**Vividness, Consciousness, and Mental Imagery**

**Making the Missing Links across Disciplines and Methods**

Editor

**Amedeo D'Angiulli**

MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade • Manchester • Tokyo • Cluj • Tianjin

*Editor* Amedeo D'Angiulli Carleton University Canada

*Editorial Office* MDPI St. Alban-Anlage 66 4052 Basel, Switzerland

This is a reprint of articles from the Special Issue published online in the open access journal *Brain Sciences* (ISSN 2076-3425) (available at: https://www.mdpi.com/journal/brainsci/special issues/Vividness Consciousness Imagery).

For citation purposes, cite each article independently as indicated on the article page online and as indicated below:

LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. *Journal Name* **Year**, *Volume Number*, Page Range.

**ISBN 978-3-0365-0412-4 (Hbk) ISBN 978-3-0365-0413-1 (PDF)**

© 2021 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications.

The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND.


**6. miRNAs in response to commonly used chemotherapy agents in pediatric acute lymphoblastic leukemia**

Despite the great effort of current treatment strategies, drug resistance still remains a major cause of chemotherapy failure and relapse in pediatric patients.

**63**

*miRNAs in Acute Lymphoblastic Leukemia: Diagnosis, Prognosis and Target Therapeutic*

miRNAs have not only become tools for classifying subtypes of ALL and in support of the prognosis of this disease, but also studies have reported the classification of patients sensitive or resistant to drugs based on the expression of

Glucocorticoids (GCs) regulate proliferation, differentiation, metabolism, and cell survival in many tissues. In lymphocytes, they affect cell cycle progression, influence immunoglobulin and lymphokine production, and induce apoptosis in immature lymphoblasts [67]. Actually, these drugs are used clinically in the treatment of childhood acute lymphoblastic leukemia (ALL) and other lymphoid malignancies. In the group of glucocorticoids that is administered to patients with ALL is the prednisone; unfortunately, a proportion of patients are insensitive to this drug. A study in 49 ALL patients showed that miR-18a, miR-532, miR-218, miR-625, miR-193a, miR-638, miR-550, and miR-633 could distinguish prednisone-sensitive patients from prednisone-insensitive patients [68]. In contrast, other authors in a group of 81 children with newly diagnosed ALL, no discriminative microRNAs were

It is well known that the presence of translocations in ALL is a frequent and prognostic influence event. In leukemia, MLL rearrangements are a common genetic alteration; MLL-AF4 acute lymphocytic leukemia (ALL), resulting from a balanced translocation between *MLL* and *AF4,* occurs in approximately 50% of ALL cases in infants, 2% in children, and 5–6% in adults. The poor prognosis of MLL-AF4 ALL to glucocorticoid-induced apoptosis is associated with its resistance to this drug [70]. miR-128b and miR-221 are commonly downregulated in MLL-rearranged ALL compared with other types of ALL; also these miRNAs downregulate mRNAs encoding CDKN1B, MLL, AF4, and both MLL-AF4 and AF4-MLL fusion genes that are thought to contribute to leukemia development [71]. Interestingly, the restoration of miRNA-128b downregulates target genes including *MLL*, *AF4*, and both *MLL-AF4* and *AF4-MLL* fusion oncogenes, and the restoration of miRNA-221 downregulates CDKN1B cooperatively. Thus, the sensitivity of MLL-AF4 ALL cells to GCs is strengthened [71]. Study developed by Kotani et al. supports the idea that restoration of miRNA-128b improves the sensitivity of MLL-AF4 ALL cells to GCs. This author mentioned that one novel mutation of miRNA-128b significantly reduced its processing, and the resultant downregulation of mature miRNA-128b gave rise to GCs resistance due to the failure to downregulate the fusion oncogenes [72]. This suggests that miRNA-128b and miRNA-221

Other microRNAs related with drug resistance in pediatric acute lymphoblastic leukemia are miR-454, which present a low expression in L-asparaginase-resistant cases, whereas miR-125b, miR-99a, and miR-100 show an upregulation of their

expression in patients resistant to vincristine and daunorubicin [69].

**7. miRNAs as therapeutic targets in acute lymphoblastic leukemia**

Nowadays, advances in our understanding of the molecular carcinogenesis of the human cancers and the extensive research on generate and implement new combined and targeted therapies, and have allowed to know specific molecular therapeutic targets. However, there is still a continuous need for development of

RNA molecules actually are the therapeutic targets promising in the molecular

oncology. The ability of miRNAs to regulate important cellular processes, by concurrently regulating multiple targets, their inherent role in carcinogenesis as oncogenes or tumor suppressor genes, and the aberrant dysregulation of their

*DOI: http://dx.doi.org/10.5772/intechopen.84318*

found for prednisolone response [69].

could be GC (dexamethasone) sensitizers potential.

new therapeutic tools for applicability.

miRNAs.

*miRNAs in Acute Lymphoblastic Leukemia: Diagnosis, Prognosis and Target Therapeutic DOI: http://dx.doi.org/10.5772/intechopen.84318*

miRNAs have not only become tools for classifying subtypes of ALL and in support of the prognosis of this disease, but also studies have reported the classification of patients sensitive or resistant to drugs based on the expression of miRNAs.

Glucocorticoids (GCs) regulate proliferation, differentiation, metabolism, and cell survival in many tissues. In lymphocytes, they affect cell cycle progression, influence immunoglobulin and lymphokine production, and induce apoptosis in immature lymphoblasts [67]. Actually, these drugs are used clinically in the treatment of childhood acute lymphoblastic leukemia (ALL) and other lymphoid malignancies. In the group of glucocorticoids that is administered to patients with ALL is the prednisone; unfortunately, a proportion of patients are insensitive to this drug. A study in 49 ALL patients showed that miR-18a, miR-532, miR-218, miR-625, miR-193a, miR-638, miR-550, and miR-633 could distinguish prednisone-sensitive patients from prednisone-insensitive patients [68]. In contrast, other authors in a group of 81 children with newly diagnosed ALL, no discriminative microRNAs were found for prednisolone response [69].

It is well known that the presence of translocations in ALL is a frequent and prognostic influence event. In leukemia, MLL rearrangements are a common genetic alteration; MLL-AF4 acute lymphocytic leukemia (ALL), resulting from a balanced translocation between *MLL* and *AF4,* occurs in approximately 50% of ALL cases in infants, 2% in children, and 5–6% in adults. The poor prognosis of MLL-AF4 ALL to glucocorticoid-induced apoptosis is associated with its resistance to this drug [70]. miR-128b and miR-221 are commonly downregulated in MLL-rearranged ALL compared with other types of ALL; also these miRNAs downregulate mRNAs encoding CDKN1B, MLL, AF4, and both MLL-AF4 and AF4-MLL fusion genes that are thought to contribute to leukemia development [71]. Interestingly, the restoration of miRNA-128b downregulates target genes including *MLL*, *AF4*, and both *MLL-AF4* and *AF4-MLL* fusion oncogenes, and the restoration of miRNA-221 downregulates CDKN1B cooperatively. Thus, the sensitivity of MLL-AF4 ALL cells to GCs is strengthened [71]. Study developed by Kotani et al. supports the idea that restoration of miRNA-128b improves the sensitivity of MLL-AF4 ALL cells to GCs. This author mentioned that one novel mutation of miRNA-128b significantly reduced its processing, and the resultant downregulation of mature miRNA-128b gave rise to GCs resistance due to the failure to downregulate the fusion oncogenes [72]. This suggests that miRNA-128b and miRNA-221 could be GC (dexamethasone) sensitizers potential.

Other microRNAs related with drug resistance in pediatric acute lymphoblastic leukemia are miR-454, which present a low expression in L-asparaginase-resistant cases, whereas miR-125b, miR-99a, and miR-100 show an upregulation of their expression in patients resistant to vincristine and daunorubicin [69].


*Edited by Farzad Ebrahimi*

This book is a result of contributions of experts from international scientific community working in different aspects of piezoelectric materials and devices through original and innovative research studies. Through its 7 chapters the reader will have access to works related to the various applications of piezoelectric materials such as piezoelectric stacks in level sensors, pressure sensors, actuators for functionally graded plates, active and passive health monitoring systems, machining processes, nondestructive testing of aeronautical structures and acoustic wave velocity measurements. The text is addressed not only to researchers, but also to professional engineers, students and other experts in a variety of disciplines, both academic and industrial seeking to gain a better understanding of what has been done in the field recently, and what kind of open problems are in this area.

ISBN 978-953-51-1045-3

Piezoelectric Materials and Devices - Practice and Applications

Photo by MegaV0lt / iStock


*Proxemics*

*Types of Nonverbal Communication*

ability of their talking way [17].

research [25].

them to learning [17, 25].

which one gets in touch becomes essential.

*Expressions*

differences and personal social status, has a particularly important role during starting language development. Children, when using gestures when they are not yet able to produce word and combining words and gestures when their repertoires are still limited, increase their communicative potential and communicate over the

Up to 3 years infants do not combine gestures with words, then they arrive to a turning point in which they start to combine them and synchronise le production of gestures and words. The start of this combination, in correspondence of kindergarten, announces a new linguistic developing phase of children and expands notably the range of their communicative systems. These characteristics of semantic integration and temporal sync, characterise the relationship between gesture and language even in adults. In fact, children from 3 years use gestures like adults [26]. As for adults, even for children, the use of gestures during a speech supports the collection of information from the memory and it lightens, by acting as an instrument, the charge of cognitive work of vocal process, by facilitating the lexical

In addition, Goldin-Meadow, Cook and Mitchell's 2009 research, showed a strong relation between gesture learning: in fact, the use of gestures helps children learning, therefore, the teacher has to stimulate it. For example, Clark et al., in 1974, showed that indicative gestures of adult speakers have helped understanding adults speech. Tfouni and Klatzky, in 1983, discovered that indicative gestures help children understanding the meaning of deictic words as, for example, "this". In 2008, McGregor reported a series of studies that show that hand gestures used in communication adult-child have been functional for the acquisition of an early vocabulary. Gesturing, by students, increases their implicit knowledge and prepares

As already said, gestures can be more or less conventional, but every child is different, so it is important to pass time with him to learn his gestures and meanings. It is fundamental, during Primary school, to promote the transition from the dimension of spontaneous expression to that of intentional gestural communication [1].

Smile is one of the first mechanisms of social intelligence that is developed by children, to the point that 90% of infants has already smiled during the first two months of life. When one relates to such young subjects, a smile can reduce many barriers during the communication; a smile is also able to create a comfortable situation, that "connects" the subjects, provides and opens the communication channels. This aspect has strong cultural roots; therefore, the essence and intensity of children smiles varies according to the sociality and the culture to which they belong [16]: as a matter of fact, in the same occasions we smile neither in the same way nor with the same frequency. At first, children find it easy to smile and laugh, but their culture can inhibit their spontaneity, especially in girls, insisting on the fact that a woman should be introverted and reserved with advancing age. To the boys, on the other hand, could be taught to hide their feelings, as a sign of masculinity, with the result that, besides the tears, they will inhibit also a smile or a laugh*.* Ultimately, it seems that a child inherits a raw action, and then refines it with social experience. A person who belongs to an expansive culture could judge insincere a smile of another person who belongs to a more reserved culture, when in reality it's just an attenuated form of expression, conveyed by the cultural contest of belonging. In this case, knowing how to be on the specific wavelength of the culture with

Look is linked to the internal emotive component of children: the expression of his own emotions, in fact, supply information on the internal status of the child that, at the same time through look direction (that is eye movement),

**74**

The space is a very important aspect, in fact, since birth are necessary relationships that are built inside an intimate and personal space. But age is an aspect that affects the space use; in fact, a research has shown that from 3 years old to almost 21, personal space increase gradually and constantly. This has been demonstrated both in naturalistic and experimental contexts. However, Proxemics is not influenced only by age, but also by cultural, familiar and gender differences [11]. The teacher, in fact, has to try to establish physical contact with his/her students, but respecting times and modality of each one of them; if not he/she risks to invade the student personal space by creating inconveniences and negative reactions, that affect the relation and the development of the child.

Throughout history, experts have succeeded in formulate various strategies to try to improve non-verbal communication in children, included those with disabilities. For example, children, especially those with ASD, often need to be taught about eye contact or to hold body contact. Eye contact can be stimulated and taught by holding objects, that they draw their attention, in front of own eyes; as time goes by, ASD individual will look up independently, when he/she chase something.

These strategies are important because, first of all, allowing all of them to learn how to communicate with each other without the barrier of verbal language, creates a sense of empathy, patience, understanding and equality.

## **3.2 The teacher of kindergarten and primary school**

The presence of motivated, prepared teachers that are also careful to children groups specificity, is an essential quality factor for the construction of a friendly, inclusive, sure and well organised environment, also capable to stimulate trust in parents and community [27]. So, the teacher has to create conditions in order that students can learn in the best conditions, by identifying his/her role of speaker, harmoniser and stimulus in relationships between students and knowledge. Context is a fundamental element for the child, because, when he realises of being in a suitable space, he starts to communicate in a relaxed manner, not only verbally, but also with his own body; in addition, the child can establish good relations with his friends in a conscious way [15].

Teachers communication is of great importance in children educative process; in fact, according to Pianta studies, have effective communicative capacities is very important for their development and education. It was determined that pre-school children who perceive their relation with their teachers as positive, warm and close had better school adaptation. However, school adaptation of students who perceive their relation with their teachers as negative were poorer compared to others. In similar studies, Brich and Ladd in 1997, and Justice, Cottone, Mashburn, RimmKaufman in 2008, it was revealed that when child-teacher relationship is negative, children exhibit negative attitudes towards school, have poor academic

success, spend less time at school environment, and avoid from being at school and cooperation in the class [4].

It is fundamental that the teacher, starting from kindergarten, is capable of transmit messages effectively, as is, that is an expert in oral expression and in verbal explanation of certain concepts. But it is not enough: it's not only about what it said, but how is said [28]. The positive or negative attitudes and behaviours that the teacher assumes towards the child, and the verbal and non-verbal messages, which he sends, are closely correlated with the confidence, autonomy and emotions of assertiveness, which the child begins to develop in this period [4]. Nonverbal messages, in fact, are a fundamental component of communication in the learning process.

For example, find, in the morning, a smiling teacher, who says hi to students and parents by welcome them with open arms, rather than with crossed arms and pour, modifies the sent message making the difference for positive relationships. Greeting is done in both examples but emotions that arise are totally different [23]. So, it must understand, that it is not only important to refer a message, but even find the right way to transmit it. This can happen only by accompanying and controlling gestures and expressions.

## *3.2.1 Nonverbal communication components in kindergarten and primary school teachers*

The teacher could be conscious of which are nonverbal messages circulating inside the class; this consciousness makes the teacher more watchful to messages sent by the child, it allows him/her to be more effective in the communication of didactic information and he/she is capable to implement the psychologic degree of closeness between student and teacher [28].

A good teacher could try to improve every aspect of his/her nonverbal communication. First of all, to make the communication style effective, it is fundamental that he/she know how to vary voice elements, as tone, rhythm, timbre, volume, cadence. Otherwise, the risk is to be monotonous, demoted, to annoy the children and not be able to attract their attention.

For what concerning postures, it is necessary to be in an upright position but not rigid, with the bust slightly extended forward; in this way children understand that the teacher is "approachable", receptive and friendly [22]. In addition, staying stationary in class and to not transmit the presence, motivation and care to children, on the other hand, walking in the class or suddenly get up, allow to achieve every student and reactivate a declining attention. Finally, it is important to speak to children in the face, avoiding to direct to them with the back turned or looking the floor. This make the student more involved in the communication and contributes to make him feel a real interlocutor.

As already demonstrated, the face of individuals transmits, besides their intention, emotions, thoughts and feelings. In the education sector, face mimicry constitutes one on communication means between the teacher and the group he has in front of him/her, and it becomes one of the most important factor to determine the environment. About it, the teacher, through his facial expression, communicates his/her mood and links to the topic a specific emotion. So, be able to relax face muscles, by smiling and keeping an eye contact, will have the effect of transmit a joy, warmth and emotive closure to children, who, by feeling relaxed and considered, will enforce the learning process. Particularly, smile can result contagious and contribute to the creation on a peaceful environment in the class; eye contact, instead, allow the teacher to have a total control in managing relationships and concentrate the attention and interest of students on him/her, facilitating

**77**

*The Body Speaks Society, School and Culture DOI: http://dx.doi.org/10.5772/intechopen.94586*

understanding [15].

education [17].

**4. Conclusions**

with our and someone else's social world [1, 8].

respect to the verbal one [6, 20].

communication. Is necessary that the teacher distributes his/her look in a circular manner, to avoid to ignore any part of the classroom, and that stops himself on every student to prove him not only to look him but to watch him. Look the student is therefore important because it increase the probability that children return the look and follow the speech carefully; in addition, through eye contact, that's the possibility to collect precious feedback, as attention level, interest, tiredness degree,

So as gestures, lessons containing gestures improve interest a more specific learning: new reasoning forms, generalisation of new types of problems, conservation of knowledge, etc. In addition, as is known that gestures can promote learning, teachers can consider to improve their students to gesture, that have the potential to activate implicit knowledge and make students particularly receptive to

Finally, the teacher figure, as well as have and use correctly nonverbal communication elements in class, has to be a good listener. If the teacher is a good listener, he makes sense of not only what children say but also their facial expressions and gestures, and body language. She/he also attracts attention to the messages she/he communicates with his body language [4]. However, the first step to arrive to a good communicative intervention is to use an "active listening" with regard to children, which consists in thinking on the student message by only absorbing it, without emit personal messages. So, active listening allows the teacher to feel important and receive information, advices and interests. In 1991, Gordon claims that active listening improves discussions in class; it allows to support the class in case of problems, both in-school and after-school, as this strategy helps the child to express lived feelings, which are considered and respected. The teacher, thanks to this type of listening, is capable of observe very carefully interests, training needs, strengths

of his/her students, that can be used to support the group-class in learning.

Since ancient times, human beings have felt the need to group in societies so establish relationships and socialise with others. This process is possible due to dialectical exchanger and in general to communication. Every communication form is possible due to signs, that link to a concrete and intelligible referent (as word), and to symbols. These two systems form the set of expressive forms (symbolic), given by language, science, myth, religion, philosophy, art, etc. It should however be noted that communication is not a simple linguistic act, but it is an action inserted in a dynamic process that a person does through another as the consequence of the information or the message sent and/or received, of transformations and changes, more or less significant, in behaviours, in attitudes, in moods, in the ways to interact

Inside the communication, as already said, it is possible to distinguish two forms, which have different characteristic and appear in totally different way. Verbal communication is deliberate and arbitrary, it serves to argue, describe and narrate, by giving information about expressed topics. On the other hand, nonverbal communication is mostly unconscious, not intentional and can be ambiguous; it gives information about the subject expressing it, but not about the expressed concepts. In addition, it is important to notice that, while verbal communication tends to be characterised by partners that, in turn, speak and listen, sending and receiving nonverbal signs normally occurs simultaneously. Communication comes before and results more effective and relevant through nonverbal channel, with

#### *The Body Speaks Society, School and Culture DOI: http://dx.doi.org/10.5772/intechopen.94586*

*Types of Nonverbal Communication*

cooperation in the class [4].

gestures and expressions.

closeness between student and teacher [28].

and not be able to attract their attention.

to make him feel a real interlocutor.

*teachers*

process.

success, spend less time at school environment, and avoid from being at school and

It is fundamental that the teacher, starting from kindergarten, is capable of transmit messages effectively, as is, that is an expert in oral expression and in verbal explanation of certain concepts. But it is not enough: it's not only about what it said, but how is said [28]. The positive or negative attitudes and behaviours that the teacher assumes towards the child, and the verbal and non-verbal messages, which he sends, are closely correlated with the confidence, autonomy and emotions of assertiveness, which the child begins to develop in this period [4]. Nonverbal messages, in fact, are a fundamental component of communication in the learning

For example, find, in the morning, a smiling teacher, who says hi to students and parents by welcome them with open arms, rather than with crossed arms and pour, modifies the sent message making the difference for positive relationships. Greeting is done in both examples but emotions that arise are totally different [23]. So, it must understand, that it is not only important to refer a message, but even find the right way to transmit it. This can happen only by accompanying and controlling

*3.2.1 Nonverbal communication components in kindergarten and primary school*

The teacher could be conscious of which are nonverbal messages circulating inside the class; this consciousness makes the teacher more watchful to messages sent by the child, it allows him/her to be more effective in the communication of didactic information and he/she is capable to implement the psychologic degree of

A good teacher could try to improve every aspect of his/her nonverbal communication. First of all, to make the communication style effective, it is fundamental that he/she know how to vary voice elements, as tone, rhythm, timbre, volume, cadence. Otherwise, the risk is to be monotonous, demoted, to annoy the children

For what concerning postures, it is necessary to be in an upright position but not rigid, with the bust slightly extended forward; in this way children understand that the teacher is "approachable", receptive and friendly [22]. In addition, staying stationary in class and to not transmit the presence, motivation and care to children, on the other hand, walking in the class or suddenly get up, allow to achieve every student and reactivate a declining attention. Finally, it is important to speak to children in the face, avoiding to direct to them with the back turned or looking the floor. This make the student more involved in the communication and contributes

As already demonstrated, the face of individuals transmits, besides their intention, emotions, thoughts and feelings. In the education sector, face mimicry constitutes one on communication means between the teacher and the group he has in front of him/her, and it becomes one of the most important factor to determine the environment. About it, the teacher, through his facial expression, communicates his/her mood and links to the topic a specific emotion. So, be able to relax face muscles, by smiling and keeping an eye contact, will have the effect of transmit a joy, warmth and emotive closure to children, who, by feeling relaxed and considered, will enforce the learning process. Particularly, smile can result contagious and contribute to the creation on a peaceful environment in the class; eye contact, instead, allow the teacher to have a total control in managing relationships and concentrate the attention and interest of students on him/her, facilitating

**76**

communication. Is necessary that the teacher distributes his/her look in a circular manner, to avoid to ignore any part of the classroom, and that stops himself on every student to prove him not only to look him but to watch him. Look the student is therefore important because it increase the probability that children return the look and follow the speech carefully; in addition, through eye contact, that's the possibility to collect precious feedback, as attention level, interest, tiredness degree, understanding [15].

So as gestures, lessons containing gestures improve interest a more specific learning: new reasoning forms, generalisation of new types of problems, conservation of knowledge, etc. In addition, as is known that gestures can promote learning, teachers can consider to improve their students to gesture, that have the potential to activate implicit knowledge and make students particularly receptive to education [17].

Finally, the teacher figure, as well as have and use correctly nonverbal communication elements in class, has to be a good listener. If the teacher is a good listener, he makes sense of not only what children say but also their facial expressions and gestures, and body language. She/he also attracts attention to the messages she/he communicates with his body language [4]. However, the first step to arrive to a good communicative intervention is to use an "active listening" with regard to children, which consists in thinking on the student message by only absorbing it, without emit personal messages. So, active listening allows the teacher to feel important and receive information, advices and interests. In 1991, Gordon claims that active listening improves discussions in class; it allows to support the class in case of problems, both in-school and after-school, as this strategy helps the child to express lived feelings, which are considered and respected. The teacher, thanks to this type of listening, is capable of observe very carefully interests, training needs, strengths of his/her students, that can be used to support the group-class in learning.


**2. EBV related pathogenesis of NPC**

The pathogenesis of NPC includes multi-stepped process that leads to the development of NPC **(Fig. 1.).** EBV infection alone cannot drive normal cells towards carcinoma development. It is thought that loss of heterozygosity (LOH on chromosome 3p and 9p, which are the location of some tumor suppressor genes), possibly as a result of inherited traits (Chinese ethnicity) as well as exposure to dietary factors (salted fish) and other environmental cofactors (Formaldehyde), is an early stage event in the pathogenesis of this disease. EBV is infected within these low-grade pre-invasive lesions, subsequent to further genetic and epigenetic alterations.

EBV was first suspected to be linked with NPC on the basis of the serological observations by Old and colleagues (Old et al., 1966) in 1966. This link was formally demonstrated later by in situ hybridization of the viral DNA in the nuclei of epithelial cells (zur Hausen et al., 1970). The full length EBV genome is contained in all malignant epithelial cells, but not in most infiltrating lymphocytes. The association with EBV is constant, regardless of the

Epstein-Barr Virus Serology in the Detection and Screening of Nasopharyngeal Carcinoma 85

EBV infection to NPC formation(Choi et al., 2011; Ji et al., 2007; Ng et al., 2010; Ng et al., 2005), the long period of pre-clinical detectable phase (PCDP) offer the opportunity for

Serological studies have shown that the clinical onset of NPC is preceded by the appearance of a high titer of various EBV antibodies such as viral capsid antigens (VCA) IgA(Li et al., 2010; Ng et al., 2010; O et al., 2007), anti-EBV DNase(Chien et al., 2001) and combined EBV EA(early antigen) + EBNA-1 (Nuclear antigen 1) IgA test(Chang et al., 2008)( **Table 1.**).

> VCA IgA (ELISA)

VCA IgA (ELISA and IF)

(ELISA)

VCA IgA (ELISA and IF)

assay)

Table 1. Reported plasma EBV antibody in NPC diagnosis and risk assessment of NPC

For NPC serodiagnosis, cell-based indirect immunofluorescent assay (IF) methods are widely considered the gold standard (Paramita et al., 2009). IF involves the separate analysis of antibody responses to VCA, EA, and EBNA, and requiring different cell lines for specific analysis. However, this method shows considerable variation among laboratories and is time-consuming, subjective, and not suitable for large-scale automatic handling. Enzymelinked immunosorbent assay (ELISA) techniques are increasingly used recently and have shown a better sensitivity and specificity compared to IFA and which are suitable for largescale application. Stage is one of the most important prognostic predictors of NPC. NPC in its early stages are highly curable with radiotherapy. Screening may change the distribution of stage and prognosis. In a cohort study undertaken in Wuzhou (Guangxi province, China) in the early 1980s (Zeng et al., 1985), total 1136 individuals identified as positive for Ig A

EBNA1 IgA (ELISA)

EA+EBNA1 IgA

VCA IgA(IF) and anti-DNase (enzyme neutralization

Sensitivity 90.6% Specificity 93.5%

Sensitivity 83.3% Specificity 87.0%

Sensitivity 94.2% Specificity 82.6%

Sensitivity 92% Specificity 98%

(7.3–66.9)

Rate ratio VCA IgA 22.0

anti-DNase 3.5 (1.4–8.7)

Rate ratio 4.7 (1.4–16)

**3. Applications of EBV antibodies and EBV DNA as markers of NPC in**

Study type Author Marker Results of the utility

screening and early diagnosis of NPC.

Case-control study O *et al.*

**3.1 Plasma EBV protein in the diagnosis of NPC**

(O et al., 2007)

Ng *et al.* (2010) (Ng et al., 2010)

(Li et al., 2010)

Yu *at al.* (2011) (Yu et al., 2011).

IF: immunofluorescent assay; ELISA: enzyme-linked immunosorbent assay

*et al.* (2001) (Chien et al., 2001)

Chang *et al.*  (2008) (Chang et al.,

2008)

Meta-analysis Li *et al.* (2010)

Cohort study Chien

**population**

patient's geographical origin and is observed in World Health Organization (WHO) types II and III. However, the association of NPC type I with EBV has long been a matter of controversy. It is now clear that WHO type I tumors are frequently associated with EBV in endemic regions, but not in non-endemic regions, where they often result from tobacco and alcohol abuse (Nicholls et al., 1997). Types II and III may be accompanied by an inflammatory infiltrate of lymphocytes, plasma cells, and eosinophils.

Fig. 1. EBV in the pathogenesis model for nasopharyngeal carcinoma

More than 95% adults in all ethnic groups across the world are healthy carriers of EBV (Ooka et al., 1991). This means that NPC oncogenesis is not simply a consequence of EBV infection. It probably results from a form of viral reactivation in combination with other events, such as cellular genetic lesions due to environmental carcinogens and/or some form of immune defects. EBV-encoded RNA signal (EBER) has been shown, by in-situ hybridization, to be present in nearly all tumor cells, whereas EBV-encoded RNA is absent from the adjacent normal tissue, except perhaps for a few scattered lymphoid cells. Premalignant lesions of the nasopharyngeal epithelium have also been shown to harbor EBV, which suggests that the infection occurs in the early phases of carcinogenesis (Gulley, 2001). Consistent with this hypothesis, is the fact that NPC generally occur several years after EBV primary infection. The expression of EBV latent genes provides growth and survival advantages to these infected cells, ultimately leading to the development of NPC. Further genetic and epigenetic alterations post-NPC development can occur, which may result in a more metastatic disease. Because of it takes years for premalignant lesion after EBV infection to NPC formation(Choi et al., 2011; Ji et al., 2007; Ng et al., 2010; Ng et al., 2005), the long period of pre-clinical detectable phase (PCDP) offer the opportunity for screening and early diagnosis of NPC.


**4. Peripheral blood leukocytes as potential biomarkers of disease activity**

A biomarker is defined as a characteristic that can be objectively measured and evaluated and serves as an indicator of normal biological processes, pathological processes or pharmacological reactions to therapy. An ideal biomarker is characterized by high sensitivity and specificity as well as a simple, cost effective, reproducible, and non-invasive detection method [6].

In this section we synthesize and integrate the most relevant data regarding the characteristics of the selected immune cells that could be considered as IFN-β treatment-related biomarkers. The main goal of this work is an attempt to help researchers to perform a good assessment of immune cells in future studies. The presented data is a result of a compilation of several studies and findings.

#### **4.1 Antigen-presenting cells**

Antigen presenting cells (APCs) are considered key players in the immune surveillance of CNS and, at the same time, they are critically involved in the pathogenesis of CNS autoimmune diseases. They are a morphologically and functionally diverse group of cells that links the innate and adaptive immune responses. These cells are specialized in the presentation of antigens to lymphocytes, particularly T cells. Included among such cells are dendritic cells (DCs), monocytes and macrophages (derived from monocytes that migrated from the blood stream to tissues). B lymphocytes that specifically capture antigens via their clonally expressed membrane immunoglobulin can also function efficiently as APCs to T cells [24].

#### *4.1.1 Dendritic cells*

In humans, DCs comprise two major subsets: plasmacytoid DCs (pDCs) and myeloid (mDCs). Through nucleic acid-sensing, pDCs activate toll-like receptors (TLR), such as TLR7 and TLR9, rapidly producing type I IFN. mDCs are dedicated APCs that have a characteristic dendritic morphology, express high levels of MHC class II molecules and recognize pathogen-derived lipids, proteins and nucleic-acids by TLR2, TLR4 and TLR3 respectively [25].

The DCs subsets may be helpful as biomarker between remission and relapse of RRMS patients treated with IFN-β. The circulating mDCs subset reduces in remission and increase in relapse RRMS patients. On the other hand, the pDCs frequency are maintain across the different phases of disease. Usually, these subsets present a low frequency in systemic circulation, so the mDCs/pDCs ratio is a good representative of the alteration observed in the DCs subsets. The mDCs/pDCs decreases in remission RRMS patients and is re-established in relapse RRMS patients, constituting a potential peripheral biomarker [26, 27].

The involvement of DCs in MS arises from studies that demonstrate the abundant presence of these cells in the inflamed CNS lesions and in the CSF of MS patients [23].

One of the immunomodulatory effects of IFN-β in the EAE model is the reduction in antigen presentation, particularly myelin-specific antigens, leading to reduced T-cell responses [25, 28]. In contrast with these effects, in remission phase it was observed that the DCs subsets increase the expression of HLA-DR and decrease in the relapse phase. The variation in HLA-DR expression is more evident in the mDCs subset. The same subset reduce the mRNA gene expression of CX3CR1; fractalkine is known to be upregulated and released in response to proinflammatory stimuli and induces adhesion, chemoattraction, and activation of leukocytes [27].

The activation status of the mDCs subset could discriminate between RRMS phases. This subset shown a highest activated status in remission than in relapse phase, through the increased HLA-DR expression and a reduced migratory capability, since reduce the mRNA gene expression of CX3CR1.

*Peripheral Biomarkers in Multiple Sclerosis Patients Treated with Interferon-Beta DOI: http://dx.doi.org/10.5772/intechopen.99006*

#### *4.1.2 Monocytes*

Monocytes represent a heterogeneous population of primary immune effector cells with distinct phenotypical and functional characteristics; their differential roles in steady-state immune surveillance and the pathogenesis of human CNS disease are poorly understood [20].

The differential expression of CD14 (part of the receptor for lipopolysaccharide) and CD16 (also known as FcγRIII) allows monocytes to be segregated into three subsets. The major subset designated "classical" monocytes (CD14++CD16− , cMo), corresponds to 80–90% of circulating monocytes. CD16 expressing monocytes are divided into a named "intermediate" monocyte (CD14++CD16+ , iMo) and a subset classified as "non-classical" monocytes (CD14+ CD16++, ncMo); each of these subsets corresponds to 5–10% of circulating monocytes [21, 29].

Patients with MS display high levels of monocyte-secreted inflammatory molecules in serum compared to healthy individuals, demonstrating a role for peripheral monocytes in the progression of the disease. Increased levels of serum tumor necrosis factor (TNF) α and β have been reported in MS relapse. Monocytes and microglia are known to act as major effectors in the demyelinating process through direct interaction and the production of proinflammatory cytokines and mediators (e.g., IL-1b, nitric oxide). CD16+ monocytes may contribute to the breakdown of the BBB by facilitating T cell trafficking into the CNS [20, 24, 30].

Research performed on monocyte pool in RRMS patients is scarce and ambiguous. A recent work achieved a significant decrease of the ncMo subset in both phases of RRMS patients, although in a higher extension in remission patients [27].

The frequency of monocytes subsets does not allow us to identify different phases of RRMS, but the HLA-DR expression could constitute a potential important biomarker between remission and relapse phases. A significant increase in HLA-DR expression in all monocyte subsets in the remission group when compared with healthy and relapse groups, has been described [27]. IFN-β enhances HLA-DR expression in circulating monocytes, but inside the CNS, one prominent model is based on the observation that IFN-β inhibits the IFNγ upregulation of MHC class II molecules on cell surface of macrophages and glial cells and therefore diminishes antigen presentation [28]. In the periphery, Kantor et al. report that the increase of MHC Class II expression in monocytes induced by IFN-β may contribute to the positive immunomodulatory effect in MS [31]. These findings were reinforced by the observation that when IFN-β-stimulated monocytes were used to stimulate autologous T cells, there was an increased secretion of anti-inflammatory cytokine IL-13 [32].

### **4.2 T cells**

#### *4.2.1 CD4+ and CD8+ T cells*

T cells are central regulators of the adaptive immune response, they help B lymphocytes to produce antibodies and secrete cytokines that provide efficient protection against pathogens. Distinct T helper (Th) cell subsets, producing one or more lineage-defining cytokines and expressing master transcription factors and homing receptors. Th subsets are differentiated from naive CD4+ T cells in response to a specific class of pathogenic microorganisms and to the cytokine milieu. This occurs in peripheral lymph nodes by mature DCs that present pathogen-derived peptides associated to MHC class II. With the involvement of their costimulatory molecules, DCs promote T cell proliferation and produce polarizing cytokines. In turn T cell was differentiated in distinct Th cell subsets, such as Th1, Th2, Th17, regulatory T (T reg) and T follicular helper (Tfh) [33].

The CD4+ T cells have been the most studied in the pathogenesis of MS, although CD8+ T cells are the dominant lymphocyte population in all stages of disease and lesions of MS patients. Naive CD8+ T cells follow a similar differentiation programme of CD4+ T cells [34, 35].

Th1 cells are described as being the pathogenic subset of T cells, whereas Th2 cells are reported to exert inhibitory effects [5]. Previous studies have pointed to a reduction in pro-inflammatory capability promoted by IFN-β therapy, consisting of a reduction of the expression of Th1-induced cytokines while enhancing Th2 responses [18]. Concerning the T cytotoxic (Tc) subsets, it has been reported the same behavior, in remission a downregulation of pro-inflammatory Tc1 responses and up-regulation of anti-inflammatory Tc2 with a beneficial effect on disease activity [36]. This dichotomy Th1, Th2 subsets and Tc1, Tc2 subsets could contribute to discriminate between remission and relapse phases.

The identification of Th17 cells helped to resolve some in adequacies of the original Th1/Th2 concept that had dominated T cell immunology research filed for almost 20 years. For a long time, it was thought that the IL-12/IFNγ pathway and Th1 cells were central to the development of autoimmune disease [37].

Both Th1 and Th17 cells have been implicated in the initiation and progression of disease in RRMS and its experimental model EAE [19]. The link between Th17 cells, IL-17 and MS relapses comes from the observation that in humans, Th17 cells are able to cross the BBB in MS lesions, enhancing neuroinflammation. In vitro studies have revealed that IL-17 blocks the differentiation and reduces the survival of oligodendrocyte lineage cells. In EAE model, it has been suggested that Th17 cells interact directly with neurons, forming antigen-independent, immune, synapselike contacts [7, 38].

It is assumed that the inhibition of Th17 cells in RRMS patients attenuates the disease, however conflicting data have been published. Axtell et al. reported that IFN-β treatment effectively blocked disease symptoms in mice with EAE induced with Th1 cells. Otherwise, in EAE induced with Th17 cells the IFN-β treatment worsened disease [19].

In RRMS patients, it is not clear whether a more specific blockade of the Th17 pathway has beneficial effects in MS patients. Treatment with an antibody directed against IL-12p40 and therefore neutralizing both IL-12 and IL-23 did not result in a significant reduction of disease activity [39].

A meta-analysis pointed out several limitations across studies that assess the levels of peripheral Th17 cells and serum Th17-related cytokines. Like the severities of the disease and clinical subtypes in MS patients; the disease duration from relapse; and that the MS treatments were not consistent; and it was postulated that most studies selected MS patients with high disease activity. There were differences in experimental methods between studies and a lack of detailed standardized methods to identify the Th17 cells and Th17-related cytokines [40].

A recent in vivo study observed an increased frequency of circulating Th17 and Tc17 cells, accompanied by increased serum levels of IL-17 in remission RRMS patients treated with IFN-β [41]. This contradiction underlines the need to clarify the role of the IL-17-producing T cells in RRMS patients.

It has been demonstrated that a significant proportion of Th17 cells convert into IFN-γ-producing T cells and have chemokine receptors from both Th17 and Th1 subtypes, referred as Th17.1 cells. The enhanced potential of Th17.1 cells to infiltrate the CNS was supported by their predominance in CSF of early MS patients and their preferential transmigration across human brain endothelial layers [42, 43]. In remission RRMS patients, it was observed that Th17 and Tc17 cells exhibited a higher degree of Th1 plasticity since there were higher frequencies of those cells simultaneously producing intracellular IL-17 and IL-2 or IFNγ or TNFα [41].

#### *Peripheral Biomarkers in Multiple Sclerosis Patients Treated with Interferon-Beta DOI: http://dx.doi.org/10.5772/intechopen.99006*

Another subset of T cells, the Tregs, are characterized by high expression of CD25 and the transcription factor *Foxp3*, which is critical for their development, lineage commitment, and regulatory functions. Tregs are a very heterogeneous population with suppressive functions that maintain tolerance to harmless food/ self-antigens and prevent autoimmune disease. Numerous studies have identified Tregs as important immunoregulators in many inflammatory and autoimmune disease conditions including asthma, MS, and type-I diabetes [37, 44].

In MS patients, both reduced or normal frequency of Tregs was observed. Libera et al. described a significant decrease in Treg cells in remission RRMS patients [45]. Haas et al. state that the frequency of Treg cells was normal in MS patients but with a lower suppressive function on autoreactive T cells [46]. Venken et al. described that RRMS patients treated with IFN-β showed restored naive Treg numbers as compared with age- and disease-duration-matched untreated patients [47].

Recently identified, the Tfh subset expresses the chemokine receptor CXCR5 as well as CD279 [48], is specialized in helping B cells to produce antibodies in the face of antigenic challenge and plays a crucial role in orchestrating the humoral arm of adaptive immune responses. Tfh cells have the unique ability to migrate into follicles in secondary lymphoid organs where they colocalize with B cells to deliver contact-dependent and soluble signals that support survival and differentiation of the latter cells. There is no complete and thorough understanding of how naïve Th cells differentiate into mature Tfh [49, 50].

Tfh cell levels are elevated in the blood of MS patients and this population is positively correlated with the progression of disability. One potential mechanism through which Tfh cells can contribute to disease is promoting the inflammatory B-cell activities, suggesting that Tfh cells cooperate with Th17 cells to induce inflammatory B cell responses in the CNS and increase disease severity [49].

The increased frequencies of Th1 cells, activated Tfh- and B-cells parallel findings from pathology studies, along with the correlation between activated Tfh- and B-cells, suggest a pathogenic role of systemic inflammation in progressive MS [51].

A similar frequency of Tfh cells between RRMS patients and healthy subjects was reported. However, this subset tend to exhibit a more proinflammatory activity, since higher frequencies of TNF-α+ Tfh cells have been observed [41]. It is well known that Tfh cells play an important role in T/B interactions in germinal centres (GC) and one potential mechanism through which Tfh cells can contribute to MS is in promoting inflammatory B-cell activities [49]. The Tfh subset and others follicular like T cells subsets, like Treg/follicular cells, are promising targets in the study of T cells in pathophysiology of MS.

## *4.2.2* γδ *T cells*

γδ T cells develop in the thymus together with αβ T cells but rearrange a different TCR, consisting of a TCR-γ and TCR-δ chain. One of the most striking characteristics of γδ T cells is their inherent ability to secrete pro-inflammatory cytokines very rapidly, which influences adaptive immunity, they carry out immediate effector functions as well as mounting a memory response upon microbial reinfection. This fast response can be explained by γδ T cells exiting the thymus already with the functional competence to produce cytokines with no need of APCs cells [52, 53].

In MS, their potential importance is increased by the finding that γδ T cells accumulate in demyelinating CNS MS plaques; these cells show evidence of oligoclonal expansion indicating a local response to currently unknown antigens. γδ T cells have been shown to be present in both MS lesions and in CSF, and sequencing studies have shown that the major γδ T subsets present in the lesion differ from those in the CSF, suggesting specific functions for these cells in lesion development. In more chronic lesions, γδ T cells may become the most prevalent type of T cell in the lesion. γδ T cells isolated from the CNS can be expanded but only in patients with relapse disease, not chronic MS patients, suggesting that these cells may have differential roles during various phases of the disease [54, 55].

The frequency, the migratory pattern, the activation status of γδ T cells in RRMS patients are unclear. Between remission and relapse RRMS patients, the γδ terminally differentiated effector memory T cells (TEMRA) and the CCR5+ γδ TEMRA decrease in relapse when compared with remission RRMS patients [56], constituting a good biomarker between phases of the disease. Probably as a result of the migratory pattern describe for this phase of MS, preferentially toward RANTES and MIP-1α, whose expression is increased during relapses [57, 58].

The decrease of Eomesodermin and granzyme B mRNA expression in CD27− γδ T cells suggests a reduction in the cytotoxic potential of the circulating pool of γδ T cells, particularly in relapsing RRMS patients [56].

### **4.3 B lymphocytes**

The most consistent immunodiagnostic feature and hallmark immunologic finding in MS patients is the presence of oligoclonal bands (OCB) in the CSF and their absence in peripheral circulation. Consequently, the pathogenic function of B cells in MS has been traditionally associated with antibody production. However, B cells have three putative biological roles: production of proinflammatory or regulatory cytokines, function as APCs and antibody production [59].

In MS, the memory B cells, plasmablasts and plasma cells preferentially cross the BBB and migrate into the CNS, where they dominate the B cell pool and exert different effector functions. B cells seem to be abnormally polarized toward a more proinflammatory phenotype [60].

More recent, somatic hypermutation studies have demonstrated that identical B cell clones can be shared between the CNS and the periphery in individual patients. These studies provide evidence of bidirectional trafficking of distinct B cell clones (both into and out of the CNS). The patterns suggest that B cells can travel back and forth across the BBB and commonly re-enter GC (in the meninges or cervical lymph nodes) to undergo further somatic hypermutations. These findings change our view of lymphocytic surveillance of CNS tissue and underline that B-cell trafficking is an important topic for future research and therapy strategies [60–62]. This news about recirculation of B cells through the BBB alters the perception of the role of B cells in MS.

B cells are released in the peripheral blood, recirculate between the secondary lymphoid tissues, and dying after a few days. According to phenotypic profile of B cell subsets, which also reflects their functional abilities and behavior, four major maturation-associated subsets can be identified in the human peripheral blood: immature/transitional, naive, memory and plasmablast [63].

In remission RRMS patients submitted to IFN-β, the percentage of immature/ transitional B cells increases. This increase can be seen as an attempt to increase anti-inflammatory cytokines. Meanwhile, a decrease in the proportion of circulating class-switched memory B cells was reported [64, 65].

The relapsing RRMS patients exhibited distinct changes in B cell subsets homeostasis, resulting in a decrease in the total population of B cells, including a decrease of the immature/transitional and naïve B cell subsets when compared with remission RRMS patients. On the other hand, the plasmablast B cell subset presented an increase in relapse RRMS patients. The ratio between immature/transitional B cells and plasmablasts can thus be considered as a potential biomarker between phases of RRMS patients. The remission RRMS patients and the healthy subjects presented a similar ratio, and the relapse RRMS patients present a decreased ratio [66].

*Peripheral Biomarkers in Multiple Sclerosis Patients Treated with Interferon-Beta DOI: http://dx.doi.org/10.5772/intechopen.99006*

According to the new and recent data about the recirculation of B cells in RRMS, it seems that the increase of plasmablasts in circulation of relapsing episodes may be due to a migration of these cells from cervical lymph nodes and/or from B cell aggregates described in the meninges of MS patients to the blood marrow in an attempt to promote the immune response [67].


**Chapter 8**

*Lifestyle and Epidemiology - The Double Burden of Poverty and Cardiovascular Diseases...*

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Mosby Elsevier, 2008: 271.

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[19] Gupta N, Goel K,

Rev. 2012; 33: 48-70.

[20] Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW., Jr. Obesity is associated with macrophage accumulation in adipose tissue. The Journal of Clinical Investigation 2003; 11:1796-1808.

[17] Deshmukh PR, Gupta SS,

anthropometric, metabolic and dietary fatty acids profiles in lean and obese dyslipidaemic Asian Indian male subjects. Eur J Clin Nutr 2007; 61: 2-9.

[16] Marshall WJ and Bangert SJ. ISBN<PHONE_NUMBER>603. "Obesity. Clinical Chemistry", 6th ed. Ch.14.London:

Dongre AR, Bharambe MS, Maliye C, Kaur S and Gar BS. Relationship of anthropometric indicators with blood pressure levels in rural Wardha. Indian Journal of Medical Research 2006; 123:

[18] Thompson M, Dana T, Bougatsos C, Blazina I and Norris SL. Screening for hypertension in children and adolescents to prevent cardiovascular disease. Paediatrics 2013; 131: 490-525.

Shah P, Misra A. Childhood obesity in developing countries: epidemiology, determinants, and prevention. Endocr

**118**

Factors Associated with Overweight and Obesity among Women Aged 15-49 Years in Zimbabwe: Evidence from the 2005/6, 2010/11 and 2015 Zimbabwe Demographic and Health Survey

*Kudzaishe Mangombe, Naomi Wekwete, Amos Milanzi, Ronald Musizvingoza and Charles Lwanga*


**4.1. Soil acidity**

**3. Long-term application of fertilizers**

192 Organic Fertilizers - From Basic Concepts to Applied Outcomes

produced about 10,500–15,000 kg hm2

are presented in **Table 3**

region [14].

**3.1. Commonly used organic fertilizers in the red soil region**

Commonly used organic fertilizers in the red soil region come mainly from green manure, farmyard manure, and crop residues (returned and left in place). In this area, rice and rapeseed are the main field crops covering 55 and 11% of the total cropped area, respectively. The amount of rice straw and rapeseed stalk account for 70–75% and 8.5–11% of the total crop residues in this region [14]. Double rice (two rice crops per year) and winter rapeseed is the main cropping pattern producing 9500–1200 kg hm2 straw yearly, but the rapeseed only yield about 1660–6900 kg hm2 residue yearly. Dry land crop straw is mainly used as livestock feed and cooking fuel, and only small portion is returned to the field. Radish (*Raphanus sativus*) and milk vetch (*Astragalus sinicus* L.) are also used as the main winter green manure which

main livestock manures in the region [14]. Crop, especially rice, above and below ground residue is another important source of soil organic matter. The nutrient contents of major organic materials used in the typical red soil region, Yujiang Country, Jiangxi Province, China,

**Table 3.** Nutrient contents of major organic materials used at the Yujiang Country, Jiangxi Province, a typical red soil

The Red Soil Ecological Experiment Station, constructed in 1985 by the Institute of Soil Science, Chinese Academy of Sciences (ISSAS), is located in Liujia Zhan, Yujiang County, Jiangxi Province, China (28°15′20″ N, 116°55′30″ E). It is one of the key laboratories for studying the ecology of red soils in China.  Long-term fertilization experiment on a typical red soil**

fresh biomass yearly. Pig and cattle manure were the

Soil pH had a significant increasing trend during the long-term organic–inorganic fertilization (**Figure 1**) from 1988 to 1995, but it gradually decreased since then. There was a significant negative linear correlation between soil pH and cultivation time after the seventh year of the experiment. This suggests that initial fertilization raised pH in the very acidic soil to near neutral, but continuous fertilization led to further soil acidification. The mechanism of pH changes remains to be explored. The CK treatment decreased soil pH by 0.07 yearly, while addition of rice straw and pig manure decreased the pH by 0.05 and 0.04 yearly, respectively (**Figure 1**). At the rate of pH decline, soil acidity of the upland red soil would reach the original soil condition in 1988 after 30 (CK and RS) or 48 (PM) years of cultivation. In addition, soil pH of RS treatment decreased faster than that of the PM treatment after the seventh year.

**Figure 1.** Changes of soil pH in the upland red soil as affected by the long-term application of organic–inorganic fertil‐ izers (1988–2009).

#### **4.2. Soil organic matter**

Compared with the CK, addition of rice straw and pig manure significantly increased soil organic matter contents in the upland red soil during the long-term fertilization (**Figure 2**) study. The rice straw treatment had a higher accumulation rate of organic matter (0.34 g kg−1 yearly) than the pig manure treatment (0.14 g kg−1) probably due to the higher amount of C and C/N ratio of the former.

**Figure 2.** Changes of soil organic matter in the upland red soil as affected by the long-term application of organic– inorganic fertilizers (1988–2009).

#### **4.3. Soil nitrogen, phosphorus, potassium**

changes remains to be explored. The CK treatment decreased soil pH by 0.07 yearly, while addition of rice straw and pig manure decreased the pH by 0.05 and 0.04 yearly, respectively (**Figure 1**). At the rate of pH decline, soil acidity of the upland red soil would reach the original soil condition in 1988 after 30 (CK and RS) or 48 (PM) years of cultivation. In addition, soil pH

**Figure 1.** Changes of soil pH in the upland red soil as affected by the long-term application of organic–inorganic fertil‐

Compared with the CK, addition of rice straw and pig manure significantly increased soil organic matter contents in the upland red soil during the long-term fertilization (**Figure 2**) study. The rice straw treatment had a higher accumulation rate of organic matter (0.34 g kg−1 yearly) than the pig manure treatment (0.14 g kg−1) probably due to the higher amount of C

**Figure 2.** Changes of soil organic matter in the upland red soil as affected by the long-term application of organic–

izers (1988–2009).

**4.2. Soil organic matter**

and C/N ratio of the former.

inorganic fertilizers (1988–2009).

of RS treatment decreased faster than that of the PM treatment after the seventh year.

194 Organic Fertilizers - From Basic Concepts to Applied Outcomes

Compared with the initial value in 1988, soil total nitrogen (TN) showed a significant increasing trend during the long-term fertilization (**Figure 3**). Both RS and PM treatments significantly increased soil TN content compared to the CK, but PM treatment was more effective in the accumulation of TN in the upland red soil.

**Figure 3.** Changes of soil total nitrogen in the upland red soil as affected by the long-term application of organic–inor‐ ganic fertilizers (1988–2009).

The upland red soil in this study is a typical acidic soil and characterized by its strong P-fixation capacity and low P availability due to the high content of aluminum and/or iron oxides, which can convert P in the soil solution to water-insoluble Fe-Al-P. Compared with the CK, rice straw addition was not significant in improving soil total phosphorus (TP) and Olsen-P, but the addition of pig manure did significantly increase soil TP and Olsen-P by 28.4–116.7% and 292.6–731.8%, respectively (**Figure 4**). There is a significant positive correlation between soil TP content and the year of cultivation (*r* = 0.843, *p* < 0.05). Based on this relationship, the soil TP content in the PM treatment was increased by 30 mg kg−1 yearly.

**Figure 4.** Changes of soil total phosphorus (P) and Olsen-P in the upland red soils as affected by the long-term applica‐ tion of organic–inorganic fertilizers (1988–2009).

During the long-term fertilization study, soil potassium (K) in the upland red soil significantly decreased at the rate of 50 or 60 mg kg−1 yearly and there was no significant difference among the three treatments (**Figure 5**). Compared with their initial values in 1988, soil total K was reduced by 1.9–12.0%, 2.8–9.3% and 0.9–14.0% in the CK, RS, and PM, respectively (**Figure 5**). The K reduction is probably due to plant uptake and removal or leaching losses.

**Figure 5.** Changes of soil total potassium (K) in the upland red soil as affected by the long-term application of organic– inorganic fertilizers (1988–2009).

#### **4.4. Soil aggregate structure**

Soil aggregate formation and stability are the results of complex interactions among biological, chemical, and physical processes in the soil, which are also important determinants of soil fertility and productivity. Distribution or/and redistribution of various sized soil aggregates in the upland red soil could be significantly affected by the long-term application of organic– inorganic fertilizers (**Figure 6**, [15]). The distribution of dry-sieved aggregates (DSA) in the upland red soil showed similar trends among CK, RS, and PM in the order of (>5) >1–0.25 > 5– 2 > 0.25–0.05 > 2–1 > (<0.053 mm), whereas the distribution of water-stable aggregates (WSA) was in the order of 0.25–0.053 > 1–0.25 > (>5)> (<0.053) > 5–2> 2–1 mm (**Figure 5**). Compared with the CK, addition of rice straw and pig manure significantly increased the proportion of DSA in 1–0.25, 0.25–0.053, and <0.053 mm fractions. No change in the 2–1 mm fraction, however, was detected. Addition of rice straw significantly decreased the proportion of WSA in the >5 mm fraction and increased the proportion of WSA in 2–1 and 1–0.25 mm fractions but did not affect the 1–0.25 mm aggregate fraction (**Figure 6**). Evidently, there was a significant difference between the effect of rice straw addition and pig manure amendment on aggregate size distribution in the upland red soil.

Overall, 86.9–93.8% of DSA and 47.4–50.0% of WSA were in the macro-aggregate (>0.25 mm) fraction in the upland red soil after 22 years of combined application of NPK fertilizer and organic amendments (**Figure 6**). Compared with the CK treatment, addition of rice straw and pig manure increased the proportion of the >0.25 DSA fraction by 4.9 and 7.9%, respectively; and only the addition of pig manure significantly increased WSA by 5.9% in the >0.25 mm fraction (**Figure 7**).

During the long-term fertilization study, soil potassium (K) in the upland red soil significantly decreased at the rate of 50 or 60 mg kg−1 yearly and there was no significant difference among the three treatments (**Figure 5**). Compared with their initial values in 1988, soil total K was reduced by 1.9–12.0%, 2.8–9.3% and 0.9–14.0% in the CK, RS, and PM, respectively (**Figure 5**).

**Figure 5.** Changes of soil total potassium (K) in the upland red soil as affected by the long-term application of organic–

Soil aggregate formation and stability are the results of complex interactions among biological, chemical, and physical processes in the soil, which are also important determinants of soil fertility and productivity. Distribution or/and redistribution of various sized soil aggregates in the upland red soil could be significantly affected by the long-term application of organic– inorganic fertilizers (**Figure 6**, [15]). The distribution of dry-sieved aggregates (DSA) in the upland red soil showed similar trends among CK, RS, and PM in the order of (>5) >1–0.25 > 5– 2 > 0.25–0.05 > 2–1 > (<0.053 mm), whereas the distribution of water-stable aggregates (WSA) was in the order of 0.25–0.053 > 1–0.25 > (>5)> (<0.053) > 5–2> 2–1 mm (**Figure 5**). Compared with the CK, addition of rice straw and pig manure significantly increased the proportion of DSA in 1–0.25, 0.25–0.053, and <0.053 mm fractions. No change in the 2–1 mm fraction, however, was detected. Addition of rice straw significantly decreased the proportion of WSA in the >5 mm fraction and increased the proportion of WSA in 2–1 and 1–0.25 mm fractions but did not affect the 1–0.25 mm aggregate fraction (**Figure 6**). Evidently, there was a significant difference between the effect of rice straw addition and pig manure amendment on aggregate

Overall, 86.9–93.8% of DSA and 47.4–50.0% of WSA were in the macro-aggregate (>0.25 mm) fraction in the upland red soil after 22 years of combined application of NPK fertilizer and organic amendments (**Figure 6**). Compared with the CK treatment, addition of rice straw and pig manure increased the proportion of the >0.25 DSA fraction by 4.9 and 7.9%, respectively;

inorganic fertilizers (1988–2009).

**4.4. Soil aggregate structure**

size distribution in the upland red soil.

The K reduction is probably due to plant uptake and removal or leaching losses.

196 Organic Fertilizers - From Basic Concepts to Applied Outcomes

**Figure 6.** Distribution of dry-sieved aggregates (DA) and water-stable aggregates in the upland red soil impacted by long-term fertilization (1988–2009). Same lowercase letters indicate no significant difference at *p* < 0.05 between differ‐ ent fertilizer treatments.

**Figure 7.** Proportion of macro-aggregate (>0.25 mm) in the upland red soil impacted by the long-term fertilization treatment (1988–2009). Same lowercase letters indicate no significant difference at *p* < 0.05 between different fertilizer treatments.


**MAJOR DEPRESSIVE DISORDER - COGNITIVE AND NEUROBIOLOGICAL MECHANISMS**

Edited by **Yong-Ku Kim**

#### **Major Depressive Disorder - Cognitive and Neurobiological Mechanisms**

http://dx.doi.org/10.5772/58711 Edited by Yong-Ku Kim

#### **Contributors**

Xiaobin Zhang, Jin Li, Sha Weiwei, Ru Bu, Kazima Bulayeva, Paul Thompson, Hwa-Young Lee, Massimo Cocchi, Lucio Tonello, Fabio Gabrielli, Zhengzhi Feng, Xiao Liu, Xiaoxia Wang, Lifei Wang, Keyu Liu, Xiao Chen, Qin Dai, Sang-Won Jeon, Yong-Ku Kim, Tabitha Payne, Madeleine Thompson

#### **© The Editor(s) and the Author(s) 2015**

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First published in Croatia, 2015 by INTECH d.o.o. eBook (PDF) Published by IN TECH d.o.o. Place and year of publication of eBook (PDF): Rijeka, 2019. IntechOpen is the global imprint of IN TECH d.o.o. Printed in Croatia

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Major Depressive Disorder - Cognitive and Neurobiological Mechanisms Edited by Yong-Ku Kim p. cm. ISBN 978-953-51-2129-9 eBook (PDF) ISBN 978-953-51-7240-6


**1. Introduction**

Theoretically, the converters in the DC grid can be connected in parallel, in series, or in hybrid mode [1]. For the parallel converters, the DC voltage of each converter is roughly the same, and the power distribution can be achieved by controlling the DC current of each converter. For converters connected in series, the current flowing through each converter is the same, and the power distribution can be regulated by adjusting the DC voltage of each converter. However, the converters connected in parallel are more suitable for DC grids due to the higher reliability, economy, and flexibility. In this configuration, the voltage polarity of each converter is fixed. In the early ages, most high voltage direct current (HVDC) systems were based on the line commutated converters (LCCs), and the DC power flow direction was fixed since the current of the thyristor could not be reversed. Due to this shortcoming in LCC, DC grid has not received much attention in the first 50 years of the HVDC transmission. However, with the development of power electronics, the voltage source converter-based HVDC (VSC-HVDC) [2–5] has drawn much attention from both academia and industry due to its flexible operation capability, and the advantages of a DC grid can be fully achieved by VSC.Ever since, the DC grid has become a new expectation of the power industry.

There are three main technical bottlenecks in the development of DC grids. One is the fast detection and isolation technology of DC faults [6,7]. The second is the DC voltage transformation technology [8,9]. The third is the power flow control technology of the DC lines [10,11]. This paper mainly deals with the first technical bottleneck and studies the fault protection principle for DC grids.

The di fficulties of DC grids in fault protection lie mainly in the following aspects [12–15]:

(1) The fault current rises very quickly. Generally, the fault current could reach its steady value within 10 ms after the fault;

To this end, this paper proposes a local protection and local action strategy for HVDC grids. This strategy is of high protection selectivity and speed, which is able to solve the above technical problems effectively.

This paper is organized as follows. Section 2 gives the basic structure and operation principle of the hybrid circuit breaker. The local protection and local action strategy is introduced in Section 3. Section 4 describes the test system constructed in this paper. To verify the improved protection speed and selectivity, a performance comparison between the proposed strategy and the conventional relay protection strategy is presented in Section 5. The conclusions are drawn in Section 6.

#### **2. Basic Structure and Operation Principle of DC Circuit Breaker**

The HVDC CB adopted in this paper is the hybrid HVDC CB proposed by ABB [16,17], as shown in Figure 1. The HVDC CB is connected between one multi-level modular converter (MMC) and one DC line. When the faults occur on the DC lines, the HVDC CB starts action to isolate the fault line.

**Figure 1.** Structure of the hybrid high voltage direct current circuit breaker (HVDC CB).

The DC circuit breaker is composed of a normal current path, a main breaker branch, and an energy absorption branch. The normal current path consists of a load commutation switch (LCS) and an ultra-fast disconnector (UFD) connected in series. Multiple main breakers (MBs) connected in series constitute the main breaker branch. The basic structure of each part is as follows:

(4) Ultra-fast disconnector (UFD). It needs to quickly disconnect the circuit under zero current state. Furthermore, the breaking time is about 2 ms.

The principle of the hybrid HVDC CB is as follows [18–20]:

#### **3. Two Basic Protection Strategies for DC Grids**

For a half-bridge sub-module (HBSM) multi-level modular converters (MMCs)-based DC grid equipped with HVDC CBs, how to quickly detect and isolate the DC faults is a very challenging problem.

The conventional strategy is to follow the practice of the AC grid. The protection action sequence is shown in Figure 2. Firstly, the relay protection system detects the fault location, and then the fault line is isolated by CBs. However, this strategy puts extremely high requirements on the speed and selectivity of the relay protection system. According to the speed of fault detection in conventional two-terminal HVDC systems, the duration for fault detection is about 10 ms [21]. If the fault detection speed in DC grids is the same as that in the conventional two terminal HVDC system, the fault current to be interrupted by the DC breaker will reach a very high level. Furthermore, this will result in huge costs of CBs. In addition, this will severely limit the application of DC grids of this structure.

**Figure 2.** Protection action sequence of strategy 1.

The other strategy is based on local protection and local action. There could be two aspects to explain local protection. The first is the local protection of the converters. If the arm current reaches twice the rated IGBT current, the converter will then be automatically blocked. Moreover, there is no need for a relay protection signal. The second means the local protection of CBs. When the current flowing through CB is more than twice its rated current, LCS will be activated immediately as well as the whole CB. That is, CBs on both sides of the line independently finish fault detection and tripping, and there is no need for a coordination between CBs. Local action means that CB only operates when the fault occurs at the DC line where CB is located. Define that the positive direction of the CB current is from MMC to the DC line. Then, only when the fault current is the same as the positive direction and reaches twice the rated CB current, CB is activated. Local action guarantees the high protection selectivity. The protection action sequence is shown in Figure 3. Practice has shown that this strategy is very suitable for DC grids. Furthermore, it has high protection speed and protection selectivity, which could greatly reduce the required breaking capacity of CBs, thereby saving the cost.

**Figure 3.** Protection action sequence of strategy 2.

The two different strategies will be studied separately in the following sections. The first strategy is to deal with the faults by the conventional DC fault relay protection. The second strategy is the local protection and local action strategy.


**5. Conclusion**

Hyperspectral imagery consists of hundreds of contiguous spectral bands, but only a subset of well-chosen bands is generally sufficient for a specific classification problem. So it is possible to design superspectral sensors dedicated to specific land cover classification tasks. This chapter presented a spectral optimization strategy to identify the most relevant spectral band subset for such sensor, optimizing both band position and width. Spectral optimization involves a band subset relevance score as well as a method to optimize it.

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This study first focused on the definition of this relevance score. Several filter, wrapper and embedded scores compatible with generic optimization heuristics were compared, and both their classification performance and selection stability were considered for band selection problem. At the end, most of them brought good results. Jeffries-Matusita distance score tended to lead to slightly better quantitative classification results than the best wrapper scores but also being less stable. Wrapper scores taking into account classification confidence performed better than classic wrapper scores expressed as a simple classification "hard label" error rate. For instance, a random forest confidence-based score was identified as one of the best criteria, considering both quantitative and qualitative analyses. As an intermediate result of this FS criteria comparison, a method to create band importance profiles according to the different criteria was proposed providing visual hints about the relevance of the different parts of the spectrum. Then the study focused on the optimization of bandwidth, which is important in a spectral sensor design context, as having wider bands is a way to limit signal noise while having too wide bands can also lead to a loss a useful information. A strategy consisting in building a hierarchy of groups of adjacent bands before applying band selection at the different levels of this hierarchy using an adaptation of an incremental algorithm for this problem. This band grouping strategy enabled to limit the problem's combinatory while considering relevant band subsets composed of spectral bands with different spectral widths. It was also a way to consider several possible solutions and evaluate their impact.

To conclude, algorithms proposed in this study were applied to design a sensor dedicated to classify urban materials [36, 72].