific tissues. In theory, new technologies have the potential to improve nutritional assessment and measures of bioavailability and may help to identify and characterize molecular targets of nutrient activity and biomarkers of effect, exposure, and susceptibility.

To highlight emerging technologies and to encourage collaboration between various disciplines, with the aim of advancing nutritional sciences, a symposium was convened at Experimental Biology 2003 on the topic "New Technologies for Nutrition Research." This session presented a cross-section of exciting and emerging technological approaches for the study of nutrition and chronic disease prevention. Experts focused on topics that included "Nanotechnology in vivo: an emerging paradigm" (presented by Stephen C. Lee, Ohio State University); "Nutrient metabolism at attomole levels: accelerator mass spectrometry for ultra-low level radiolabel tracing in nutrition" (presented by Andrew J. Clifford, University of California-Davis); "Nanotechnology: a tool for the food science and technology of the new millennium" (presented by Carmen I. Moraru, Rutgers, the State University of New Jersey); "Nanodevices for real-time optical intracellular sensing" (presented by Martin A. Philbert, University of Michigan); and "Mass spectrometric techniques for following gene and protein expression" (presented by Robert L. Hettich, Oak Ridge National Laboratory). The sections that follow provide a synopsis of each of the topics presented with highlights for nutrition research applications where possible.

	Nanotechnology in vivo: an emerging paradigm

TOP ABSTRACT Nanotechnology in vivo: an... Nutrient metabolism at attomole... Nanotechnology: a tool for... Nanodevices for real-time... Mass spectrometric techniques... Concluding Remarks LITERATURE CITED

 
Dr. Lee’s presentation highlighted in vivo applications of nanotechnology in human medicine. Since many physiologic functions emerge from activities and interactions of individual nanoscale macromolecules, nanodevices are dimensionally appropriate for intervention in human disease. Dr. Lee emphasized that biotechnology is a critical source of prefabricated, functional components for nanodevices to be used in vivo (9–13). Semibiological nanodevices can be multifunctional, offering multifaceted therapeutic services, as opposed to the unitary biochemical activities of traditional pharmaceuticals. Incorporation of imaging and therapeutic functions in a single nanoscale entity is a common strategy for emerging nanotherapeutics, and is intended to give the clinician prognostic information simultaneous with therapeutic intervention (13–18).

The more sophisticated interventions afforded by nanotherapeutics are likely to depend on a combination of therapeutic targeting to disease sites, controlled release of therapeutics preferentially at disease sites, and by differential device activity in different physiological environments, potentially under direction of an external physician/ operator. These attributes will maximize the benefit of therapy at disease sites while minimizing systemic toxicities (13–15).

Many emerging nanotherapeutics are essentially delivery devices based on nanoparticulate materials (allowing minimally invasive parenteral administration), with a strong emphasis on control of therapeutic action in time and space. Targeted delivery devices depending on biologic affinity interactions [using the emerging vascular address system (16,17)] as well as others depending on physical/chemical properties of nanoscale particulates (enhanced permeability and retention effect, 17–19) have emerged in recent years, as have pro-drug strategies for delivery devices that are active only at preselected sites of disease (17,19–21). Other related modalities have allowed the control of activity or assembly of functional nanodevices at particular sites or at particular times in response to a signal provided by an external operator. Such signals might be physical [a magnetic field, 22)] or biochemical [an enzyme to process the therapeutic to an active form (23,24)] in nature.

Emerging in vivo nanotechnology will allow clinicians unprecedented abilities to monitor therapy in real time, as well as stringent control of the systemic consequences of therapy. These benefits of nanotherapeutics are likely to be pursued first for disease states exhibiting large unmet patient needs (oncology, cardiovascular disease). In time, lessons learned from specific delivery of potentially toxic materials to maximize their therapeutic benefits might be applied to other in vivo delivery tasks, such as delivery and distribution of nutrients and nutraceuticals.

	Nutrient metabolism at attomole levels: accelerator mass spectrometry for ultra-low level radiolabel tracing in nutrition

TOP ABSTRACT Nanotechnology in vivo: an... Nutrient metabolism at attomole... Nanotechnology: a tool for... Nanodevices for real-time... Mass spectrometric techniques... Concluding Remarks LITERATURE CITED

 
It is becoming increasingly apparent that all humans do not respond identically to either diets or medicines, so their needs differ according to differences in their genetic make-up and physiologic status. Ultra-low level use of isotope tracers and kinetic modeling of data sets are being increasingly used to quantify and interpret metabolism of nutrients and bioactive diet components, as it might occur in vivo in humans. Dr. Andrew Clifford provided such an example with the nutrient folate. Folate is an essential nutrient that is involved in many metabolic pathways, including DNA methylation and nucleotide synthesis. Food folate is predominantly of the pteroylpolyglutamate (PolyGlu)³ form, and during absorption it is converted to pteroylmonoglutamyl level. Disruption of folate metabolism is associated with severe illness in genetically susceptible individuals and other subgroups. Despite the importance of folate, gaps exist in our quantitative understanding of folate metabolism in humans. These gaps likely exist because folate metabolism is complex, a suitable animal model that mimics human folate metabolism has not been identified, and suitable experimental protocols for in vivo studies in humans are only now being developed (25,26). In general, the 7-d duration of previous studies (bar one) of folate metabolism is too short to resolve body folate pools that turn over most slowly. The slow turning over pools can be a major determinant of plasma folate kinetics late in a study. Dr. Clifford described an experimental approach for using accelerator mass spectrometry (AMS) and kinetic modeling of the resulting data to quantify the dynamic and kinetic behavior of human folate metabolism under normal conditions and how it might respond to single nucleotide polymorphisms in their folate relevant genes.

In the research described, a very low dose of ¹⁴C-labeled pteroylmonoglutamate (0.5 nmol, 100 nCi) plus 79.5 nmol pteroylmonoglutamate was ingested by each of 13 normal adults. Complete collections of urine and feces were made for at least 28 and 14 d, respectively. Up to 47 serial blood samples were collected in the 150 d that followed dosing. The ¹⁴C in all specimens was analyzed (27,28) and the dataset was analyzed by organizing current concepts of folate metabolism into a model suitable for quantitative hypothesis testing (29,30).

The study revealed the following: 1) absorbed dose is 79% of the dose administered; 2) mean dietary folate intake is 1046 nmol/d, bile folate is 5351 nmo/d, and 92% of the mix (1046 + 5351) is absorbed; 3) 1/4 of 1% of plasma folate is destined for RBC production; 4) about 35% of folate taken up by viscera is processed to polyGlu forms; 5) plasma residence time is on the order of 10 min; 6) nearly all body folate is visceral and nearly all visceral folate is PolyGlu; 7) folate uptake by marrow is saturable at about 1 mmol/d; 8) visceral PolyGlu is a direct precursor of p-ABA-Glu; and 9) preliminary data suggests that single nucleotide polymorphisms in folate relevant genes are likely to alter some of the above listed aspects of human folate metabolism. Finally, it is important to note that parameters, such as mean residence times, distributions, and fluxes, etc., of folate are explicitly model-dependent. Future experiments may require model revision; then these derived features of folate metabolism may require revision also. At the same time, and because AMS can detect attomole levels of ¹⁴C, ultra low-level doses (130 kBq of ¹⁴C that impart a lifetime added radiation exposure equivalent to that from a 15-min-flight at jetliner altitude) will provide datasets for elucidating the metabolism of several nutrients and bioactive dietary components in order to better match needs to genetic make-up and physiologic status of individuals.

	Nanotechnology: a tool for the food science and technology of the new millennium

TOP ABSTRACT Nanotechnology in vivo: an... Nutrient metabolism at attomole... Nanotechnology: a tool for... Nanodevices for real-time... Mass spectrometric techniques... Concluding Remarks LITERATURE CITED

 
Dr. Moraru’s presentation focused on the potential of nanotechnology for modern food science and technology. Four broad areas of food science and technology where nanotechnology is very likely to have a substantial impact were identified: health and nutrition, development of novel materials, food processing, and food safety (31).

A significant benefit for health and nutrition is poised to arise from more efficient delivery systems, able to deliver the active compounds directly to the appropriate sites, maintain their concentration at suitable levels for long periods of time, and prevent their premature degradation. Nanostructured materials, such as nanoparticles and nanospheres, could be used in the future to develop high performance delivery vehicles for biologically active substances of food origin, such as nutraceuticals (31). Another exciting development in this area is anticipated to be the use of nanostructured carriers for enhanced encapsulation and delivery of flavors in foods. Research efforts are already being made to develop food-based delivery vehicles such as polysaccharide/protein coacervates, liposomes or dendrimers. Stable phospholipid-divalent cation precipitates composed of naturally occurring materials, called cochleates, have been developed and patented (32). Cochleates are used for the encapsulation and delivery of a wide range of bioactive materials, including compounds with poor water solubility, protein and peptide drugs, large hydrophilic molecules, and in the future they could also be applied to the encapsulation and targeted delivery of functional food biomolecules.

In the food packaging arena, nanomaterials with enhanced mechanical and thermal properties are being developed to ensure better protection of foods from the exterior mechanical, thermal, chemical, or microbiological factors. Nanostructuring adds value to traditional materials by enhancing their mechanical strength, superconductivity, and ability to incorporate and efficiently deliver active substances into biological systems, at low costs and limited environmental impact. This would endow an additional level of safety and functionality to packaged foods. A promising class of new materials is represented by nanocomposites, made out of nanoscale structures with morphology and interfacial properties that give them unique characteristics. Nanocomposites started being used for coating plastic films as an alternative to silica and alumina coated films for food packaging. The addition of natural nanostructured materials (i.e., natural smectite clays) can render plastics that are lighter, stronger, and more heat-resistant, with improved oxygen, carbon dioxide, moisture, and volatile barrier properties (31,33). Such materials could enhance considerably the shelf life and safety of packaged foods.

Many of the microbial safety problems encountered in the food industry are related to the contamination of food processing equipment and surfaces with bacteria and bacterial and fungal spores. One of the most important properties of microbial cells and spores related to surfaces contamination and biofouling is adhesion. The quantification of microbial adhesion has been facilitated by the development of nanotools such as the Atomic Force Microscope (AFM) (31,34). Nanotechnology based strategies involving modification of surface chemistry and structure will probably be used in the future to prevent bacteria from adhering to food processing equipment.

A variation of this technology could involve the active coating of food contact surfaces for controlled release of antimicrobial compounds, triggered by environmental conditions such as temperature and humidity. In the same area of food safety, newly developed antimicrobial nanoemulsions are finding applications in decontamination of food equipment, packaging, or even the surface of some foods (i.e., fruits and vegetables). Additionally, nanotechnology is helping design antigen detecting biosensors to facilitate the early identification of pathogen contamination, thereby increasing the security of the food supply.

Another topic that was discussed was biomaterial characterization at the nanoscopic level. AFM is currently used to study the topography of foods and other biomaterials, and also for the structural investigation of delicate food biopolymer structures, such as hylan, xanthan gum, or kappa-carageenan gels. Force microscopy techniques enabled the study of rheological properties of single chains of proteins, polysaccharides, or DNA, and the intra- and intermolecular interactions in which these molecules participate (31,35,36). AFM force measurements allow quantifying the nano-mechanical properties of biofilm surfaces, which has many potential applications for foods and other biological soft materials.

Overall, nanotechnology offers a myriad of new and exciting opportunities for better understanding the structure and functionality of food systems, which is expected to result in improved nutritional quality and safety of foods, to the benefit of the science, industry, but first of all of the consumers.

	Nanodevices for real-time optical intracellular sensing

TOP ABSTRACT Nanotechnology in vivo: an... Nutrient metabolism at attomole... Nanotechnology: a tool for... Nanodevices for real-time... Mass spectrometric techniques... Concluding Remarks LITERATURE CITED

 
Dr. Philbert discussed real-time reversible chemical sensing and light based approaches using probes encapsulated by biologically localized embedding (PEBBLE) for intracellular chemical analysis (37). These nano-sized spherical devices consist of sensor molecules entrapped in a chemically inert matrix with the ability to carry out real time sensing of ions and small molecules. This inert coating limits interferences like those from protein binding while also providing protection to the cellular contents. Depending on the type of sensor materials, three different matrices are commonly used: hydrophobic, hydrophilic, and amphilic. Ratiometric measurements can be performed through these nanoparticles using two or more components. PEBBLEs incorporating glucose oxidase, for example, allow for measurement of the oxygen tension within the PEBBLE as well as the measurement of glucose concentration. A ratiometric oxygen sensor PEBBLE has two different dyes embedded in its core (38). The fluorescence of the measuring dye is quenched very efficiently in the presence of oxygen and its intensity is decreased with increasing local oxygen concentration. The reference dye is not sensitive to oxygen, and its fluorescence remains the same. This technology can be readily coupled with routine confocal microscopy for visualization. There is very little, if any, photobleaching and leaching of the dyes from the matrix. PEBBLEs help overcome the serious problem of free dyes where nonspecific protein binding interferes with sensing capacity. Additionally, by enclosing the dyes within a matrix, PEBBLEs protect cells from any potential harmful chemical effects of the sensors. These nanoprobes can thus serve as noninvasive optical biosensors that can be directed to desired sites by coating the PEBBLE surface with the appropriate ligands. PEBBLEs can help in time resolution of events as well as in stochastic modeling of rare intracellular events. These nanoprobes could serve as multifunctional platforms for imaging and delivery. It is conceivable that PEBBLE technology can be utilized to monitor nutrient metabolism, effects on reactive oxygen species generation, and ion distributions (39,40). Fluorescent quantum dots, about 2 to 7 nm in diameter, provide highly sensitive probes that can be used to explore biomolecules, organelles, cells, and tissues at the nanoscale. Further refinements of PEBBLE technology will likely enable the development of intra- and extracellular sensors of redox status and alterations in cellular function. These refinements will need to include development of biologically-based PEBBLEs that encapsulate functional peptides and/or proteins.

	Mass spectrometric techniques for following gene and protein expression

TOP ABSTRACT Nanotechnology in vivo: an... Nutrient metabolism at attomole... Nanotechnology: a tool for... Nanodevices for real-time... Mass spectrometric techniques... Concluding Remarks LITERATURE CITED

 
Dr. Hettich focused on the emerging field of proteomics and particularly on the use of mass spectrometry (MS) as a molecular level analytic technique. It is a platform for high throughput characterization of proteins and can serve to integrate experimental and computational biology methods. The mass measurement accuracy and structural interrogation capability of MS provide unique capabilities for identification of peptides and proteins. Unique ionization techniques, including matrix assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI), have enabled the transfer of proteins into the gas phase, facilitating their analysis with MS (41,42). MS approaches for proteomics consist of either a bottom-up or top-down approach. The bottom-up approach is excellent for determining protein identities but limited in terms of characterization of molecular forms of intact proteins. It typically involves proteolytic digestion of complex protein samples followed by analysis of peptides by liquid chromatography tandem mass spectrometry (LC-MS/MS). A protein database is then queried to identify the proteins from the analyzed peptide information. The top-down approach is optimal for determining the molecular forms of intact proteins (including post-translational modifications) but is limited in terms of the number of proteins identified. Integration of both the approaches provides both extensive protein identification and information on posttranslational processing. An evaluation of this approach with the microbe Shewanella oneidensis helped identify over 850 expressed proteins in addition to protein processing and gene translation start sites (43). ESI in combination with Fourier transform ion cyclotron resonance mass spectrometry (FTICR) was utilized to identify intact proteins from Shewanella oneidensis, while a liquid chromatography and tandem MS approach was taken to identify proteins from peptide component mixtures. The strength of the tandem MS platform lies in its ability to derive sequence information for a specific peptide in the presence of multiple peptides in the sample. In combination with other platforms, MS is a powerful tool for extracting proteomic information. For example, multidimensional liquid chromatography in combination with MS provides additional separation ability to enhance the dynamic range of molecular mass measurements for peptides and proteins in complex samples.

	Concluding Remarks

TOP ABSTRACT Nanotechnology in vivo: an... Nutrient metabolism at attomole... Nanotechnology: a tool for... Nanodevices for real-time... Mass spectrometric techniques... Concluding Remarks LITERATURE CITED

 
Recent advances in biomedical technology will likely assist in advancing our understanding of disease prevention and health promotion, as well as medical diagnostics and therapeutics. The symposium "New Technologies for Nutrition Research" highlighted new and emerging technologies that are currently relevant or likely to be so in the not-so-distant future for the nutritional sciences. For example, nanoparticles could be developed for preferential release of a bioactive food component at a molecular target known to influence heart disease or other health outcome. With the use of nanoscale optical sensors, such as PEBBLES, it may be soon be possible to detect reactive analytes, i.e., hydroxyl radicals, in living cells in real time. Using accelerator mass spectrometry, coupled with attomole radiolabeled-isotope detection capability, techniques are now available to examine and model the metabolism of various bioactive food components, including folate (25,26) and ß-carotene (44,45). AMS may also be utilized for the detection of biomarkers or molecular targets of relevance to nutrition and cancer and other chronic diseases. For example, monitoring the influence of isothiocyanates, a bioactive food component found in cruciferous vegetables, on DNA adduct formation following a low dose of [¹⁴C]PhIP ([¹⁴C]2-amino-1- methyl-6-phenylimidazol(4,5-b)pyridine) and [³H]IQ ([³H]2-amino-2-methylimidazolo(4,5-f)quinolone) (genotoxic heterocyclic amines) has been made possible through the use of AMS methodology (46). Furthermore, the advent of proteomic technologies now provides the tools necessary to understand how nutrients and dietary components impact peptides and proteins at the cellular level. This could potentially help in understanding, at the functional level, the complexities of nutrient-gene interactions. Proteomic technologies can help to elucidate pathways involved in metabolism of nutrients and to identify variations in enzyme metabolism that could potentially predispose to health or disease. Exciting developments in food science include the use of nanostructured carriers for enhanced encapsulation and delivery of flavors in foods, as well as advances in food storage and packaging to minimize bacterial contamination. This symposium was designed to enhance knowledge and understanding about certain emerging biology-based technologies that may be utilized and/or modified for nutrition and food science research. It is our hope that in showcasing these new technologies investigators will begin and/or continue to explore their utility and capacity in nutritional science approaches to the study of disease prevention and therapy.

	ACKNOWLEDGMENTS

 
A special thanks is extended to C. I. Moraru, Q. Huang, and J. L. Kokini of the Food Science Department and Center for Advanced Food Technology, Rutgers University, New Brunswick, NJ, for their assistance in preparing the food science perspective for this summary and the presentation at the Experimental Biology 2003 symposium.

	FOOTNOTES

 
¹ Presented at the Experimental Biology Meeting, April 11–15, 2003 San Diego, CA. The symposium was sponsored by the American Society for Nutritional Sciences and supported in part by an educational grant from Invitrogen life technologies. The proceedings are published as a supplement to The Journal of Nutrition. This supplement is the responsibility of the guest editors to whom the Editor of The Journal of Nutrition has delegated supervision of both technical conformity to the published regulations of The Journal of Nutrition and general oversight of the scientific merit of each article. The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or the publisher, editor, or editorial board of The Journal of Nutrition. The Guest Editor for the symposium publication is Sharon A. Ross, Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, and Pothur R. Srinivas, Vascular Biology Research Program, Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.

³ Abbreviations used: AFM, Atomic Force Microscope; AMS, accelerator mass spectrometry; ESI, electrospray ionization; LC-MS/MS, liquid chromatography tandem mass spectrometry; MALDI, matrix assisted laser desorption/ionization; MS, Mass spectrometry; PEBBLE, probes encapsulated by biologically localized embedding; PolyGlu, pteroylpolyglutamate.

	LITERATURE CITED

TOP ABSTRACT Nanotechnology in vivo: an... Nutrient metabolism at attomole... Nanotechnology: a tool for... Nanodevices for real-time... Mass spectrometric techniques... Concluding Remarks LITERATURE CITED

 

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