*3.1. Nuclear Energy Sector*

Nuclear industry, accounting for 4.5% in the global energy balance, has already made a considerable contribution to energy sector development (Figure 3), due to the relatively low cost of electricity generation [55]. The development dynamics of the nuclear energy sector differ greatly in various countries, because of varying available resources and access to alternative sources of energy, as well as project experience.

Prospects for its further development are questionable. On the one hand, the low production cost of energy generation, as well as the higher efficiency of the plants (the majority having a capacity use rate of more than 80%) [56], could mitigate the technological transformation of the energy sector. On the other hand, the diagram shows that sharp declines in nuclear energy generation are caused by accidents at plants that directly influence not only the energy generation process, but also produce fears on the expediency of the further use of nuclear energy. Here, for example, a final decision about the immediate decrease in the share of the nuclear energy in the country balance was taken by Germany in 2011 after the accident at Fukushima and the first-step measures included the shutdown of power units commissioned before the 1980s.

**Figure 3.** Dynamics of nuclear energy generation volumes. Based on BP Energy Overviews.

The problem of existing physical depreciation of energy generating facilities is topical for the nuclear energy sector even today. As of the end of 2018, the number of nuclear reactors in the world amounted to 450 [57], 281 of which (62.4%) were more than 30 years old, 26% were aged 10 to 30 years, and only 11.6% were younger than 10 years old. In accordance with IEA data [58], the highest average ages of nuclear plants are seen in the USA (39 years old), Europe (35 years old), Russia (31 years old) and Japan (29 years old). The highest shares of nuclear plants under 10 years old are observed in China (80%), India (40%), Russia (25%) and Korea (24%).

Strengthening security measures taken during the construction of the third-generation reactors enables the mitigation of risk of accidents, but increases the unitary cost of the generated energy (more than doubling the cost, compared to fully depreciated facilities) [59]. In general, with the increasing wear and tear of the reactor, the risk of unforeseen incidents increases, and therefore, activities in the field of nuclear energy should be accompanied by the availability of an appropriate license confirming the safety of power generating facilities.

It can be said that nuclear energy has some advantages compared to other energy technologies. First of all, a comparatively low energy generation cost with a minimal carbon footprint. Secondly, technology readiness with high technical efficiency. Thirdly, the technological scalability of both smalland large-scale capacities, which may ensure stable and uninterrupted energy generation.

Despite this, there are three key barriers that do not allow a significant expansion of nuclear plant usage. Firstly, the development of nuclear energy generation is associated with the development of nuclear weapons, which is a very negative and destabilizing factor [60].

Secondly, notwithstanding their higher reliability, global history knows examples of man-made catastrophes, which has produced a very adverse effect upon acceptance of the technology. To restore its image, great pains must be taken in terms of marketing and notifying society about the safety measures taken at modern energy generating facilities [61].

Thirdly, one of the most complicated problems is the handling of nuclear waste [62], requiring significant financial costs on the one hand and availability of hi-tech facilities preventing radioactive contamination of the environment on the other.


[3] Valdez-Perez MA, Fernandez-Luqueno F, Franco-Hernandez O. Cultivation of beans (Phaseolus vulgaris) in limed or unlimed wastewater, sludge, vermicompost or inorganic amended soil. Scientia Horticulturae. 2011;128: 380-387. DOI: 10.1016/j.scienta.2011. 01.016

[4] Takahashi K. Physiological disorders in Chinese cabbage. In: Talekar NS, Griggs TD, editors. Chinese Cabbage. Shan Hua, Taiwan: AVRDC; 1981. pp. 225-233

[5] Aminul M, Nasrulhaq A, Motior R, Sofian M, Aqeel M. Effects of organic fertilizers on the growth and yield of bush bean, winged bean and yard long bean. Brazilian Archives of Biology and Technology. 2016;59:1-9. DOI: 10.1590/ 1678-4324-2016160586

[6] Derkowska E, Paszt L, Trzcinsky P, Przibyl M, Weszczak K. Influence of biofertilizers on plant growth and rhizosphere microbiology of greenhouse-grown strawberry cultivars. Acta Scientiarum Polonorum-Hortorum Cultus. 2015;14:83-96

[7] Aluko OA, Olanipekun TO, Olasoji JO, Abiola IO, Adeniyan ON, Olanipekun SO, et al. Effect of organic and inorganic fertilizer on the yield and nutrient composition of jute mallow. Global Journal of Agricultural Research. 2014;2:1-9

[8] Ghimire A. A Review of Organic Farming for Sustainable Agriculture. Tribhuvan University; 2002

crops. Journal of Plant Nutrition. 2010;

DOI: http://dx.doi.org/10.5772/intechopen.86914

Comparative Assessment of Shrimp Hydrolyzates as Alternative Organic Fertilizers for Legumes

[17] Yang R, Su YZ, Wang T, Yang Q. Effect of chemical and organic

fertilization on soil carbon and nitrogen accumulation in a newly cultivated farmland. Journal of Integrative Agriculture. 2016;15:658-666. DOI: 10.1016/S2095-3119(15)61107-8

[18] Swisher ME. An Investigation of the

[19] Celestin NP. Effects of Inorganic and Organic Fertilizers on Nutrient Uptake, Soil Chemical Properties and Crops Performance in Maize Based Cropping Systems in Eastern Province of Rwanda. Kenyatta University; 2013

Potential for the Use of Organic Fertilizer on Small, Mixed Farms in Costa Rica. University of Florida; 1948

[20] Eroa MG. Production and characterization of organic fertilizer from Tubang-Bakod (Jatrophacurcas) seed cake and chicken manure. Asia Pacific Journal of Multidisciplinary

[21] Chavan BL, Vedpathak MM, Pirgonde BR. Effects of organic and chemical fertilizers on cluster bean (Cyamopsis tetragonolobus). European Journal of Experimental Biology. 2015;5:

Research. 2015;3:9-13

34-38

153

33:351-361. DOI: 10.1080/<PHONE_NUMBER>3470406

[9] Cespedes L, Stone MC, Dick RP. Organic soil amendments; impacts on snap bean common root rot and soil quality. Applied Soil Ecology. 2006;31: 199-210. DOI: 10.1016/j.apsoil.2005. 05.008

[10] Association of Official Agricultural Chemists. Method 923.03: Ash of Flour (Direct Method). 2005

[11] Albalasmeh AA, Berhe AA, Ghezzehei TA. A new method for rapid determination of carbohydrate and total carbon concentrations using UV spectrophotometry. Carbohydrate Polymers. 2013;97:253-261. DOI: 10.1016/j.carbpol.2013.04.072

[12] Young JH, Nelson GL. Research of hysteresis between sorption and desorption isotherms of wheat. Transactions of ASAE. 1967;10:756-761

[13] Tucker LC. Comparison of Two Different Organic Fertilizer Sources for Flue-Cured Tobacco. Virginia Polytechnic Institute and State University; 2015

[14] Arthur EM, Tuller PM, de Jonge LW. Evaluation of theoretical and empirical water vapor sorption isotherm models for soils. Water Resources Research. 2016;52:190-205. DOI: 10.1002/2015WR017681

[15] Woodruff WF, Revil A. CECnormalized clay-water sorption isotherm. Water Resources Research. 2011;47:1-15. DOI: 10.1029/ 2011WR010919

[16] Nelson PV, Pitchay DS, Niedziela CE, Mingis NC. Efficacy of soybeanbaseliquid fertilizer for greenhouse

Comparative Assessment of Shrimp Hydrolyzates as Alternative Organic Fertilizers for Legumes DOI: http://dx.doi.org/10.5772/intechopen.86914

crops. Journal of Plant Nutrition. 2010; 33:351-361. DOI: 10.1080/<PHONE_NUMBER>3470406

References

[1] Bassoyouni FA, Abu-Bakr SM, Rehim MA. Evolution of microwave irradiation and its application in green chemistry and biosciences. Research on Chemical Intermediates. 2012;38:283-322. DOI:

Food Preservation and Waste Exploitation

[8] Ghimire A. A Review of Organic Farming for Sustainable Agriculture.

[9] Cespedes L, Stone MC, Dick RP. Organic soil amendments; impacts on snap bean common root rot and soil quality. Applied Soil Ecology. 2006;31: 199-210. DOI: 10.1016/j.apsoil.2005.

[10] Association of Official Agricultural Chemists. Method 923.03: Ash of Flour

Ghezzehei TA. A new method for rapid determination of carbohydrate and total

[12] Young JH, Nelson GL. Research of hysteresis between sorption and desorption isotherms of wheat.

Transactions of ASAE. 1967;10:756-761

[13] Tucker LC. Comparison of Two Different Organic Fertilizer Sources for

[14] Arthur EM, Tuller PM, de Jonge LW. Evaluation of theoretical and empirical water vapor sorption isotherm models for soils. Water Resources Research. 2016;52:190-205. DOI:

[15] Woodruff WF, Revil A. CECnormalized clay-water sorption isotherm. Water Resources Research.

[16] Nelson PV, Pitchay DS, Niedziela CE, Mingis NC. Efficacy of soybeanbaseliquid fertilizer for greenhouse

Flue-Cured Tobacco. Virginia Polytechnic Institute and State

10.1002/2015WR017681

2011;47:1-15. DOI: 10.1029/

2011WR010919

University; 2015

Tribhuvan University; 2002

(Direct Method). 2005

[11] Albalasmeh AA, Berhe AA,

carbon concentrations using UV spectrophotometry. Carbohydrate Polymers. 2013;97:253-261. DOI: 10.1016/j.carbpol.2013.04.072

05.008

[2] Brink M, Belay GE. Plant resources of

10.1007/s11164-011-0348-1

tropical Africa: Conclusions and recommendations based on PROTA 1.

In: Cereals and Pulses. Leiden:

[3] Valdez-Perez MA, Fernandez-Luqueno F, Franco-Hernandez O. Cultivation of beans (Phaseolus vulgaris) in limed or unlimed wastewater, sludge, vermicompost or inorganic amended soil. Scientia Horticulturae. 2011;128: 380-387. DOI: 10.1016/j.scienta.2011.

[4] Takahashi K. Physiological disorders in Chinese cabbage. In: Talekar NS, Griggs TD, editors. Chinese Cabbage. Shan Hua, Taiwan: AVRDC; 1981.

[5] Aminul M, Nasrulhaq A, Motior R, Sofian M, Aqeel M. Effects of organic fertilizers on the growth and yield of bush bean, winged bean and yard long bean. Brazilian Archives of Biology and Technology. 2016;59:1-9. DOI: 10.1590/

[6] Derkowska E, Paszt L, Trzcinsky P, Przibyl M, Weszczak K. Influence of biofertilizers on plant growth and rhizosphere microbiology of

greenhouse-grown strawberry cultivars. Acta Scientiarum Polonorum-Hortorum

[7] Aluko OA, Olanipekun TO, Olasoji

Olanipekun SO, et al. Effect of organic and inorganic fertilizer on the yield and nutrient composition of jute mallow. Global Journal of Agricultural Research.

JO, Abiola IO, Adeniyan ON,

Backhuys; 2006

01.016

pp. 225-233

1678-4324-2016160586

Cultus. 2015;14:83-96

2014;2:1-9

152

[17] Yang R, Su YZ, Wang T, Yang Q. Effect of chemical and organic fertilization on soil carbon and nitrogen accumulation in a newly cultivated farmland. Journal of Integrative Agriculture. 2016;15:658-666. DOI: 10.1016/S2095-3119(15)61107-8

[18] Swisher ME. An Investigation of the Potential for the Use of Organic Fertilizer on Small, Mixed Farms in Costa Rica. University of Florida; 1948

[19] Celestin NP. Effects of Inorganic and Organic Fertilizers on Nutrient Uptake, Soil Chemical Properties and Crops Performance in Maize Based Cropping Systems in Eastern Province of Rwanda. Kenyatta University; 2013

[20] Eroa MG. Production and characterization of organic fertilizer from Tubang-Bakod (Jatrophacurcas) seed cake and chicken manure. Asia Pacific Journal of Multidisciplinary Research. 2015;3:9-13

[21] Chavan BL, Vedpathak MM, Pirgonde BR. Effects of organic and chemical fertilizers on cluster bean (Cyamopsis tetragonolobus). European Journal of Experimental Biology. 2015;5: 34-38

**155**

**Chapter 8**

**Abstract**

*and Younes Moussaoui*

made from soda-HP pulping process.

fibrous suspension, pulping

**1. Introduction**

Cellulosic Fibers from

Lignocellulosic Biomass for

This chapter gives a brief overview of the cellulose extraction from Opuntia (Cactaceae) fibers. The suitability of this food waste for pulp and paper production was investigated by the determination of the chemical composition and testing two procedures of delignification: chemical and semichemical pulping processes. Chemical pulping procedure was carried out by using soda-anthraquinone (soda-AQ ) mixture, and semichemical pulping process was performed by softening the raw material using soda-hydrogen peroxide (soda-HP) mixture; this operation was followed by mechanical grinding. The obtained fibrous suspensions were characterized by measuring their dimension parameters (fiber length, fiber width, and fine elements), polymerization degree, and their retention water capacity. The effect of pulping process on yield and fiber characteristics in each pulp was studied. The surface morphologies of the produced papers were studied using scanning electron microscope (SEM), and results show the good distribution and individuality of fibers. The structural and mechanical properties of the prepared paper were presented and discussed. Mechanical strength results show the good tenacity of papers

**Keywords:** *Opuntia ficus-indica*, food waste, lignocellulosic fibers, deliberate fibers,

*Opuntia ficus-indica* is a xerophyte plant belonging to the Cactaceae family, well adapted to drought conditions thanks to its succulent nature that allows it to store extraordinary quantities of water [1]. *Opuntia ficus-indica* was used in traditional medicine for therapeutic, cosmetic, anticarcinogenic, anti-inflammatory, antioxidant, antiviral, and antidiabetic goods [2–4]. Thereby, *Opuntia ficus-indica* waste has received significant attention from numerous researches and was investigated because of its important chemical composition which has a high nutritional value, mainly due to their mineral, protein, dietary fiber, and phytochemical contents [4–9]. By-products of *Opuntia ficus-indica* were used by Bensadon et al. [4] as a source of good-quality antioxidant dietary fiber. Furthermore, *Opuntia ficusindica* cladodes have interesting medical antioxidant activity [10, 11]. Likewise, methanol extract of *Opuntia ficus-indica* flowers has an anti-inflammatory effect on

Papermaking Applications

*Faten Mannai, Hanedi Elhleli, Ramzi Khiari*

#### **Chapter 8**


**2. The Ampferer-type subduction: convergence and assembly of the previously rifted lithosphere**

Ampferer-type subduction occurs only at passive continental margins that hyperextend into rift basins, often accompanied by exhumation of the (subcontinental) mantle and may reach the stage of (magma-poor) embryonic oceans [7]. Such an embryonic basin-margin system is likely to be more laterally homogeneous than ocean basins, which contain significant spreading ridges. Under these conditions, the mechanical weakness of the serpentinized mantle and the hyper-thinned continental lithosphere serve as focal points for the initiation of convergence and downward thrusting of these basins beneath passive continental boundaries [7, 30–32]. The main features for recognizing Ampferer-type subductions are (i) coherent structural units or nappes (flake tectonics) transported over long distances modified by moderate deformation and comprising the (ultra-) high-pressure continental and oceanic fragments and (ii) the lack of Penrose-type oceanic crustal fragments [7, 38]. The Ampferer-type subductions instead comprise fragments of basins flooded by exhumed subcontinental mantle, like the magma-poor Iberia-Newfoundland oceancontinent transition zones (OCTs) [39–41].


**2. Methodology of meta-analysis**

The results of a single study can be influenced by characteristics of the study setting, the sampled population, timing, locations and the subjective bias of the researchers. Causal factors of certain effects can only be unearthed by a synthesis of multiple studies rather than a single study. Some general trends and underlying principles can only be deduced across a large body of case studies or empirical studies. Therefore, since its very beginning, the methodology of meta-analysis is expected to be such a solution to synthesize amount of studies and get to the essences of problems with as least as possible bias.

Beecher (1995) undertook the earliest example of a meta-analysis and Glass (1976) coined the term "meta-analysis" to refer to a philosophy, not a statistical technique. The meta-analysis method began as a statistical procedure for combining and comparing research findings from different studies focusing on similar phenomena (Nijkamp and Pepping 1997-98), and a variety of meta-analytical methods have been developed in the past decades(Nijkamp 1999).

In some studies, "meta-analysis", "meta-synthesis", "synthesis review", and some other terms, are not distinguished clearly, but there are uses of the technique in various research fields. While some researchers refer to the term "meta-analysis" as the quantitative integration and analysis of the findings from all empirical studies relevant to an issue and amenable to quantitative aggregation (Glass 1976), most treat the terms "literature review", "synthesis review", "synthesis analysis" and "meta-analysis" as equivalent. Also some researchers separate "meta-summary" and "meta-synthesis". For example, in study of Sandolowski and Barroso (2003) in the field of nursing, the qualitative meta-summary is explained as involving the extraction and further abstraction of findings, and the calculation of manifest frequency effect sizes while meta-synthesis is an interpretive integration of qualitative findings that are themselves interpretive syntheses of data, including the phenomenologies, ethnographies, grounded theories, and other integrated and coherent descriptions or explanations of phenomena, events, or cases that are the hallmarks of qualitative research. (Sandelowski and Barroso 2003).

Here the definition of "meta-analysis" is simply taken as the general term of all the different nominal meta-methods, as "…an analytical framework for comparative research that aims to draw inferences on common issues with different but allied empirical backgrounds" (Matarazzo and Nijkamp 1997).

Meta-analysis has now become a widely accepted research tool, encompassing a range of procedures used in a variety of disciplines, such as medicine, nursing, psychology, labor economics, environmental science, and transportation science (Gaarder 2002; Yu 2002; Greenaway, Milne et al. 2004; Travisi, Florax et al. 2004). The wide employment of metaanalysis is partially because that it is an integration which is more than the sum of parts in that it offers novel interpretations of findings(Sandelowski and Barroso 2003). In the study of Sandolowski and Barroso(2003), they found that this kind of interpretations will not be found in any single report, but rather are inferences derived from taking all of the reports in a sample as a whole. Their validity does not reside in replication logic, but rather in inclusive logic whereby all findings are accommodated and in the craftsmanship exhibited in the final product(Sandelowski and Barroso 2003).

Under the Meta-analysis framework, appropriate methods can be selected according to different research questions. Commonly used methods include the counting method, classical Meta-analysis method, Meta-analysis on effectiveness, homogeneity testing and other methods.

1. Vote-counting

128 Sociological Landscape – Theories, Realities and Trends

Therefore, the rationale of this study is promoted by factors on both sides of methodology

• What are the pivotal methodological issues of the qualitative meta-analysis when applied? With the development of more than three decades, various frameworks have been brought out for the application of meta-analysis. Although it is widely accepted that with the basic principles, the techniques could be different according to characteristics of research fields, there are still problems of relative uncertainty. The aim of methodological is to discuss these pivotal issues with the vulnerability research as an

• What are the key driving causes to the vulnerability to natural hazards? Compared with the increase in the number of advanced research on vulnerability, in the real world people are still suffering from rising vulnerability to natural hazards. Especially with the shocks from 2004 tsunami, 2005 and 2007 hurricanes, the coastal hazards came to the attention focus. With the application of meta-analysis, the aim of research is to recognize the key factors contributing to vulnerability, and synthesize the driving

To achieve the above aims, this paper applies meta-analysis in the qualitative studies with the context of the vulnerability research questions. In the second section, the methodology of meta-analysis is introduced; in the third section, the findings of the application of metaanalysis in vulnerability research are presented; finally, in the forth section, there are the

The results of a single study can be influenced by characteristics of the study setting, the sampled population, timing, locations and the subjective bias of the researchers. Causal factors of certain effects can only be unearthed by a synthesis of multiple studies rather than a single study. Some general trends and underlying principles can only be deduced across a large body of case studies or empirical studies. Therefore, since its very beginning, the methodology of meta-analysis is expected to be such a solution to synthesize amount of

Beecher (1995) undertook the earliest example of a meta-analysis and Glass (1976) coined the term "meta-analysis" to refer to a philosophy, not a statistical technique. The meta-analysis method began as a statistical procedure for combining and comparing research findings from different studies focusing on similar phenomena (Nijkamp and Pepping 1997-98), and a variety of meta-analytical methods have been developed in the past decades(Nijkamp 1999). In some studies, "meta-analysis", "meta-synthesis", "synthesis review", and some other terms, are not distinguished clearly, but there are uses of the technique in various research fields. While some researchers refer to the term "meta-analysis" as the quantitative integration and analysis of the findings from all empirical studies relevant to an issue and amenable to quantitative aggregation (Glass 1976), most treat the terms "literature review", "synthesis review", "synthesis analysis" and "meta-analysis" as equivalent. Also some researchers separate "meta-summary" and "meta-synthesis". For example, in study of Sandolowski and Barroso (2003) in the field of nursing, the qualitative meta-summary is explained as involving the extraction and further abstraction of findings, and the calculation

discussions on both the vulnerability and the implementation of meta-analysis itself.

studies and get to the essences of problems with as least as possible bias.

and research question:

applied case.

relationship between these factors.

**2. Methodology of meta-analysis**

This approach is similar to the narrative review, which divides the results of previous researches into three groups of significant positive results, significant negative results, and non-significant results. The result of the group with most literature number then represents the entire field of study. This method is relatively simple to determine the general trend of a large number of case studies. However, this is an inaccurate statistics which relies on the statistical significance. Also each individual study is limited by the collection of samples, so the final results of vote-counting do not necessarily reflect the true situation.

2. Classic or Glassian Meta-analysis

This approach evolves from the early Glass Meta-analysis. It defines research questions first, then collects case studies, followed by encoding the outputs of each features, and finally analyzes the relationship between the output values and the study characteristics. This method of Meta-analysis and its subsequent improved methods have three common characteristics: First, the selection criteria of literature is liberal, generally based on the research needs. Second, the units of analysis are the results of each single studies, and through selecting the appropriate sample size (ie, the number of literature)**,** the comparative analysis is taken. Third, Meta-analysis methods usually weaken the characteristics of each individual study, and present the overall average characteristics instead.

A Meta-Analysis Framework and

comprises seven steps:

strategy);

data(Sandelowski and Barroso 2003).

1. Formulation of the research questions;

analysis steps is shown in figure 1.

3. Analysis and synthesis of the theories (meta-theory); 4. Identification of an analytic strategy (meta-analysis); 5. Analysis of the methods in collected cases (meta-method); 6. Synthesis of the outputs of the above processes (meta-synthesis);

analysis level and implementation level(Matarazzo and Nijkamp 1997).

Fig. 1. The levels and corresponding steps of a meta-analysis

7. Presentation and dissemination of the findings.

Its Application for Exploring the Driving Causes to Social Vulnerability 131

Generally, Meta-analysis methods include constant comparison, taxonomic analysis, the reciprocal translation of in vivo concepts, and the use of imported concepts to frame

The mata-analysis requires the establishment of an analytic strategy and coding system to categorize data and to interpret findings in relation to predefined research questions. According to Glasmeier and Farrigan (2005) the synthesis process on qualitative research

2. Selection and appraisal of primary research (development of a literature search

The process of meta-analysis is not a linear process. 3), 4) and 5) are parallel steps that focus on different aspects of theories, contents and methodologies. Also, the various steps overlap and are circular. The development of the coding system continues throughout all stages, in order to substantiate the process and make sure that all important information is included. In this way, the coding system can be modified, revised and supplemented according to the concrete cases. Also Matarazzo and Nijkamp (1997) present the meta-study as six different "levels", each of which assumes a particular importance from a methodological point of vview. The levels are named real-world level, study level, pre-meta-analysis level, study selection level, meta-

Combining the different steps and the levels together, meta-analysis is essentially a kind of "mining" or "emerging" of integrated findings. An integrated map of undertaking meta-

Practice has proved that the classic Meta-analysis in many areas has good applicability, and is considered as "research on research" (Greenaway, Milne et al. 2004). However, this classical method has some weaknesses. The most obvious one is that because this method averages all case studies, and the differences between the various studies are ignored. Therefore the reliability of the analysis results is very susceptible to those flawed researches. In addition, if a single case study has a large sample size, it is possible that the weight given to this study is relatively large, which affects the results of the analysis.

3. Study effect meta-analysis

This method of Meta-analysis improves the classical methods on two aspects. First, the literature becomes more selective, excluding case studies which have defects in the methods and probably mislead the analysis results. Second, the method takes each individual study as the unit of analysis, rather than the results of each individual study. Thus, in essence, each individual research is given the same weight, and the results of the Meta-analysis will not be affected by sample size. However, this method will directly reduce the amount of data involved in the analysis, also the subjectivity of the researchers possibly affects the research.

4. Tests of homogeneity

The idea of homogeneity testing originated from pattern recognition. Some scholars believe that the traditional statistical test method is not suitable for Meta-analysis. The effective sample size is affected by many factors: the reliability of measurement, sampling limits, reporting errors of data processing, unreported factors, etc. Homogeneity test can effectively distinguish the nuances in different samples. If the homogeneity test is significant for a group of researches, it can be deduced that this group of researches belongs to one category. With this method, people can classified the collected large number of empirical studies, figuring out the similar characteristics of each category.

A variety of Meta-analysis methods has long been used in research field of laboratory medicine, clinical medicine and behavioral science. There are also applications in experimental or quasi-experimental studies in the economic environment (Travisi, Florax et al. 2004). For example, a New Zealand government-funded research built a framework for future implementation of very effective guidelines drawn from the Meta-analysis of 10 government aided community projects (Greenaway, Milne et al. 2004). In recent years, Meta-analysis methods began to be used in the environment and climate change related researches.


**9. Connexins**

112 Cancer Prevention – From Mechanisms to Translational Benefits

A good example is the study of the proteins of the methyl-CpG-binding domain (MBD) that "read" and interpret the signals in DNA methylation and are critical mediators of various epigenetic processes. We currently know that the family of MBD proteins is formed by five MBD1 and MeCP2 -4 members. There is also a member of non-classical MBD protein called Kaiso that uses a "zinc finger" domain to bind to methylated DNA and mediate transcriptional repression. The factor Kaiso and its partner p120ctn are considered similar to the β-catenin-TCF/LEF (T-cell factor / Lymphoid Enhancing factor) pair that regulate genes of canonical Wnt pathways, with the peculiarity that Kaiso (the difference in TCF/LEF) can interact with the epigenome in cancer development. As usually, hypermethylation is a recognized gene silencing mechanism in processes of tumorigenesis and drug resistance. Obviously, the MBD protein and Kaiso could be important modulators of tumorigenesis and excellent therapeutic targets for developing anti-cancer therapies (Sansom et el., 2007). Therefore, the role of protein detection methods in the diagnosis, prognosis and even in the development of therapies against cancer is unquestionable in the current epigenetic scenery

**7. The multifunctional protein and its relation to cellular compartments**

A single protein can have different functions in a cell and these functions concern the compartment where they are located. One of the best documented examples is that transglutaminase 2 (TG2) may act as a transglutaminase, G-protein kinase, protein disulfide isomerase or as an adapter protein. These multiple biochemical activities are involved in a wide variety of cellular processes such as differentiation, cell death, inflammation, cell migration and others. The specific microhabitats and subcellular compartments of location of the plasma membrane, cytoplasm, nucleus, mitochondria, or extracellular space are important in the development of different biochemical activities by the same protein

Thus, in our search for a drug target, e.g., cancer, we must always know the location of a given protein in the cell and be aware of how this cell places these proteins in different micro environments, and that more often than not these different functions may occur simultaneously. So part of the strategy to find the correct pharmacological targets is the previous understanding of the structure and the establishment of subcellular microenvironments inside the cells and the better knowledge of the complex and dynamic

Therefore, immunohistochemistry provides information that cannot be obtained in any other way, which is the relationship between the pathological state and the dimension of the altered compartment (Oliver and Jamur, 2009; Dabbs, 2010), of great relevance to the

Surprisingly, over the past few decades multifunctional proteins provided the basis of the study of some diseases, including cancer. Alterations and aberrations of the multifunctional proteins regarding their distribution and subcellular localization have been used to diagnose the pathological state. I will consider briefly connexins, β-catenin and kaiso as examples of

subcellular compartmentalization that will be further explained.

**8. The multifunctional proteins, compartments and cancer**

establishment of the cancer diagnosis, as we shall see soon.

these proteins and their role in cancer development.

of disease etiology (Yoshimura et al., 2011).

structure (Park et al., 2010).

Connexins can be channels of intercellular communication or proteins that trigger processes of proliferation or apoptosis, depending on the cellular context (Goodenough & Paul, 2003).

Traditionally, it was believed that the role of connexins in cancer development was related to its role in intercellular communication channel or gap junctional intercellular communication activity (GJIC). In fact, cancer was the first disease to be associated with connexin disorders (Loewenstein, 1979). The evidence was mainly related to the use of tumor-promoting agents (non-mutagenic carcinogens) and mitogens that decreased the activity of connexin-mediated intercellular communication (Budunova & Williams, 1994) and, on the other hand, antineoplastic agents or chemicals promoting cell coupling through these proteins (King & Bertram, 2005). It was also shown that tumor-derived cells were deficient in expression of connexins (Lee et al., 1992; Laird et al., 1999) and that studies of overexpression of these proteins showed decrease in cellular proliferation (Yamasaki & Naus, 1996). This created a favorable scenario that could lead one to believe that the decrease in expression of connexins and, thus, intercellular communication, was related to cell proliferation and tumor progression.

The most important work on the change in concepts regarding these channels of communication was the transfection of connexin43 that makes it possible reversing the neoplastic phenotype of a strain of human glioblastoma cells and that showed that phenotypic reversion was associated with a cytoplasmic localization of connexins without increasing the ability to establish intercellular communication between cells (Huang et al, 1998). Therefore, a new concept has arisen, according to which connexins could have two different functions not necessarily connected: (i) intercellular communication in the plasma membrane and (ii) direct modulation of cell growth control in cell cytoplasm.

Concerning the connexin role in regulating cell proliferation, two hypotheses have been developed: 1) a downregulation of connexins from the plasma membrane is an indirect result of the activation of MAPK (mitogen-activated protein kinase) and Akt (phosphoinositide-activated kinase) and 2) they act as negative regulators of intercellular junctions (Kojima et al., 2004). However, other lines of evidence indicated that the connexins were directly involved in the regulation of cell growth and that its downregulation would contribute to (and not be a consequence of) the loss of cell cycle control (Vinken et al., 2006).

A detailed study supporting this latter idea used transfection of connexin 43 in human osteosarcoma cells, which inhibited cell proliferation without restoring intercellular communication (Zhang et al., 2001). In this model direct connexin 43 changes the expression of p27/Kip1 (the cyclin-dependent kinase inhibitor). Importantly, Cx43, or at least the carboxy terminal tail of this protein has been localized within the nucleus with the use of immunohistochemistry, confirming an intracellular regulatory role (Dang et al., 2003; Cofre & Abdelhay, 2007).

In primary breast tumors, immunohistochemistry can clearly detect the cytoplasmic expression of connexins 43 and 26, being a commonly used diagnostic test for this stage of the disease (Kanczuga-koda et al., 2006). However, immunohistochemistry shows that in the same metastatic tumor cells taken from the lymph node, the expression of connexin43 and 26 changes and has now expanded, though in the plasma membrane. This increased expression in the cell membrane is considered the earliest event in the process of metastasis

Kaiso and Prognosis of Cancer in the Current Epigenetic Paradigm 115

shall see later, this classical interpretation may change when additional information on

In clinical practice aberrant changes in the expression of β-catenin in the nucleus have made it possible to suggest the use of this molecule as a complement to the differential diagnosis of various cancers, including cancers of the gastrointestinal tract, lung and tumors of gynecological origin (Montgomery & Folpe, 2005). Also, the absence or loss of nuclear expression of β-catenin expression associated with strong cytoplasmic P-cadherin was associated with melanoma aggressiveness and poor patient survival, establishing an important prognostic value in these types of cancer for β-catenin (Bachmann et al., 2005).

Fig. 1. Canonical and non-canonical Wnt signaling pathway. Crosstalk between Kaiso, Kaiso–p120ctn, β-catenin and Endossomal compartments. a. In the absence of Wnt ligands or in the case of high E-cadherin concentrations, β-catenin and p120ctn associate with E-

macromolecular complex formed by the cytoplasmic protein APC (adenomatous polyposis coli), Axin and disheveled (DSH) stimulate the phosphorylation of β-catenin. Directly responsible for this phosphorylation is the protein casein kinase 1 (CK1) and glycogen synthase kinase 3 (GSK3). Β-catenin phosphorylated is destined to a ubiquitin-mediated degradation of β-catenin. c. The activation of canonical pathway leads to stabilization of β catenin. Therefore, Wnt signaling would finally prevent β-catenin degradation, which could then (d.) translocate to the nucleus, and perform its transcriptional activity, associate with lymphoid enhancer-binding protein (LEF)/T-cell factor (TCF). e. If E-cadherin is mutated or

cadherin, promoting intercellular adhesion. b. In the absence of Wnt binding, a

subcellular compartmentalization is gained.

(Kanczuga-koda et al., 2006). The important diagnostic value of IMH is evident in the resolution stage of the disease.

Although the role of connexins in the process of metastasis is controversial because some studies indicate that connexin expression is inversely proportional to metastatic capacity of a primary tumor (Nicolson et al., 1988), other studies reveal that connexins might be involved in metastasis (Carystinos et al., 2001).

At least it is clear that, unlike previously thought, connexins have a tumor suppressor function, but not from a classical point of view, since there are no mutations of this protein associated with carcinogenesis. So, they seem to have different effects on different stages of carcinogenesis, (depending on the connexin isoform or cell type in which it is expressed). Connexins seem to favor cell proliferation when they are downregulated (cytoplasmic localization) and increase the potential for invasion and metastasis when they are overexpressed (initially in the plasma membrane) (for a review of this literature sees Crespin et al., 2008). As we shall see at the end of this chapter, this issue needs to be clarified for a better understanding of subcellular compartmentalization and mechanisms of regulation of intracellular signaling.


**5. Conclusions**

In this study, taking the geometric characteristic size into consideration, samples consisting of solid struts with different section characteristic sizes (0.4 to 1.4 mm) were fabricated by selective laser melting with three scan speeds (700, 1300, and 1900 mm/s). The morphology features, relative density, microstructure, and mechanical properties were measured and a simple thermal model was presented to systematically explain the effect of geometric characteristic size under different scan speed conditions. The following was determined:

(1) The geometric characteristic size influenced the physical characteristics of the LPBF-produced struts by affecting the cooling condition. A small geometric characteristic size resulted in a poor cooling condition. The effect may only become obvious when the geometric characteristic size is small (<1 mm).

(2) The relative density of the solid strut with an *L*s value of 0.4 mm reached the highest value of 96.8% when the *v* was 1900 mm/s, but the relative density of the solid strut with an *L*s value of 1.4 mm reached the highest value of 98.1% when the *v* was 1300 mm/s. The solid strut with smaller geometric characteristic size had a more obvious size error. To a certain degree, the nanohardness and elastic modulus increased with increasing scan speed, and decreased with the decline of the geometric characteristic size when the geometric characteristic size was smaller than 1 mm.

(3) In contrast to the solid bulk forming process, for a superior forming quality, a higher scan speed should be set for the LPBF-manufacturing of porous structures, especially for structures with small geometric characteristic size in solid struts.

**Author Contributions:** Experiment design and writing, H.L. and D.X.; data analysis of μCT, Y.M.; data analysis of microstructure and nanoindentation, J.S. and C.W.; writing—review and editing, L.S. and Z.T.

**Funding:** This research was funded by the Advanced Research Project of Army Equipment Development (301020803), the Key Research and Development Program of Jiangsu (BE 2015161), the Young Scientists Fund of the National Natural Science Foundation of China (51605473), the Jiangsu Provincial Research Foundation for Basic Research, China (BK 20161476), the Science and Technology Planning Project of Jiangsu Province of China (BE 2015029) and the Science and Technology Support Program of Jiangsu (BE 2014009-1, BE 2014009-2, BE 2016010-3).

**Conflicts of Interest:** The authors declare no conflicts of interest.


• **Exogeneity**

Based on Pearson correlation matrix, the fluctuation of HML, CRHML, and AMLH depend upon the history data of other factors. For details, HML is related to the AMLH of last term. CRHML has a small correlation with HML AMLH bridge its relationships with RMW of last term. Finally, with respect to Rm-Rf, its volatility is partly connected to last term's RMW and AMLH.

Figure 7 summarizes the endogeneity and exogeneity for predicting direction of seven risk factors. In the chi-square test, RMW, SMB, and CMA factor can be only predicted by the last term direction of themselves. With confidence level of 95%, CRHML's direction can forecasted by its history data with HML and the increase and decrease of HML can be predicted by last term direction and AMLH at 90% confidence level. For market factor (Rm-Rf)—even if single stock history data cannot predict next term—with RMW and AMLH, market factor can estimate the direction of its next term with 95% confidence. With a confidence level of 90%, AMLH's fluctuation direction can forecast by RMW. The details of prediction are presented in Appendix D.

**Figure 7.** Summary of endogeneity and exogeneity for predicting direction of seven risk factors.

### 4.2.2. Trading Strategy with Trend Analysis

In the last two parts, with the examination of chi-square test, the directions of fluctuation of seven factors are predictable, yet the range of fluctuation is still unknown.

Therefore, in order to forecast the positive and negative levels of each risk factor, trend analysis is conducted.

The above seven graphs in Figure 8 describe the trend of each factor. The orange line is the four-season moving average. SMB, HML, and CMA are mostly below 0. By contrast, RMW and CRMHL are above 0. While AMLH and Rm-Rf fluctuate around 0.4.

**Figure 8.** Four seasons moving average of seven factors.