**10. Conclusion**

• Shaping strategies: the ability to change how an entire marketplace operates—and seize

The platform can be measured in terms of the level of activity or the number of users in the

Measuring the performance of a platform is important for ensuring the value for money and to ensure the achievement of the intended objectives. For most platforms, the switching cost varies extensively, thus marketers need to keep track on their choices and the changes within the entire platform ecosystem. For the online-based platforms, there are several metrics that are provided by the systems, but they should be evaluated from both technical and marketing perspectives. The number of viewers, for example, may seem as an attractive measure but

Marketers can strategically influence the way people behave and interact in the platform. This can be done by the ability to synchronize the principal and secondary value of a platform. Most of the value generated from the platform is an outcome of the activity level that platforms generate. Segmenting, targeting, and positioning the products and services with a right platform member should be done by an external looking (focusing on the users). This will

To some extent, the ability to control platforms will be contingent on the nature of governance (dedicated vs. referrals). Even though there is value that can be generated from a platform, there is a need for organization and to provide a soft control mechanism which will ensure that the primary role of the platform is sustainable and the secondary is achieved. Failure to balance the two will have negative results on the other. Another form of control is the control of supply. Normally, the supply control can be done with the non-digital platforms or in combination of digital. For example, imagine that you are traveling within a ship, and in this controlled environment, your only choice on what to buy will depend on what is available. This is what I refer to as an artificial scarcity, which can be strategically established within a platform.

A platform system consists of a core, its complements, and the interfaces between them [2]. The new companies are made of powerful platform ecosystem uniquely able to attract, match, and connect people to enable them to transact. These platforms often use open business model that do not require keeping or manufacturing anything, but harness the power of communities to enable transaction. This is different from traditional organizations which tend to run as linear [1]. Platform-based ecosystems are a vital source of dynamism and innovation for many technologies, products, and services in the global economy. A defining feature of platform ecosystems

guarantee that the marketing activities are allied with the platform context.

more value by doing so.

platform.

34 Marketing

**8.2. Measuring performance of the platform**

may have less to do the increase in sales.

**8.3. Influence and control platforms**

**9. Platform ecosystem**

The platform strategy is a growing area, which has provided the business firms with multiple opportunities for generating value. Whatever a platform does, it only comes down to two main issues, which are relationship building and solution delivery (products and services). Within this line is where a range of other things come to feature. Platforms thus form an important part of the marketing strategy. Dynamic and demanding environments will favor those who are able to learn best and fast. Business leaders who understand this will likely seek out platforms, which make work lighter for their participants, but also grow their knowledge, accelerate performance improvement, and enhance their capabilities in the process.


**Meet the editor**

Dr. Rajunor Ettarh is Professor and Vice-Chair for Education in the Department of Structural and Cellular Biology at Tulane University School of Medicine, where he also serves as Director of the Graduate Program in Anatomy. A Fellow of the Royal Society of Medicine in London, he spent much of his research career in Ireland, where his main interests centered on radiobiology and epithelial cell

biology of the digestive tract, the regulatory mechanisms that mediate uninhibited proliferation in gastrointestinal cancers, and potential therapeutic targets. He has published extensively, has previously edited two books on colorectal cancer, and reviews for a number of cancer journals.

## Contents

#### **Preface XI**

## Preface

Colorectal cancer remains a major health issue for many developed regions around the world. The good news is that early detection has significantly improved overall survival rates and continues to do so. A number of prevention strategies contribute to this positive trend – all of which are presented and discussed in this series of chapters. What are the risks? The risks are not good: a 5% risk of being diagnosed with colorectal cancer in one's lifetime. The odds are however getting better: 5-year survival rates of up to 90% if the dis‐ ease is discovered early. For those with predisposing risk factors such as family history, in‐ flammatory bowel disease or adenomatous polyposis, surveillance is recommended.

Surveillance guidelines outlined by several organizations are presented in detail in this book. Whether the aim is to prevent colorectal cancer or to detect the disease early, the role of fecal occult blood tests as well as inspections of the colon by flexible sigmoidoscopy and colonoscopy have been extensively studied and reported. Modalities include programmatic screening of target populations as well as opportunistic tests of patients. What about out‐ comes? Measured around incidence and mortality, screening remains cost effective, al‐ though its value continues to be debated. The issue of interval colorectal cancer remains a challenge. The role that modalities such as computed tomographic colonoscopy and genetic stool testing play in prevention and detection will only become clearer with more data and evidence. Today, a patient who undergoes a colonoscopy for screening purposes stands a much better chance of being effectively surveyed for prevention of colorectal cancer. Pa‐ tients can rely increasingly on the improved datasets and technical advances that are being made in colonoscopic equipment and skills. The future of surveillance looks increasingly positive as long as progress continues, particularly in the partnership between clinicians and computer scientists, for the development of better tools and methods.

#### **ACKNOWLEDGMENTS**

This book would not have been possible without the support of my family. I am also espe‐ cially indebted to process managers Ivona Lovrić and Iva Lipović whose immense patience, timely reminders, and constant assistance and support made the task of editing this book easier.

> **Dr. Rajunor Ettarh** Tulane University, School of Medicine, New Orleans, LA, USA

**Screening with Colonoscopy**


**2.4 Conclusion**

Among the six different sample extraction methods, two precipitate-based methods (method B and method C) were not suitable for the low recovery of lysozyme. Both method A and method D obtained good recoveries of six food additives simultaneously, but the major problem of method A is the lower reproducibility and much more time cost than method D. SPE was a simple and rapid method for the extraction of six food additives. From the results of method D–F, Poly-Sery HLB cartridge was confirmed as the most appropriate material for its high recovery.


**4. Conclusion**

In this chapter, we have reviewed digital demodulation algorithms for interferometric metrology systems. Digital demodulation has the potential for producing a more robust and less costly sensor system. In general, the savings in optical and electronic hardware is traded-off with complex software algorithms. Consider the information shown in Table 1 of the specific digital demodulation techniques presented in this chapter.

Note that each of the digital demodulation methods presented in Table 1 is based on a homodyne approach. The heterodyne techniques require additional optical and electronic hardware to shift the frequency of one of the interfering optical beams. A key advantage of digital demodulation is a significant reduction in cost and hardware system complexity.

We have also presented a new demodulation algorithm for the well-known phase-generated carrier modulation scheme. Our algorithm is based on a frequency domain approach and requires both the magnitude and phase information present in the signal. This demodulation scheme suffers from the need for active feedback control. One possible approach to ameliorate this limitation is to investigate the use of a more sophisticated modulation signal. In the demodulation algorithm presented in Section 3, the carrier signal is a pure sinusoid and the desired output is the fixed phase *R* . We have studied interferometers, which use the phase-generated carrier modulation scheme and detect the amplitude of a *sinusoidally* varying phase *R t*( ) . These systems produce harmonics, which we detect and then compute their ratio to remove the dependence on unknown quantities.

Table 1. Comparison of digital demodulation techniques presented in this chapter.

It may be possible to design a carrier signal, which produces an appropriate set of harmonics that can be mathematically manipulated to cancel out any variations in *M* and *W* , yet still be solvable for the fixed phase *R* . The trade-off would be a true open-loop system, which would not require stringent initialization procedures, at the expense of a sophisticated carrier modulation signal. Further investigation into the viability of this approach is suggested.

#### **5. Acknowledgment**

The authors would like to recognize funding support from Weatherford International, Inc. for research related to the phase-generated carrier demodulation scheme presented in Sec. 3.

#### **6. References**

**Homodyne/Heterodyne** Homodyne Homodyne Homodyne Homodyne **Passive/Active** Active Active Passive Passive

It may be possible to design a carrier signal, which produces an appropriate set of harmonics that can be mathematically manipulated to cancel out any variations in *M* and *W* , yet still be solvable for the fixed phase *R* . The trade-off would be a true open-loop system, which would not require stringent initialization procedures, at the expense of a sophisticated carrier modulation signal. Further investigation into the viability of this

The authors would like to recognize funding support from Weatherford International, Inc. for research related to the phase-generated carrier demodulation scheme presented in Sec. 3.

Barbour, N. & Schmidt, G., Inertial sensor technology trends. *IEEE Sensors Journal*, vol. 1, no.

Bush, J., Davis, C. A., McNair, F., Cekorich, A., & Bostick, J., Low cost fiber optic

Cekorich, A., Bush, J., & Kirkendall, C., Multi-channel interferometric demodulator. *Proceed.*

Cekorich, A., Demodulator for interferometric sensors.*Proceed. of the SPIE*, vol. 3860,

Cole, J. H., Danver, B. A., & Bucaro, J. A., Synthetic-heterodyne interferometric

Culshaw, B. & Giles, I. P., Frequency modulated heterdyne optical fiber Sagnac

interferometric sensors.*Proceed. of the SPIE – Second Pacific Northwest Fiber Optic*

*of the SPIE – Third Pacific Northwest Fiber Optic Sensor Workshop*, vol. 3180, (May

demodulation. *IEEE J. Quantum Electron.*, vol. QE-18, no. 4, (April 1982), pp. 694-

interferometer. *IEEE J. Quantum Electron.*, vol. QE-18, no. 4, (April 1982), pp. 690-

Table 1. Comparison of digital demodulation techniques presented in this chapter.

**Phasegenerated carrier (frequency domain)**

Down-hole oil well drilling bit parameter measurement

> Real-time processing

**J1 ... J4 3x3 fiber**

MEMS vibrating amplitude measurement

> Real-time processing

**coupler**

Ballistic shock (velocity) measurement

> Postprocessing

**Phasegenerated carrier (time domain)**

Biological cell contraction measurement

> Real-time processing

**Demodulation Technique**

**Application**

**Real-time/Postprocessing**

approach is suggested.

**5. Acknowledgment**

4, (December 2001), pp. 332-339

(December 1999), pp. 338-347.

1997), pp. 1-11.

697.

693).

*Sensor Workshop*, vol. 2872, (May 1996), pp. 1-12.

**6. References**


*Edited by Xu-bo Yuan*

This book focuses on recent advancement of gene delivery systems research. With the multidisciplinary contribution in gene delivery, the book covers several aspects in the gene therapy development: various gene delivery systems, methods to enhance delivery, materials with modification and multifunction for the tumor or tissue targeting. This book will help molecular biologists gain a basic knowledge of gene delivery vehicles, while drug delivery scientist will better understand DNA, molecular biology, and DNA manipulation.

Non-Viral Gene Therapy

Non-Viral Gene Therapy

*Edited by Xu-bo Yuan*

Photo by Rost-9D / iStock


DNA methylation is one example of an epigenetic modification, where a methyl group is covalently added to the C5 position of cytosine residues that occur directly adjacent to guanine residues. Many genes contain regulatory regions that are rich in cytosine-guanine dinucleotide repeats ("CG islands") (Hirst & Marra, 2009), and in general, a high degree of methylation in these regulatory regions results in diminished gene expression- a silencing that is often critical to many cellular processes. Methylation is a heritable modification and is maintained with cell division; however, methyl groups can be lost due to enzymatic removal or failure to accurately copy methylation pattern during replication (Oommen, Griffin, Sarath, & Zempleni, 2005). Alterations in methylation patterns have been associated with various disease states including cancer, Type 2 diabetes, and Alzheimer's Disease (Coppieters & Dragunow, 2011; Hirst & Marra, 2009; Ling & Groop, 2009; Martin-Subero & Esteller, 2011). These changes in epigenotype occur as a result of aging and environmental influences, including dietary exposures, and more work needs to be done to fully demonstrate a clear cause and effect relationship between diet induced changes in

Folate is a micronutrient that can directly influence DNA methylation status via its effects on the one carbon metabolism pathway, whereby folate serves as an important co-enzyme

importance of epigenetic drifts to the diet-disease risk relationship.

**4.1.1 Effects of dietary folate on epigenotype**

epigenotype and risk for disease (Jaenisch & Bird, 2003).

Table 1. Examples of diverse genetic mutations that may have co-evolved with changes in food supply.

Ability to digest lactose in milk

Ability to detect certain substances with bitter taste

More copies of the AMY1 gene result in increased salivary amylase protein

Sensorineural deafness, distal renal tubular acidosis, male infertility

GIP is resistant to serum degradation, and exhibits a higher bioactivity

Increased activity for ethanol oxidation

Table 1. Examples of diverse genetic mutations that may have co-evolved with changes in

**selected mutation Selection Advantage**

Allowed for consumption of dairy as staple food(Jarvela et al., 2009).

Allowed for detection and aversion of certain plants that contained substances which could cause iodine deficiencies and thyroid disordes(Wooding et al., 2004).

Populations that consume high starch diets have more copies of the AMY1 gene, allowing for more efficient digestion of starches(Perry et al., 2007).

Possibly allowed for climate adaptation through water-electrolyte homeostasis and prevention of dehydration(Moreno-Estrada et al., 2010).

May have been beneficial for individuals who had unconstrained access to the food supply in agricultural societies by preventing hyperglycemia (Chang et al., 2011)

Ability to metabolize fermented rice products (Peng et al., 2010)

**Abbreviation Protein Phenotype with**

hydrolase

2, member 38

Gene

Forkhead-box transcription factor I1

peptide (GIP)

Alcohol Dehydrogenase 1B (class 1), beta polypeptide

LCT Lactase-phlorizin

TAS2R38 Taste receptor, type

AMY1 Salivary Amylase

GIP Gastric inhibitory

**Gene**

FOXI1

ADH1B

food supply.

#### **4.1 Dietary influences on epigenetic evolution**

Epigenetic modifications are biochemical alterations that are made to DNA or DNA packaging proteins that modify the availability of genes to transcription machinery, thereby affecting gene expression. Epigenetic modifications such as DNA methylation or histone acetylation, for example, are responsible for differential expression allowing for a liver cell to greatly differ in structure and function from a skin cell, even though they share the same genetic make-up (Morgan, Santos, Green, Dean, & Reik, 2005). The "epigenotype," determined at conception, is inherited from the parents, but it can be greatly influenced by gestational conditions (Cooney, Dave, & Wolff, 2002; Nicoletto & Rinaldi, 2011; Wolff, Kodell, Moore, & Cooney, 1998). This is best exemplified by the *Agouti* mouse, where the epigenetic status of the Agouti gene, namely presence or absence of methylation at nine particular cytosines within a regulatory region 5' of the *Agouti* start site, results in a strikingly visible phenotype, as it causes variation in coat color and body weight as well as proneness to developing Type 2 Diabetes (Dolinoy, 2008). Experiments with these mice have demonstrated that maternal diet lacking in certain nutrients affects the epigenetic status of this gene and the related phenotypes (Cooney et al., 2002; Dolinoy, Huang, & Jirtle, 2007; Wolff et al., 1998).

In addition to the influence of gestational environment, epigenotype can also be influenced by environmental factors post-development and can be thought to evolve throughout one's lifetime. The changes that occur in epigenotype over time are referred to as "Epigenetic Drift" (Fraga et al., 2005; Nicoletto & Rinaldi, 2011). Studies conducted with identical twins that analyzed epigenetic patterns at different ages demonstrated that while twins share highly similar epigenetic patterns at young ages, this similarity decreases over time, and the disparity is likely due to environmental influences including diet composition (Fraga et al., 2005). Prospective intervention studies in twins that consume foods comprising of distinct dietary patterns, and including diverse staple foods may be useful to determine the relative importance of epigenetic drifts to the diet-disease risk relationship.

#### **4.1.1 Effects of dietary folate on epigenotype**

DNA methylation is one example of an epigenetic modification, where a methyl group is covalently added to the C5 position of cytosine residues that occur directly adjacent to guanine residues. Many genes contain regulatory regions that are rich in cytosine-guanine dinucleotide repeats ("CG islands") (Hirst & Marra, 2009), and in general, a high degree of methylation in these regulatory regions results in diminished gene expression- a silencing that is often critical to many cellular processes. Methylation is a heritable modification and is maintained with cell division; however, methyl groups can be lost due to enzymatic removal or failure to accurately copy methylation pattern during replication (Oommen, Griffin, Sarath, & Zempleni, 2005). Alterations in methylation patterns have been associated with various disease states including cancer, Type 2 diabetes, and Alzheimer's Disease (Coppieters & Dragunow, 2011; Hirst & Marra, 2009; Ling & Groop, 2009; Martin-Subero & Esteller, 2011). These changes in epigenotype occur as a result of aging and environmental influences, including dietary exposures, and more work needs to be done to fully demonstrate a clear cause and effect relationship between diet induced changes in epigenotype and risk for disease (Jaenisch & Bird, 2003).

Folate is a micronutrient that can directly influence DNA methylation status via its effects on the one carbon metabolism pathway, whereby folate serves as an important co-enzyme

The Nutrigenome and Gut Microbiome: Chronic

or nutrients are presented to the intestinal tract.

influence dietary-mediated host protection against chronic disease.

**4.3 Nutri-metabolome interactions and chronic disease**

consider.

Disease Prevention with Crop Phytochemical Diversity 349

established in childhood, and continues to evolve throughout one's lifetime. GI microbes are critical components of the early digestive development process and affect the amount of energy extracted from the diet (Ley et al., 2008). The microbiome acts as a metabolic filter between what is ingested, what is absorbed into the bloodstream, and what small molecules

The microbiome provides protective immune and metabolic functions for the human host (Laparra & Sanz, 2010). The metabolic enzymes and pathways provided by the microbiome are vast, allowing for biotransformation of many molecules including lipids, carbohydrates and phytochemicals (Laparra & Sanz, 2010). It is an integral part of the human digestive system, providing essential functions for the host such as biosynthesis of vitamins (e.g. vitamin K) and digestion of otherwise non-digestible carbohydrates (e.g. cellulose, psyllium, and pectin) (L. V. Hooper, Midtvedt, & Gordon, 2002). An oligosaccharide that is nondigestible by the host but can be fermented by the microbiome is known as a "prebiotic", and these molecules will stimulate the growth and/or activity of different species of microorganisms within the microbiome, thus having the potential to change phylotype(Laparra & Sanz, 2010). Emerging evidence suggests that the diet modifiable gut microbiome is a promising area of exploration for chronic disease control and prevention (Cani et al., 2008; Delzenne & Cani, 2011; Kau et al., 2011; Ley et al., 2005) **(Figure 2**). In addition to essential nutrients, there are a number of non-essential nutrients that differ across genetically diverse varieties of a single plant food, such as rice and dry beans (Heuberger et al., 2010; Mensack et al., 2010). These foods demonstrate promising potential to affect the microbiome via fibers and bioactive phytochemicals (e.g. polyphenolics, triterpenoids etc.), and may reveal a role for phytonutrient/phytochemical teamwork to

Nutrient-based dietary guidelines for overweight and chronic disease prevention may undoubtedly require an assessment of the gut microbiome to establish ideal nutritional phylotypes. A growing body of evidence exists for determining which dietary patterns are associated with improved human health (Adebamowo et al., 2005; Batres-Marquez, Jensen, & Upton, 2009; de Munter et al., 2007; Hung et al., 2004; Lanza et al., 2006; Michels et al., 2006; Mozaffarian et al., 2011; Sofi, Abbate, Gensini, & Casini, 2010). While age, sex, life stage, and other factors contribute to the variation in our nutrient requirements among individuals within a population, the opportunities to explore how plant diversity may benefit human health are astounding. Because human genetic variation confers tolerance/intolerance for certain foods and the genetic contribution to dietary requirements within and among human populations remains to be evaluated rigorously, the potential to continue to co-evolve with our food supply is a promising endeavor to

Brown rice consumption was recently shown to have an inverse association with risk for developing Type 2 Diabetes (Sun et al., 2010), however the importance of the rice genotype for this effect is unknown. Recent evidence for metabolome diversity in cooked brown rice from genetically diverse varieties suggests that rice crop varieties may differ in these health

promoting and disease fighting properties (Heuberger et al., 2010; Ryan et al., 2011).

in the production of S-adenosylmethionine, the DNA methyl donor (Kim, Friso, & Choi, 2009). Folate depletion and/or folate supplementation can affect the methylation status of certain genes. Studies beyond the scope of this chapter demonstrate the precise mechanisms by which folate status effects epigenotype and gene expression (Jacob et al., 1998; Rampersaud, Kauwell, Hutson, Cerda, & Bailey, 2000).

Legumes represent a major staple plant food that is naturally rich in folate (e.g. lentils and dry beans) (U.S.D.A, 2009). It is unknown whether the vast genetic diversity of the Leguminosae family and consumption rates of legumes can influence DNA methylation. Populations with staple legume consumption have shown lower chronic disease prevalence that may be due to a number of reported bioactivities. (Adebamowo et al., 2005; Bazzano et al., 2001; Michels et al., 2006; Papanikolaou, 2006; Singh & Fraser, 1998; Villegas et al., 2008). There is potential for legume folate, bioactive compounds, and essential nutrients to affect methylation status and influence epigenotype, yet the relationship to disease risk in humans is currently unknown.

#### **4.1.2 Effects of butyrate on epigenotype**

Modifications to the histone proteins, which interact and tightly bind DNA so it can eventually be condensed into chromatin, are another category of epigenetic modifications that make up epigenotype. The tails of the histone proteins are targets for modifications because they protrude from the histone/DNA complex known as the nucleosome. Specific residues in these histone tails may undergo methylation, phosphorylation or acetylation (Cobiac, 2007; Sawan & Herceg, 2010). Modifications to histones affect their DNA binding affinity and may result in more or less condensation of the DNA, and thus influences gene transcription at that location. Histone acetylation is generally associated with less condensation and increased gene transcription. Histone acetyltransferases and deacetyltransferases affect acetylation, and aberrant acetylatione has been associated with disease such as cancer, neurodegenerative disorders, and Type 2 Diabetes (Cobiac, 2007; Sawan & Herceg, 2010; Gray & DeMeyts, 2005; Mattson, 2003).

There have been some accounts of dietary factors affecting histone aetyltransferases. In particular, the short chain fatty acid, butyrate, was reported to inhibit histone acetytransferase (Timmermann, 2003). Short chain fatty acids are produced in the gastrointestinal tract from dietary fiber and resistant starch microflora fermentation. Legumes and whole grains represent food staples that are rich sources of dietary fiber that leads to production of short chain fatty acids, including butyrate. This is another example of how changes in staple food crops may interact with the microbiome and epigenome to affect risk of developing chronic diseases.

#### **4.2 The gut microbiome and dietary evolution of phylotype**

The community of microbes within our gut and the genes they harbor is known as the microbiome (Zaneveld et al., 2008). Each individual has a distinct microbiota fingerprint, and the composition is subject to change from acute and chronic environmental influences such as diet, illness and travel (Dethlefsen, McFall-Ngai, & Relman, 2007). The microbiome includes species of bacteria, archaea, fungi, viruses, protozoans, and sometimes multicellular organisms, though bacteria are the predominate population and reach 100 trillion cells in the colon (Lee & Mazmanian, 2010). The microbiome composition can also be referred to as "phylotype". In mammals, phylotype is established after birth, becomes more

in the production of S-adenosylmethionine, the DNA methyl donor (Kim, Friso, & Choi, 2009). Folate depletion and/or folate supplementation can affect the methylation status of certain genes. Studies beyond the scope of this chapter demonstrate the precise mechanisms by which folate status effects epigenotype and gene expression (Jacob et al., 1998;

Legumes represent a major staple plant food that is naturally rich in folate (e.g. lentils and dry beans) (U.S.D.A, 2009). It is unknown whether the vast genetic diversity of the Leguminosae family and consumption rates of legumes can influence DNA methylation. Populations with staple legume consumption have shown lower chronic disease prevalence that may be due to a number of reported bioactivities. (Adebamowo et al., 2005; Bazzano et al., 2001; Michels et al., 2006; Papanikolaou, 2006; Singh & Fraser, 1998; Villegas et al., 2008). There is potential for legume folate, bioactive compounds, and essential nutrients to affect methylation status and influence epigenotype, yet the relationship to disease risk in humans is currently unknown.

Modifications to the histone proteins, which interact and tightly bind DNA so it can eventually be condensed into chromatin, are another category of epigenetic modifications that make up epigenotype. The tails of the histone proteins are targets for modifications because they protrude from the histone/DNA complex known as the nucleosome. Specific residues in these histone tails may undergo methylation, phosphorylation or acetylation (Cobiac, 2007; Sawan & Herceg, 2010). Modifications to histones affect their DNA binding affinity and may result in more or less condensation of the DNA, and thus influences gene transcription at that location. Histone acetylation is generally associated with less condensation and increased gene transcription. Histone acetyltransferases and deacetyltransferases affect acetylation, and aberrant acetylatione has been associated with disease such as cancer, neurodegenerative disorders, and Type 2 Diabetes (Cobiac, 2007;

There have been some accounts of dietary factors affecting histone aetyltransferases. In particular, the short chain fatty acid, butyrate, was reported to inhibit histone acetytransferase (Timmermann, 2003). Short chain fatty acids are produced in the gastrointestinal tract from dietary fiber and resistant starch microflora fermentation. Legumes and whole grains represent food staples that are rich sources of dietary fiber that leads to production of short chain fatty acids, including butyrate. This is another example of how changes in staple food crops may interact with the microbiome and epigenome to affect

The community of microbes within our gut and the genes they harbor is known as the microbiome (Zaneveld et al., 2008). Each individual has a distinct microbiota fingerprint, and the composition is subject to change from acute and chronic environmental influences such as diet, illness and travel (Dethlefsen, McFall-Ngai, & Relman, 2007). The microbiome includes species of bacteria, archaea, fungi, viruses, protozoans, and sometimes multicellular organisms, though bacteria are the predominate population and reach 100 trillion cells in the colon (Lee & Mazmanian, 2010). The microbiome composition can also be referred to as "phylotype". In mammals, phylotype is established after birth, becomes more

Rampersaud, Kauwell, Hutson, Cerda, & Bailey, 2000).

**4.1.2 Effects of butyrate on epigenotype**

risk of developing chronic diseases.

Sawan & Herceg, 2010; Gray & DeMeyts, 2005; Mattson, 2003).

**4.2 The gut microbiome and dietary evolution of phylotype**

established in childhood, and continues to evolve throughout one's lifetime. GI microbes are critical components of the early digestive development process and affect the amount of energy extracted from the diet (Ley et al., 2008). The microbiome acts as a metabolic filter between what is ingested, what is absorbed into the bloodstream, and what small molecules or nutrients are presented to the intestinal tract.

The microbiome provides protective immune and metabolic functions for the human host (Laparra & Sanz, 2010). The metabolic enzymes and pathways provided by the microbiome are vast, allowing for biotransformation of many molecules including lipids, carbohydrates and phytochemicals (Laparra & Sanz, 2010). It is an integral part of the human digestive system, providing essential functions for the host such as biosynthesis of vitamins (e.g. vitamin K) and digestion of otherwise non-digestible carbohydrates (e.g. cellulose, psyllium, and pectin) (L. V. Hooper, Midtvedt, & Gordon, 2002). An oligosaccharide that is nondigestible by the host but can be fermented by the microbiome is known as a "prebiotic", and these molecules will stimulate the growth and/or activity of different species of microorganisms within the microbiome, thus having the potential to change phylotype(Laparra & Sanz, 2010). Emerging evidence suggests that the diet modifiable gut microbiome is a promising area of exploration for chronic disease control and prevention (Cani et al., 2008; Delzenne & Cani, 2011; Kau et al., 2011; Ley et al., 2005) **(Figure 2**). In addition to essential nutrients, there are a number of non-essential nutrients that differ across genetically diverse varieties of a single plant food, such as rice and dry beans (Heuberger et al., 2010; Mensack et al., 2010). These foods demonstrate promising potential to affect the microbiome via fibers and bioactive phytochemicals (e.g. polyphenolics, triterpenoids etc.), and may reveal a role for phytonutrient/phytochemical teamwork to influence dietary-mediated host protection against chronic disease.

#### **4.3 Nutri-metabolome interactions and chronic disease**

Nutrient-based dietary guidelines for overweight and chronic disease prevention may undoubtedly require an assessment of the gut microbiome to establish ideal nutritional phylotypes. A growing body of evidence exists for determining which dietary patterns are associated with improved human health (Adebamowo et al., 2005; Batres-Marquez, Jensen, & Upton, 2009; de Munter et al., 2007; Hung et al., 2004; Lanza et al., 2006; Michels et al., 2006; Mozaffarian et al., 2011; Sofi, Abbate, Gensini, & Casini, 2010). While age, sex, life stage, and other factors contribute to the variation in our nutrient requirements among individuals within a population, the opportunities to explore how plant diversity may benefit human health are astounding. Because human genetic variation confers tolerance/intolerance for certain foods and the genetic contribution to dietary requirements within and among human populations remains to be evaluated rigorously, the potential to continue to co-evolve with our food supply is a promising endeavor to consider.

Brown rice consumption was recently shown to have an inverse association with risk for developing Type 2 Diabetes (Sun et al., 2010), however the importance of the rice genotype for this effect is unknown. Recent evidence for metabolome diversity in cooked brown rice from genetically diverse varieties suggests that rice crop varieties may differ in these health promoting and disease fighting properties (Heuberger et al., 2010; Ryan et al., 2011).

The Nutrigenome and Gut Microbiome: Chronic

**5.1 Loss of dietary phytochemical diversity**

& Thompson, 2009).

intakes.

Disease Prevention with Crop Phytochemical Diversity 351

Since this time of early domestication, agricultural developments involve continuous improvements of genetic traits in our staple crop species, and have not considered traits of nutritional importance (Sands, Morris, Dratz, & Pilgeram, 2009). This has also been referred to as the "breeders dilemma". Recently, crop domestication has come with a price, and that price is a loss of genetic diversity that has occurred on two levels. First, there has been a loss of biodiversity in overall diet composition, as nearly 70% of all of the calories consumed by humans are supplied by only 15 crops (Ross-Ibarra et al., 2007), with the majority of these calories not coming from the basic raw or cooked form of the plant food, but from some more processed form. Secondly,there has been a loss of genetic diversity within each individual staple crop species themselves, as it has been estimated that cultivation has resulted in the loss of up to 95% of the genetic variation for many traits (M. D. T. Thompson

Primary metabolites produced by plants are compounds such as proteins, carbohydrates, and lipids that serve structural and functional purposes, and comprise essential nutrients in the human diet. Other phytochemicals produced by the plant that have no recognized role in the maintenance of fundamental life processes in the plants that synthesize them, but do have an important role in the interaction of the plant with its environment are known as secondary metabolites (Oksman-Caldentey & Inze, 2004). Secondary metabolites serve as chemical messengers functioning in the interaction of plants with their abiotic and biotic environment in processes such as communication, reproduction, or defense mechanisms (Hartmann, 2007). There are over 200,00 different plant secondary metabolites, and many have been studied for their bioactivity and enhanced human health importance **(Table 2)**, which has led in large part to their development as dietary supplements (Espin, Garcia-Conesa, & Tomas-Barberan, 2007), though secondary metabolites are typically included in the human diet via consumption of fruits, vegetables, spices, flavouring agents, or beverages (Mandlekar, Hong, & Kong, 2006). While the increased consumption of dietary supplements may have replaced the availability and intake of these chemicals from food in the past couple decades, there is emerging interest in achieving intakes of these "nonessential nutrients" from whole foods (Liu, 2003, 2004). The loss of genetic variation in staple food crops that make up our food supply is a serious concern for a number of reasons. Of particular emphasis in this chapter is the loss of genetic diversity that translates to reduced dietary phytochemical intake from foods that make of the bulk of our caloric

**5.2 Food crop diversity as a feasible dietary solution to chronic disease susceptibility** One of the main tenets of a Paleolithic diet that we have diverged from compared to our present diets is the amount and diversity of plant foods and fiber that is consumed. Diet composition of plant foods is believed to have decreased from about 2/3 of total intake to less than 10% of total intake, while fiber intake is believed to have decreased from about 104 g/day in Paleolithic times to about 15.2 g/day in present times (Jew et al., 2009b). Because there is growing evidence that maintaining intake of diverse phytochemicals is of utmost importance for maintaining health and preventing chronic disease (M. D. T. Thompson &

Fig. 2. Interactions between bioactive phytochemicals from genetically diverse staple food crops and the gut microbiome for chronic disease control and prevention.

#### **5. Plant crop genetic diversity**

Plants are among the oldest living complex organisms, and have had to face evolutionary pressures from pathogens such as insects, bacteria, and fungi from the very beginning of their evolutionary history. As they have developed defense mechanisms to protect themselves from infectious threats, these organisms have evolved counter-mechanisms of their own, necessitating further adaptations by plants, thus creating a cycle of co-evolution. This co-evolution of plants and the species that attack them has led to the development of an immense array of over 200,000 different phytochemicals present in plant life today (Hartmann, 2007; Macias, Galindo, & Galindo, 2007).

As humans transitioned from hunter gatherer societies to agricultural societies, they began cultivating crops, and both consciously and unconsciously selected for certain agronomic traits that rendered the crop more desirable for production in a particular climate and environment (Ross-Ibarra, Morrell, & Gaut, 2007). These selective pressures resulted in what is known as the "domestication syndrome", whereby certain traits are present in all domesticated crops compared to wild plants. These traits are ones that have made the crop easier to cultivate, including traits such as agricultural production of a larger fruit or grain, a more robust plant, more robust growth of the central stem compared to the side stems, and the loss of natural seed dispersal, which renders the plant dependant on humans for propagation (Doebley, Gaut, & Smith, 2006).

Fig. 2. Interactions between bioactive phytochemicals from genetically diverse staple food

Plants are among the oldest living complex organisms, and have had to face evolutionary pressures from pathogens such as insects, bacteria, and fungi from the very beginning of their evolutionary history. As they have developed defense mechanisms to protect themselves from infectious threats, these organisms have evolved counter-mechanisms of their own, necessitating further adaptations by plants, thus creating a cycle of co-evolution. This co-evolution of plants and the species that attack them has led to the development of an immense array of over 200,000 different phytochemicals present in plant life today

As humans transitioned from hunter gatherer societies to agricultural societies, they began cultivating crops, and both consciously and unconsciously selected for certain agronomic traits that rendered the crop more desirable for production in a particular climate and environment (Ross-Ibarra, Morrell, & Gaut, 2007). These selective pressures resulted in what is known as the "domestication syndrome", whereby certain traits are present in all domesticated crops compared to wild plants. These traits are ones that have made the crop easier to cultivate, including traits such as agricultural production of a larger fruit or grain, a more robust plant, more robust growth of the central stem compared to the side stems, and the loss of natural seed dispersal, which renders the plant dependant on humans for

crops and the gut microbiome for chronic disease control and prevention.

**5. Plant crop genetic diversity**

(Hartmann, 2007; Macias, Galindo, & Galindo, 2007).

propagation (Doebley, Gaut, & Smith, 2006).

Since this time of early domestication, agricultural developments involve continuous improvements of genetic traits in our staple crop species, and have not considered traits of nutritional importance (Sands, Morris, Dratz, & Pilgeram, 2009). This has also been referred to as the "breeders dilemma". Recently, crop domestication has come with a price, and that price is a loss of genetic diversity that has occurred on two levels. First, there has been a loss of biodiversity in overall diet composition, as nearly 70% of all of the calories consumed by humans are supplied by only 15 crops (Ross-Ibarra et al., 2007), with the majority of these calories not coming from the basic raw or cooked form of the plant food, but from some more processed form. Secondly,there has been a loss of genetic diversity within each individual staple crop species themselves, as it has been estimated that cultivation has resulted in the loss of up to 95% of the genetic variation for many traits (M. D. T. Thompson & Thompson, 2009).

#### **5.1 Loss of dietary phytochemical diversity**

Primary metabolites produced by plants are compounds such as proteins, carbohydrates, and lipids that serve structural and functional purposes, and comprise essential nutrients in the human diet. Other phytochemicals produced by the plant that have no recognized role in the maintenance of fundamental life processes in the plants that synthesize them, but do have an important role in the interaction of the plant with its environment are known as secondary metabolites (Oksman-Caldentey & Inze, 2004). Secondary metabolites serve as chemical messengers functioning in the interaction of plants with their abiotic and biotic environment in processes such as communication, reproduction, or defense mechanisms (Hartmann, 2007). There are over 200,00 different plant secondary metabolites, and many have been studied for their bioactivity and enhanced human health importance **(Table 2)**, which has led in large part to their development as dietary supplements (Espin, Garcia-Conesa, & Tomas-Barberan, 2007), though secondary metabolites are typically included in the human diet via consumption of fruits, vegetables, spices, flavouring agents, or beverages (Mandlekar, Hong, & Kong, 2006). While the increased consumption of dietary supplements may have replaced the availability and intake of these chemicals from food in the past couple decades, there is emerging interest in achieving intakes of these "nonessential nutrients" from whole foods (Liu, 2003, 2004). The loss of genetic variation in staple food crops that make up our food supply is a serious concern for a number of reasons. Of particular emphasis in this chapter is the loss of genetic diversity that translates to reduced dietary phytochemical intake from foods that make of the bulk of our caloric intakes.

#### **5.2 Food crop diversity as a feasible dietary solution to chronic disease susceptibility**

One of the main tenets of a Paleolithic diet that we have diverged from compared to our present diets is the amount and diversity of plant foods and fiber that is consumed. Diet composition of plant foods is believed to have decreased from about 2/3 of total intake to less than 10% of total intake, while fiber intake is believed to have decreased from about 104 g/day in Paleolithic times to about 15.2 g/day in present times (Jew et al., 2009b). Because there is growing evidence that maintaining intake of diverse phytochemicals is of utmost importance for maintaining health and preventing chronic disease (M. D. T. Thompson &

The Nutrigenome and Gut Microbiome: Chronic

**6. Concluding remarks**

**7. Acknowldegements**

110:865-878, 2008.

Med 161:2573-2578, 2001.

**8. References**

Disease Prevention with Crop Phytochemical Diversity 353

Thompson, 2009; Heuberger et al., 2010; Ryan et al., 2011), it stands to reason that including more phytochemicals (both in terms of quantity and variety) in the diet has great potential for benefiting human health and decreasing risk for chronic disease (Figure 3). Recent evidence from the NIH-AARP cohort study that prospectively evaluated the diet-disease relationships of more than a half a million Americans supports that legumes and whole grains were the most significant sources of fiber intake compared to fruit and vegetable consumption for protection against chronic disease risk(Park, Subar, Hollenbeck, & Schatzkin, 2011). These findings provide strong rationale for evaluating **staple** food crops as a powerful vehicle for delivery of health promoting phytochemicals and bioactive food

The shift to the modern Western diet, lacking in fiber and phytodiversity while providing an overabundance of macronutrients, has happened relatively fast in evolutionary terms. Much of human nutrigenetic variation is the result of natural selection for genotypes that allowed for metabolism of diet available at the time. The selection of these gene mutations with the evolving food supply was a very slow process requiring thousands of years and many generations. While it is not feasible to change genotype that is amendable to current changing environmental conditions, or poor lifestyle choices, we have other layers to our genome that are modifiable. The epigenome and the microbiome are by nature short term modulators between our environment and our genes. In our quest to diminish chronic disease, we will need to harness this ability to affect the short-term evolutionary potential of the epigenome and microbiome and determine what dietary patterns have the most optimal effects on epigenotype and phylotype. Maintaining genetic diversity within our food crops is an important concept that can be appreciated across diverse scientific disciplines for providing an extensive array of molecules that, like folate or phenolics, may be beneficial modulators of the epigenome and microbiome. Genetic Diversity in staple food crops, because they are the most widely consumed, will play an especially important role in

The authors wish to thank the CSU Crops for Health program and the CSU Animal Cancer

Adebamowo CA, Cho E, Sampson L, et al.: Dietary flavonols and flavonol-rich foods intake

Amarowicz RP, R.: Legumes as a source of natural antioxidants. Eur. J. Lipid Sci. Technol.

Batres-Marquez SP, Jensen HH, Upton J: Rice consumption in the United States: recent evidence from food consumption surveys. J Am Diet Assoc 109:1719-1727, 2009. Bazzano LA, He J, Ogden LG, et al.: Legume consumption and risk of coronary heart disease

in US men and women: NHANES I Epidemiologic Follow-up Study. Arch Intern

components that comprise a large part of total plant food and caloric intake.

optimizing the diet-gene-epigenetic-microbiomic-disease relationships.

Center Nutrition laboratory for their insights and discussion for this chapter.

and the risk of breast cancer. Int J Cancer 114:628-633, 2005.

Table 2. Secondary metabolites from plants and bioactive mechanisms of action for chronic disease prevention (Amarowicz, 2008).

Fig. 3. Identifying relationships between food crop genetic diversity, dietary phytochemical diversity, and the potential opportunities for human health benefit.

Thompson, 2009; Heuberger et al., 2010; Ryan et al., 2011), it stands to reason that including more phytochemicals (both in terms of quantity and variety) in the diet has great potential for benefiting human health and decreasing risk for chronic disease (Figure 3). Recent evidence from the NIH-AARP cohort study that prospectively evaluated the diet-disease relationships of more than a half a million Americans supports that legumes and whole grains were the most significant sources of fiber intake compared to fruit and vegetable consumption for protection against chronic disease risk(Park, Subar, Hollenbeck, & Schatzkin, 2011). These findings provide strong rationale for evaluating **staple** food crops as a powerful vehicle for delivery of health promoting phytochemicals and bioactive food components that comprise a large part of total plant food and caloric intake.

### **6. Concluding remarks**

352 The Molecular Basis of Plant Genetic Diversity

**(Amarowicz, 2008) Biologic Activity**

**Examples**

γ-Oryzanol (Rice) Flavonoids Phenolic acids Procyanidins Anthocyanidins α-lipoic acid

tocotrienols and tocopherols

β-sitosterol Campesterol Stigmasterol

Table 2. Secondary metabolites from plants and bioactive mechanisms of action for chronic

Fig. 3. Identifying relationships between food crop genetic diversity, dietary phytochemical

diversity, and the potential opportunities for human health benefit.

Vitamin E Alpha, gamma, delta

**Secondary Metabolites in whole grains and legumes**

> Antioxidants and Polyphenols

> > Phytosterols

disease prevention (Amarowicz, 2008).

The shift to the modern Western diet, lacking in fiber and phytodiversity while providing an overabundance of macronutrients, has happened relatively fast in evolutionary terms. Much of human nutrigenetic variation is the result of natural selection for genotypes that allowed for metabolism of diet available at the time. The selection of these gene mutations with the evolving food supply was a very slow process requiring thousands of years and many generations. While it is not feasible to change genotype that is amendable to current changing environmental conditions, or poor lifestyle choices, we have other layers to our genome that are modifiable. The epigenome and the microbiome are by nature short term modulators between our environment and our genes. In our quest to diminish chronic disease, we will need to harness this ability to affect the short-term evolutionary potential of the epigenome and microbiome and determine what dietary patterns have the most optimal effects on epigenotype and phylotype. Maintaining genetic diversity within our food crops is an important concept that can be appreciated across diverse scientific disciplines for providing an extensive array of molecules that, like folate or phenolics, may be beneficial modulators of the epigenome and microbiome. Genetic Diversity in staple food crops, because they are the most widely consumed, will play an especially important role in optimizing the diet-gene-epigenetic-microbiomic-disease relationships.

#### **7. Acknowldegements**

The authors wish to thank the CSU Crops for Health program and the CSU Animal Cancer Center Nutrition laboratory for their insights and discussion for this chapter.

#### **8. References**

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### *Edited by Mahmut Çalışkan*

The Molecular Basis of Plant Genetic Diversity presents chapters revealing the magnitude of genetic variations existing in plant populations. Natural populations contain a considerable genetic variability which provides a genomic flexibility that can be used as a raw material for adaptation to changing environmental conditions. The analysis of genetic diversity provides information about allelic variation at a given locus. The increasing availability of PCR-based molecular markers allows the detailed analyses and evaluation of genetic diversity in plants and also, the detection of genes influencing economically important traits. The purpose of the book is to provide a glimpse into the dynamic process of genetic variation by presenting the thoughts of scientists who are engaged in the generation of new ideas and techniques employed for the assessment of genetic diversity, often from very different perspectives. The book should prove useful to students, researchers, and experts in the area of conservation biology, genetic diversity, and molecular biology.

The Molecular Basis of Plant Genetic Diversity

The Molecular Basis of Plant

Genetic Diversity

*Edited by Mahmut Çalışkan*

Photo by agsandrew / iStock


Use of Transforms in Biomedical Signal Processing and Analysis

*Ette Harikrishna and Komalla Ashoka Reddy*

## **Abstract**

Biomedical signals like electrocardiogram (ECG), photoplethysmographic (PPG) and blood pressure were very low frequency signals and need to be processed for further diagnosis and clinical monitoring. Transforms like Fourier transform (FT) and Wavelet transform (WT) were extensively used in literature for processing and analysis. In my research work, Fourier and wavelet transforms were utilized to reduce motion artifacts from PPG signals so as to produce correct blood oxygen saturation (SpO2) values. In an important contribution we utilized FT for generation of reference signal for adaptive filter based motion artifact reduction eliminating additional sensor for acquisition of reference signal. Similarly we utilized the transforms for other biomedical signals.

**Keywords:** Fourier transform, biomedical signals, electrocardiogram signal, photoplethysmographic signal, wavelet transform

## **1. Introduction**

The essence of mathematical design cannot be ignored in the analysis of real world engineering applications i.e. the research in engineering and mathematics is a two way parallel track that interrelates and coordinates towards value added research. In specific, the use of transforms in the field of electrical, electronic and communication engineering is unimaginable. In the present scenario of Covid-19 pandemic, world is looking to sustainable development of biomedical devices for critical monitoring and efficient vaccination for human survival [1–4]. In general, the Fourier transform (FT) is a mathematical tool which transforms the time domain signal into a frequency domain representation used in analysis of biomedical, wireless communication, signal and image processing applications. In literature, many researchers had used this tool in frequency domain analysis of all biomedical signals like electrocardiogram (ECG), photoplethysmographic (PPG) and blood pressure (BP).

In continuation to FT, different transforms were developed to analyze and design of various applications based on the requirement [5, 6]. In general, the FT is used in analysis of stationary signals; the wavelet transform (WT) is a mathematical tool used in analysis of both stationary and non-stationary signals. Discrete wavelet transform (DWT) used in enormous application in various engineering fields.

So, in this chapter we addressed some of the research challenges in ECG and PPG signal processing using Fourier and Wavelet transforms.