3. 1-Density

The real Finsler spaces, as generalizations of real Riemannian manifolds, were introduced in Ref. [1] about a century ago and have been studied by many researchers (see, for instance, Refs. [2– 4]), and Finsler spaces (see, for instance, Refs. [5, 6]) have become an interest of research for the studies of geometry, including differential geometry and integral geometry, in recent decades. By the way, there are applications of Finsler geometry in physics and engineering, and in particular, Finsler geometry can be applied to engineering dynamical systems, on which one can see Ref. [7]. As a typical Finsler space, Lp space, 1 < p < ∞, has the main features of a Finsler space. As such, we focus on Lp space, 1 < p < ∞, in this chapter, but some results can be generalized to general Finsler spaces, on which one can refer to Ref. [8]. The Lp space, 1 < p < ∞, as a generalization of Euclidean space, has a rich structure in functional analysis (see, for instance, Refs. [9, 10]), and particularly in Banach space. Furthermore, it has broad applications in statistics (see, for instance, Refs. [11, 12]), engineering (see, for instance, Ref. [13, 27]), mechanics (see, for instance, Ref. [14]), computational science (see, for instance, Ref. [15]), biology (see, for instance,

, 1 < p < ∞, also has broad applications, in particular, signal processing in engi-

, lðr;θÞ∈ Gr1ðR2

ðx;y;r;θÞ : x cos ðθÞ þ y sin ðθÞ ¼ r

π1 and π2 are the natural projections of fibers. The Gelfand transform of a 2-density ϕ ¼

GTðϕÞ ¼ π1�π�

This chapter is structured as follows: In Section 2, we provide a description on Gelfand transform, which is one of the most fundamental transforms in integral geometry; in Section 3, we introduce density needed for the measure of length of curves; in Section 4, we further study the Lagrangian subspaces of complex Lp spaces; in Section 5, we work on tangent bundle of unit sphere in Minkowski space and its symplectic or Lagrangian structure; in Section 6, we apply the Lagrangian structure to establish the length formula in integral geometry; and in Section 7, we further apply the Lagrangian structure of a Minkowski space to establish the

, 0 < p ≤ 1, in the sense of conjugacy to the

Gr1ðR2Þ (1)

o

2ϕ; (2)

Þ,ðx;yÞ∈ lðr;θÞ

o ;

Ref. [16]), and other areas. Along this direction, Lp

formula for the Holmes-Thompson area in integral geometry.

R2 ← π1 F! π2

ððx;yÞ, lðr;θÞÞ : ðx;yÞ∈ R2

≃ n

.

neering, on which one can see Refs. [17–19].

scenario of Lp

30 Lagrangian Mechanics

2. Gelfand transform

Given a double fibration:

jdr∧dθj is defined as

which is a 1-density R2

F ¼ n

where

Lemma 3.1. For any v ¼ ðα;βÞ∈Tðx;yÞR2;

$$\text{GT}(\varphi)((x,y),\ v) = \mathbf{4}|v|.\tag{3}$$

Proof. For v ¼ ðα;βÞ∈ Tðx;yÞR2 ; there exists

$$\vec{v} = (\alpha\beta, \alpha\cos(\theta) + \beta\sin(\theta), \theta) \in T\_{((x,y), \, l(r,\theta))}\mathbf{F},\tag{4}$$

such that dπ1ð~vÞ ¼ v. Therefore, we have

$$\begin{split} \text{GT}(q)(\upsilon) &= \int \int \pi\_2^\* \varrho(\vec{v}, \bullet) \\ &= \int \sum\_{((x), \flat) \in \mathcal{A} \cap (\partial \mathcal{O}) \times \text{spin}(\partial \mathcal{O})} |(\vec{v}, \bullet)| \\ &= \int |a \cos(\theta) + \beta \sin(\theta)| d\theta \\ &= \int |\upsilon \cdot (\cos(\theta), \sin(\theta))| d\theta \\ &= \int |\upsilon \cdot (\cos(\theta), \sin(\theta))| d\theta \\ &= |\upsilon| \int\_0^{2\pi} \cos(\theta\_0 + \theta) d\theta \text{ where } \alpha = |\upsilon| \cos \left(\theta\_0\right), \beta = |\upsilon| \sin \left(\theta\_0\right) \\ &= 4|\upsilon|. \end{split} \tag{5}$$

Remark 3.2. By Alvarez's Gelfand transform for Crofton type formulas, we know that

$$\int\_{l\in\mathbb{R}^2} \mathfrak{F}(\gamma\mathbb{1}(r,\theta)) \mathrm{d}r \mathrm{d}\theta = \int\_{\mathcal{V}} \mathrm{GT}(\varphi). \tag{6}$$

Thus, we have now proved the Crofton formula: Given a differentiable curve γ in R2 , the length of γ can be computed in the following formula:

$$\text{Length}(\gamma) = \frac{1}{4} \int\_{l \in \mathbb{R}^2} \#(\gamma \lhd(r, \theta)) \text{d}r \text{d}\theta. \tag{7}$$


Contents

**III**

**Chapter 17 277**

Future of Bovine Amniotic Membrane: Bovine Membrane Application on Wound Healing, Surgery and Prospect of Use for Urethral Reconstruction

*by I Gusti Bagus Adria Hariastawa and Jemmy Andijaya Sutantio*


**7.7 Route 2: pacific region**

The *pfdhfr* CNRNI double mutant is predominant in malaria-endemic regions in the Pacific. The CNRNI has been reported to have two lineages, one which is indigenous and the other from Southeast Asia [92]. Resistance to pyrimethamine was observed in the early 1960s, after its introduction in a mass drug administration [68].


*Article* **Particle Size Distribution and Enrichment of Alkali and Heavy Metals in Fly Ash on Air and Oxy-Fuel Conditions from Sludge Combustion**

**Ha-Na Jang 1, Heung-Min Yoo 2 and Hang Seok Choi 1,\***

**Abstract:** Comparative tests in air and oxy-fuel combustion were conducted in a 30 kWth circulating fluidized bed (CFB) pilot plant for waste sludge combustion. General combustion characteristics of the CFB, such as pressure profiles, temperatures along the bed, and flue gas composition, were different under the air and oxy-fuel conditions. At the bottom and in the fly ash, alkali and heavy metals had different distributions under the air and oxy-fuel combustion conditions. The particle size distribution in fly ash from air combustion was dominated by coarse particles, over 2.5 μm in size, whereas with oxy-fuel combustion, most particles were submicron in size, approximately 0.1 μm, and a smaller quantity of coarse particles, over 2.5 μm in size, formed than with air combustion. Mass fractions of Al, Ca, and K, below 2.5 μm in size, were found in the ashes from oxy-fuel combustion and in higher quantity than those found in air combustion. Submicron particle formation from Cr, Ni, Cu, and Zn in the fly ash occurred more during oxy-fuel combustion than it did in air combustion.

**Keywords:** waste sewage sludge; oxy-fuel combustion; circulating fluidized bed; particle size distribution; alkali and heavy metals


**6. Street Art in the Canido Neighborhood: The Recovery of a Historically Stigmatized Neighborhood in the City of Ferrol**

The neighborhood of Canido, together with those of Ferrol Vello, La Magdalena, and the now-disappeared Esteiro, form the origins of an enlightened 18th century city, which emerged after the new naval policy of Felipe V came into force in 1726 in Spain (Figure 4). Its choice as the capital of one of the three maritime areas of Spain, the north, marked the beginning of the construction of an arsenal and shipyards, the orthogonal neighborhoods of Esteiro (known as the "frame " by its perimeter), the New Community of the Magdalena, and a whole series of defensive infrastructures materialized in the bastioned wall of the city and in the castles and batteries built on the margins of a natural port—the Ferrol estuary—an area of high geostrategic value until the first third of the 20th century [68].

The neighborhood is located on the top of a mountain to the north of the city with which it shares its name, between the cove of the Malata and the Magdalena neighborhood to the south, while in the west, it joins the early naval center of the old quarter. After successive proposals for fortification of the square, the one presented by the military engineer Pedro Torbé in 1768 definitively integrated this poorly populated rural space within the boundaries of the departmental city, being protected by one of the 12 bastions, known as Canido or Santiago. As well as its strategic nature, due to its altitude and exposure to the estuary, the peripheral and limit value in the administrative level can be added, a value that would play an important role in the process of expansion of the city from 1939 at the end of the civil war.

**Figure 4.** Canido neighborhood in the city of Ferrol.

Early reports refer to the place or village of Canido, which presupposes its earlier agricultural beginning, whose imprint is still noticeable in the traditional housing of the neighborhood. The rural exodus, attracted by the naval activity, would gradually turn this space into an alluvial neighborhood, capable of maintaining a part-time agricultural activity—unlike the one in Esteiro, erected from a new plant to house the shipyard workers and their families—supported mainly by women, who would have the opportunity to enter the labor market in one of the industrial initiatives (food, pencils, and textiles) from the 1940s. The male workforce was mainly concentrated in the shipyards of Bazán and Astano and participated in an increasingly diversified industrial sector, which was almost always related to the sea. Among others, the net factory (DEFER), PYSBE (Fisheries and Dryers of Cod of Spain), the Peninsular timber factory, the Hispania pencils factory, Soaps Pucho and properly in Canido the Fenya (Naval and Artillery Electrical Fabrications), the Piñon manufacturing company, and Industrial Pencils (ILASA). The settlement of workers in the neighborhood contributed to changing its physiognomy, causing profound internal social changes that were supported by the development of a militant commitment and solidarity strategies, which strengthened the affective and identity ties and generated a strong sense of belonging. While the bonding sentiment developed, initiatives at a parish level emerged to combat a daily life marked by the struggle against the difficulties of wages, hunger, poverty, inhuman housing, both parents working, and children in the street [69].

Its peripheral physical and structural origin, the peculiarities of its growth and development, as well as the recurring crises that plagued the city and its region were also accompanied by processes of social exclusion and segregation, materialized in perceptible forms of urban fragmentation and marginality, sometimes loaded with negative connotations and stereotypes, which were, without a doubt, defense strategies of the most favored groups to justify the existing social inequalities within the framework of the prevailing developmentalism. Stereotypes that can still be seen in the sociocultural imaginary and that condition the perception that some inhabitants of the city of Ferrol have of the neighborhood in general and in particular of its limits with the Magdalena neighborhood. The conformation as a structural periphery is related to the process of devaluation of the area that led to the opening of the municipal cemetery—the Canido cemetery—in 1804 after more than 25 years of heated controversies between the local authority and the neighborhood. On the other hand,

the periphery, understood as a remote and disconnected space from the illustrated city, was favored with the opening of the street of San Eugenio in a north-south direction, which was immediately converted by citizens into the street of the dead and corresponds to the current street of La Coruña.

This fact, which responds to the implementation of sanitation budgets, was not isolated, as evidenced by the transfer or erection of new charitable welfare infrastructures in the open crossroads on the hillside, initiated with the opening of the new building of the charity hospital in March 1786, whose lands were acquired almost at the same time as those of the cemetery. Subsequently, this culminated with the nursery, the school for poor girls, the nursing home, and centers for social care and the company stores in the Dictatorship (1939–1975).

The presence of these institutions, together with the industrial enclaves, contained the prices of the abundant land and favored initiatives of private housing cooperatives—for example, the houses of the housing cooperative of Santa Cruz and, on a smaller scale, those of naval government officials, which were accompanied by the construction of the noncommissioned dwellings of the army at the door of Canido (currently Plaza de Canido, a newly created node) and by those built on the initiative of the Board of Trustees of Houses of the Navy for noncommissioned officers outside the entrance to Canido, extending the neighborhood to the east following the axis drawn by the old county road 646 and the newly built council housing. The emergence of these new promoters resulted in the emergence of new social upheavals and interior peripheries, degraded spaces located in the inner city, which in the past formed a periphery that was frozen in time [70] that materialized in an significant trade union and protest activity within the framework of specialized Catholic Action movements in the absence of democracy.

This construction fever began in the 1950s after the closure of the cemetery and fundamentally materialized in the decades of the 1960s and 1970s. This resulted in the expansion of the neighborhood to the east, and also to the west, coming into contact with the old quarter, where a small, upper class garden city arose, which was interwoven with the buildings that rise up the hillside as the northern extension of the Magdalena neighborhood, especially after the transfer from the hospital to the new dormitory suburb of Caranza and the opening of sections of the diagonal project dedicated to Doctor Fleming.

The increase in housing stock was accompanied by the improvement and opening of new urban roads and resulted in a significant increase in the population, whose immediate consequences were manifested in the erection of the new parish of the Holy Cross, which closed on 13 October 2019 after 55 years of operation, and the creation of public educational institutions for children and the current primary school—the Canido Infant and Primary Education Center (the former Reyes Catolicos school)—and the subsidiary of the women's institute on the grounds of the former graveyard, along with other private initiatives, all of which was accompanied by the proliferation of small commercial and artisanal activities to meet the demand of new residents.

To delimit the neighborhood is difficult. The Madoz dictionary [71] and the History of Ferrol de Montero Aróstegui [72] both break the space up as part of the Magdalena neighborhood or the historic center. At this time, the limits proposed by the city council coincided in the southern part with the layout of the grid of the enlightenment.

In line with its expansion process and its socio-economic peculiarities, urban deterioration processes do not affect all internal sectors equally. They are located mostly in the areas adjacent to the early roads that converge in the Stone cross square, the main node of the old enclave (Atocha-Riego, Alegre, Insúa, Alonso López), a crossing that has become an iconiclandmark of the neighborhoo, in the surroundings of the Plaza de la Tahona, Muiño do Vento, and in the corral of Chapón, which contrast more, if possible, with the recent estate built on the site of the old Fenya or on the new avenue of the painter Pérez Parrallé. It is worth noting that we are currently helping with the launch of major, new housing developments in the neighborhood [73], which support the recent prominence of this space in the framework of a city in perpetual crisis, due to both the decrease in the number of people living there and an aging population. It has been listed as the oldest city in Spain according to 2018 data from

the Galician Institute of Statistics [74], since those over 64 represent 27.4% of the urban population, two points above the average of the region of Galicia (24.9%).

This is also felt when you see that Canido currently has the lowest average age of the old walled enclosure—45.4 years, only surpassed by two small districts located in the greater area outside the gates that develops on the axis traced along the road of Castile, the main (and until 1968 the only) communication route that links it to the state road network. The best neighborhood in Galicia [75], as was recently awarded by Galician Television, is the result and recognition of an important neighborhood action that has managed to combine the historical legacy, secular traditions such as the exaltation of nature in May - Los Maios -, the recovery of old icons that give it its own personality, such as the Chapon yard, the bulwark, or the public laundry, with the strength of identity and belonging ties, the result of a hard shared experience, to undertake a whole series of strategies that allowed the deterioration and abandonment initiated with the naval crisis of the late 1970s to be left behind. From an identity of resistance [76], collectively and jointly built during the dictatorship, the residents of Canido have managed to rebuild it through a project based on elements of their collective culture. Its objective is to implement a neighborhood project through different initiatives that combine the complaint and visibility of problems with actions aimed at the sustainable improvement of the living conditions of the inhabitants, the recovery of heritage and public spaces both from the environmental point of view and also for living side by side, and encouraging new buildings that attract and settle new residents who collaborate on the path of demographic recovery and in the process of economic revitalization.

There are many initiatives that have been carried out, among which we can highlight the second-hand market [77]; the flowery orchards of Canido [78] (in which the environmental component is combined with the principles of land Art, the Mercalegre art market [79]); and fundamentally the street art festival, Meninas de Canido, in which cultural activity has become an important local development strategy. With this, the neighborhood has been reborn as a neighborhood that tourists visit again and, above all, that neighbors can enjoy again; a neighborhood in which new small businesses are emerging, in which children go out to play in the street and in which adults meet again in the bars of the stone cross square to have a drink; and a neighborhood in which the neighbors no longer leave, but new ones arrive [80]. The increase of the neighborhood in a city that loses an average of 800 inhabitants in the last year (770 in 2018) supports this collective project, which we will analyze in depth in the following sections.

### *6.1. Las Meninas de Canido: the Art of the Museum on the Street*

Las Meninas de Canido is an artistic and cultural festival where image and sound take to the streets as a vindication of a living neighborhood in permanent transformation. Its origin dates back to 2008, when it arose as a complaint mechanism to the situation of deterioration in the Canido neighborhood in Ferrol, a neighborhood in which the population did not want to reside and where there was no business or investment.

The artist Eduardo Hermida was its promoter. According to Hermida, it hurt to see how the neighborhood he had grown up in was degrading. That is why, remembering his childhood when he painted the wall of one of the houses in his neighborhood with chalk, he decided to begin to capture art in its streets. For this, he chose one of his favorite painters, Velázquez, and among his works, he chose Las Meninas, because it is perhaps his most recognizable work.

His goal was twofold: on the one hand, with the color of the works, he wanted to give light to the facades—victims of abandonment, deterioration, or vandalism; and on the other, he sought to take art from museums to the street in order to offer free culture to people who had no means to visit a museum or go to a concert. This is how, in 2008, the colorful performance of the Meninas de Canido began. In that year, Eduardo Hermida invited a group of artists from diverse, new, and renowned trajectories to participate in a pictorial marathon that would last 12 hours. The idea was to represent the Meninas painting on the walls of degraded homes, as if they were a canvas. It was an activity buoyed by music and one in which the local residents played an active role by offering supplies to the participants. The municipality collaborated by donating the material for the realization of the paintings, and thanks to the successful day, the initiative was repeated in later years.

Over the years, the Meninas de Canido has become more popular both nationally and internationally, and its organizational model has changed.

**Figure 5.** (**a**) Unmasked Menina Shfir; (**b**) Menina of Infanta Margarita Lily Brik.

The festival takes place in early September, and the 2018 edition welcomed more than 100,000 visitors. Since its inception, more than 1200 artists have participated in it, some from Syria, Slovenia, Poland, Brazil, or Taiwan, which gives the neighborhood a universality. Along its streets, there are more than 300 pictorial works that can be enjoyed (Figure 6).

**Figure 6.** Meninas in the Canido neighborhood.

In addition, a mobile app known as VISUAR for IOS system and Visar Augmented Reality for Android mobiles have been created, through which information about the works can be obtained as well as some animations that can be seen by standing in front of them.

The festival has aroused interest in cities outside Spain, and Eduardo Hermida has given presentations in forums in Paris and Kiev. Other Spanish cities, such as Madrid, intend to develop a similar initiative in several districts, while other cities are also targeting chromatism. These include Cambre, with its Chromatic Mural Fest, or Carballo, with its initiative Breaking Down Walls with Paint (Figure 7). It has been shown that art has very positive effects, not only from the point of view of the physical improvement of neighborhoods but also of social valorization.

**Figure 7.** Murals in Carballo.


*2.10. In Vivo Antitumor Tests*

B16F10 cells (1 × 106 ) were injected subcutaneously into each C57BL/6 mouse to establish a B16F10-melanoma bearing mice model to evaluate the antitumor efficiency in vivo. The tumor-bearing mice were randomly divided into 7 groups one week after inoculation of melanoma cells (*n* = 5), as follows: PBS-treated group (denoted as PBS), free aCTLA-4 + aPD-1 mixed solution group (aCTLA-4 + aPD-1), aCTLA-4/aPD-1 co-loaded hydrogel group (aCTLA-4 + aPD-1)@gel, Dox solution group (Dox), Dox-loaded hydrogel group (Dox@gel), free Dox + aCTLA-4 + aPD-1 solution group (Dox + aCTLA-4 + aPD-1), and Dox/aCTLA-4/aPD-1 co-loaded hydrogel group (Dox + aCTLA-4 + aPD-1)@gel. The volume of paratumorally injected solution in each group was 50 µL. The dosages of Dox, aCTLA-4 and aPD-1 were controlled as 4 mg/kg, 1 mg/kg and 2 mg/kg, respectively, in the formulations containing each ingredient. The average melanoma volume and body weight were recorded and calculated in each group at predetermined time points. The melanoma volume was calculated according to the following equation: V (mm3 ) = L × W2/2, where L (mm) means the length of melanoma and W (mm) represents the width of melanoma. The mice were euthanized when the volume of tumor was higher than 1500 mm3 , except those that died naturally. The survival time for all the treated groups was investigated in a separate study (*n* = 7).


**3.3.1 Status Monitoring Application Ontology**

The Status Monitoring Application Ontology is used to express the *SAV* of the status monitor agent. To model the behaviour of all components and subsystems considering from sensor data to possible model outputs, the Status Monitoring Application Ontology is designed and built based on ontology design patterns (Blomqvist & Sandkuhl, 2005). Ontology patterns facilitate the construction of the ontology and promote re-use and consistency if it is applied to different environments. In this work, the representation of the monitoring concepts are based on a system observation design pattern. Some of the most important concepts identified for status monitoring are:

**4.2 Mission plan adaptation agent**

Π*q* =

planning.

Σ*q*, Ω*q*

The Path Towards Permanent Presence of Underwater Networks

processes using partial plan representation of the mission plans.

πq−1

ψ0Π0 Πq−1 Πq Πq−1

209 Embedded Knowledge and Autonomous Planning:

Fig. 7. Schematic representation of the autonomous mission generation, replan and repair

This section describes the mission environment model used by the mission plan repair techniques presented in this chapter. We continue using the mission environment model previously described. We generalise this model to any step *q* in the mission execution timeline. An instance of an UUV mission environment at a given step *q* can be simply defined as

the available resources in the system *PV* and the set of actions or capabilities *AV*. The mission problem model Ω*q* contains the current platform state *xq* and the mission requirements *QO*. Based on this model, we analyse how to calculate mission plans on the plan space (Sacerdoti, 1975). A plan space is an implicit directed graph whose vertices are partially specified plans and whose edges correspond to refinement operations. In a real environment where optimality can be sacrificed by operability, partial plans are seen as a suitable representation

A partial plan *ψ* is a tuple containing a set of partially instantiated actions and a set of constraints over these partially grounded actions. Constraints can be of the form of ordering constraints, interval preservation constraints, point truth constraints and binding constraints. Ordering constraints indicate the ordering in which the actions should be executed. Interval preservation constraints link preconditions and effects over actions already ordered. Point truth constraints assure the existence of precondition facts at certain points of the plan. Binding constraints on the variables of actions are used to ground the actions to variables of the domain. Figure 8 shows a partial plan representation of an UUV mission. Partial plans are flexible to modification. They provide an open approach for handling extensions such as temporal and resource constraints. Due to nature of the constraints, it is easy to explain a partial plan to a user. Additionally, it is easily extensible to distributed multi-agent mission

Figure 7 explains the processes of mission plan repair and mission plan replan for mission plan adaptation for UUVs using a partial plan representation of the mission plans. At the initial step, a partial ordered plan *ψ*0 is generated satisfying the original mission environment Π0. The *ψ*0 is then grounded into the minimal mission plan *π*0 including all constraints in *ψ*0. At step *q*, the semantic knowledge-based framework is updated by the diagnosis information Π˙ *q* providing a modified awareness of the mission environment Π*q*. From here, two mission adaptation processes are possible: *Mission replan* generates a new partial plan *ψq*, as done at the first stage, based only on the knowledge of Π*q*. On the other hand, *mission plan repair* re-validates the original plan by ensuring minimal perturbation of it. Given the partial plan at the previous step *ψq*−1 and the diagnosis information Π˙ *q*, the mission repair problem produces a solution partial plan *ψq* that satisfies the updated mission problem Π*q*, by modifying *ψq*−1. The final step for both approaches is to ground *ψq* to its minimal mission plan

because they are a flexible constrained-based structure capable of being adapted.

ψq−1 ψq ψq−1 ψq

Π˙ q Π˙ q q − 1 q q − 1 q

π0 πq πq

. The mission domain model Σ*q* contains the set of propositions defining

πq−1

Πq

Please note how some of these concepts are related to concepts of the Core Ontology (e.g. an *observation* comes from a *sensor*). These Core Ontology elements are the enablers for the knowledge exchange between service-oriented agents. This will be shown in the demonstration scenario of Section 5.3.


*5.3. Limitations of this Research and Future Work*

The scope of this study was limited regarding the validation of the UAS technology in a relevant environment but not in an operational environment as the UAS flights were only trialled without the direct implementation of the data. Thus, this study did not address gaps and challenges on how the expressed stakeholder needs were actually met in the context of Rwanda. Future work could address this with a strong focus on implementation to evaluate the fitness-of-use of UAS workflows with due consideration of the entire innovation chain including GIS applications. This could be coupled with the design and evaluation of appropriate governance and capacity building models to allow the prototype demonstration of UAS-based workflows in an operational environment. Additionally, further research will be needed to explore the role of UAS compared to other geospatial technologies such as satellite data and classical aerial photographs in providing base data that serves as a spatial framework for the various land administration functions [49].


**5. Conclusions**

The current study demonstrated that LBE had protective effects on renal NLRP3 inflammasome-associated hyperinflammation in T2DM mice. Simultaneously, LBE at a high dose stimulated AMPK/SIRT1 activation and attenuated oxidative stress, although some molecular markers were selectively regulated at different treatment doses of LBE in in T2DM mice. Conclusively, the present study suggests that LB might have potential benefit to prevent and ameliorate hyperglycemia-induced renal inflammation under diabetic conditions.

**Author Contributions:** Conceptualization: Y.L.; data curation: J.E.P.; formal analysis: Y.L. and J.E.P.; investigation: Y.L and S.Y.K.; funding acquisition: Y.L.; methodology: Y.L., J.E.P., and H.L.; supervision: Y.L.; writing, review, and editing: J.E.P., H.L., and Y.L. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was supported by a grant (2018R1D1A1B07046778) funded by the Ministry of Education, Science and Technology, Republic of Korea.

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.


Acknowledgements

they found out that there are differences such as GDP growth, capital market development

Bas et al. [35] also investigated capital structure in emerging markets. They examined the capital structure in 25 countries from different regions. It should be noted that according to their study listed companies that prefer equity financing instead of long-term debt financing. They also investigated the effect of company size. Large companies are more diversified and default risk is reduced as a result of higher leverage. Hence, small and large companies have different debt policies. Also, large and traded companies can easily get access to finance that

Jong et al. [36] examined the importance of country and firm-specific factors in the leverage choice of companies from 42 countries. They found that the impact of several firm-specific factors (tangibility, company size, growth and profitability) on cross-country capital structure

According to the studies mentioned above, the capital structure in emerging markets is determined, in addition to factors similar to those in developed countries, by specific factors. These include the development of the capital market, inflation or the size of businesses [37]. The weak development of the capital market, especially bond market, means that the company cannot take advantage of the possibility of issuing a bond. Therefore, it is not possible to determine the market value of debt, and market value-based theories of the tax shield cannot be applied. Within the models reviewed in the chapter, we can suggest the use of models with a book value of debt because they are suitable for all businesses, regardless of size and

In addition to debt value used (market versus book); it is also questionable to estimate the cost of capital (discount factor). For example, the cost of equity is traditionally estimated by CAPM model. However, if the company is non-listed, the model is inappropriate or inaccurate. Also the weighted average cost of capital is difficult to quantify. Damodaran [37] has created the database

The tax shield is also affected by the tax system and corporate and personal tax rate or loss

Under the conditions of emerging markets, the tax shield represents a significant source of value and is therefore part of several methods of investment decision analysis. Leasing is a frequent form of financing for small and medium enterprises; net advantage to leasing model includes an analysis of interest and depreciation tax shields; value of tax shield may be a decisive factor for selecting a portfolio of investment projects (using a modified resource-constrained project scheduling problem with discounted cash flows). In addition, other methods of investment decision-making may be adjusted for the existence of a tax shield, like risk analysis [41–44].

The chapter deals with the analysis and classification of selected approaches to the quantification of tax shields. Theories are based on the premise of the perfect capital market and a clearly

to help estimate the cost of equity and debt. In addition, a build-up model is often used.

carried forward, which affects the effective tax rate and tax burden [38–40].

depends more on the economic conditions of the country.

40 Financial Management from an Emerging Market Perspective

is significant and consistent with conventional theories.

tradability of a company on the capital market.

and inflation rates.

5. Conclusion

The chapter is an output of the science project VEGA 1/0428/17 Creation of New Paradigms of Financial Management at the Threshold of the 21st Century in Conditions of the Slovak Republic.


**1. Introduction**

#### **1.1. Breast cancer**

Breast carcinoma is one of the most frequently diagnosed cancers among women worldwide with a high frequency reported in the West [1, 2]. This highest incidence of breast cancer in American whites and in most European countries reveal the long-standing high prevalence of reproductive factors associated with increased risk of breast cancer, including early menarche, late child bearing age, few pregnancies, hormone replacement therapy and increased mammography [3, 4]. In Israel, the increased incidence of breast cancer may reflect the disproportionately high prevalence of BRCA1 and BRCA2 mutations [5, 6].

Western lifestyle is another most important factor for Britain's high number of breast cancer cases fuelled by the women overeating, too much drinking and too little exercise doing in routine life. In addition, breastfeeding is also an important factor, which reduces the chance of developing breast cancer. Eastern women do not drink alcohol than women in the United Kingdom, and obesity ratio is much lower in Asian women than in western women, whereas breastfeeding rates are much higher in Asians (http://www.dailymail.co.uk/news/article-1301445/Western-lifestyle-blame-soaring-breast-cancer-rates.html). Affected women with breast cancer are usually young and often present with advanced disease [7]. According to a World Health Organization (WHO) estimate, around 25.2% people are diagnosed with breast cancer annually. The exact reason why a woman develops breast cancer is still unrevealed; though certain risk factors enhance a person's probability of getting breast cancer.

The factors that play a significant role in the aetiology of breast cancer include genetic [8, 9], hormonal [10, 11], environmental [12], lifestyle [13] and reproductive factors [14]. In addition, ovarian hormones (endogenous estrogen) are the key risk factors for the development of breast cancer and their progression among post-menopausal women [15, 16]. However, it is unclear that to what degree the effects of other risk factors may be mediated by their links with circulating free estradiol. Intake of vegetables and fruits are related with a substantial decrease of breast cancer risk [17, 18]. Vegetables are rich in antioxidants and certain phytochemicals may contribute to the reduced risk of breast cancer [19–21]. Plant-based diets are also high in fibres, which can decrease serum estrogen and could, in this way, contribute to reduced risk of breast cancer [22, 23]. In addition, increased consumption of fruit and vegetables are associated with lower rates of obesity, which is a crucial risk factor for post-menopausal breast cancer [24]. High energy intake, physical sluggishness, high body mass index (BMI) and weight put on are coupled to an increased breast [25] cancer risk. Low levels of HDL-C in breast cancer patients than in control subjects have also been documented [26]. But still, data from prospective studies are very limited (Moorman, 1998). Furthermore, consanguineous marriages are common in certain racial groups, which will increases the risk of breast cancer [27].

Among these contributing factors, vitamin D and its receptor gene polymorphisms may play a pivotal role in the development of mammary gland tumourigenesis [28].

#### **1.2. Vitamin D and vitamin D receptor (VDR)**

Vitamin D and VDR are the two most important participants playing a key role in vitamin D endocrine system in the prevention of breast cancer. Vitamin D is a sunshine vitamin, which is involved in a variety of actions and also reduces the risk of many cancers [29, 30].

VDR is a member of nuclear receptor (NR) superfamily and transcription regulating factor also called NR1I1 or nuclear receptor subfamily 1, group I and member 1. VDR is a high‐affnity, low‐capacity receptor having a molecular weight of about 48–55 kD. VDR is expressed in majority of human tissues. But some cells have decrease or no VDR expression including RBCs, mature cardiac and skeletal muscles and cerebellar Purkinje cells [31]. Its actions are preceded by the formation of heterodimer with retinoid X receptor (RXR), which causes the conforma‐ tional changes in VDR and allow the binding of vitamin D3 at ligand binding domain (LBD). In addition, the heterodimer complex then binds with a specific sequence present in the DNA called vitamin D response element (VDRE). Genomic pathway involves the expression of genes in a tissue‐specific manner [28].

#### *1.2.1. VDR domains*

**1. Introduction**

136 A Critical Evaluation of Vitamin D - Clinical Overview

**1.1. Breast cancer**

Breast carcinoma is one of the most frequently diagnosed cancers among women worldwide with a high frequency reported in the West [1, 2]. This highest incidence of breast cancer in American whites and in most European countries reveal the long-standing high prevalence of reproductive factors associated with increased risk of breast cancer, including early menarche, late child bearing age, few pregnancies, hormone replacement therapy and increased mammography [3, 4]. In Israel, the increased incidence of breast cancer may reflect the dispropor-

Western lifestyle is another most important factor for Britain's high number of breast cancer cases fuelled by the women overeating, too much drinking and too little exercise doing in routine life. In addition, breastfeeding is also an important factor, which reduces the chance of developing breast cancer. Eastern women do not drink alcohol than women in the United Kingdom, and obesity ratio is much lower in Asian women than in western women, whereas breastfeeding rates are much higher in Asians (http://www.dailymail.co.uk/news/article-1301445/Western-lifestyle-blame-soaring-breast-cancer-rates.html). Affected women with breast cancer are usually young and often present with advanced disease [7]. According to a World Health Organization (WHO) estimate, around 25.2% people are diagnosed with breast cancer annually. The exact reason why a woman develops breast cancer is still unrevealed;

though certain risk factors enhance a person's probability of getting breast cancer.

common in certain racial groups, which will increases the risk of breast cancer [27].

a pivotal role in the development of mammary gland tumourigenesis [28].

Among these contributing factors, vitamin D and its receptor gene polymorphisms may play

The factors that play a significant role in the aetiology of breast cancer include genetic [8, 9], hormonal [10, 11], environmental [12], lifestyle [13] and reproductive factors [14]. In addition, ovarian hormones (endogenous estrogen) are the key risk factors for the development of breast cancer and their progression among post-menopausal women [15, 16]. However, it is unclear that to what degree the effects of other risk factors may be mediated by their links with circulating free estradiol. Intake of vegetables and fruits are related with a substantial decrease of breast cancer risk [17, 18]. Vegetables are rich in antioxidants and certain phytochemicals may contribute to the reduced risk of breast cancer [19–21]. Plant-based diets are also high in fibres, which can decrease serum estrogen and could, in this way, contribute to reduced risk of breast cancer [22, 23]. In addition, increased consumption of fruit and vegetables are associated with lower rates of obesity, which is a crucial risk factor for post-menopausal breast cancer [24]. High energy intake, physical sluggishness, high body mass index (BMI) and weight put on are coupled to an increased breast [25] cancer risk. Low levels of HDL-C in breast cancer patients than in control subjects have also been documented [26]. But still, data from prospective studies are very limited (Moorman, 1998). Furthermore, consanguineous marriages are

tionately high prevalence of BRCA1 and BRCA2 mutations [5, 6].

VDR contain five functional domains (**Figure 1**) including:

Both N‐ter and C‐ter has activation function (called AF‐2) in translation [33].

#### *1.2.2. Vitamin D/VDR actions*

**Figure 1.** The crystal structure of VDR showing its functional domains [34]. (A) Schematic representation of VDR domains. (B) LBD of the VDR which contains 12 alpha helices. (C) The binding mode of Vitamin D in the hormone-binding pocket. (D) The DBD of the Vitamin D. The two zinc atoms are represented in blue in colour, whereas beta sheets are represented in yellow colour.

## **2. Bio‐activation and metabolism of Vitamin D in normal breast**

It is already known that vitamin D affects the breast cancer cell growth but limited information is available about its delivery, uptake and metabolism in mammary cells. Vitamin D is either derived from the gastrointestinal (GIT) absorption or synthesized within the skin under the exposure of UVB radiations, which then undergoes the 25-hydroxylation in liver in presence of 25-hydroxylase resulting in the production of 25(OH)D3. 25(OH)D3 is the precursor molecule for the synthesis of active Vitamin D3 (1,25(OH)2D3). It is a major circulating form of vitamin D, which is stored in adipose tissues. It is also an accurate biomarker of vitamin D, which determines the overall status of vitamin D in the body. However, the precursor does not readily binds to the VDR and must be converted into its active form, 1,25(OH)2D3, which has high binding affinity to VDR. The conversion of precursor vitamin D into its active metabolite occurs in the presence of 1-α-hydroxylases. Immunohistochemistry and *in situ* hybridization studies indicated strong expression of 1α-hydroxylase protein and mRNA in the distal convoluted tubule, the cortical and medullary part of the collecting ducts and the papillary epithelia. Lower expression was observed along the thick ascending limb of the loop of Henle and Bowman's capsule. Weaker and more variable expression of 1α-hydroxylase protein and mRNA was seen in proximal convoluted tubules, and no expression was observed in glomeruli or vascular structures [36]. Whereas lesser expression of 1*α*–hydroxylase was also observed in non–renal cells including keratinocytes, macrophages, prostatic epithelium, colonocytes [37, 38] and breast epithelium [39] to lesser extent. Kidneys and non-renal 1-α-hydroxylases are encoded by the same gene mapped on the chromosome 12 [40]. However, the presence of this enzyme on non-renal tissues indicated that the non-renal tissues have the ability of vitamin D bio-activation, responsible to convert 25(OH)D3 into 1,25(OH)2D3. 1,25(OH)2D3 is virtually not detected in human serum under anephric conditions, which means that kidneys are the major source of 1,25(OH)2D3 in circulation. These observations emphasize that 1,25(OH)2D3 produced by the non-renal tissues is not released in the bloodstream. However, they act locally upon binding to VDR on the same tissues from where it is synthesized. Such local actions of vitamin D are likely included in proliferation, differentiation and apoptosis, which are discussed below in later sections.

#### **2.1. Bio‐activation pathways in breast cells**

The above information supports the hypothesis that two distinct pathways may be involved in the bio-synthesis and bio-activation of vitamin D in breast such as 1,25(OH)2D3 and 25(OH)D3 (vitamin D precursor) pathways [41, 42].

#### *2.1.1. Endocrine pathway*

**Figure 1.** The crystal structure of VDR showing its functional domains [34]. (A) Schematic representation of VDR domains. (B) LBD of the VDR which contains 12 alpha helices. (C) The binding mode of Vitamin D in the hormone-binding pocket. (D) The DBD of the Vitamin D. The two zinc atoms are represented in blue in colour, whereas beta sheets

It is already known that vitamin D affects the breast cancer cell growth but limited information is available about its delivery, uptake and metabolism in mammary cells. Vitamin D is either derived from the gastrointestinal (GIT) absorption or synthesized within the skin under the exposure of UVB radiations, which then undergoes the 25-hydroxylation in liver in presence of 25-hydroxylase resulting in the production of 25(OH)D3. 25(OH)D3 is the precursor molecule for the synthesis of active Vitamin D3 (1,25(OH)2D3). It is a major circulating form of vitamin D, which is stored in adipose tissues. It is also an accurate biomarker of vitamin D, which determines the overall status of vitamin D in the body. However, the precursor does not readily binds to the VDR and must be converted into its active form, 1,25(OH)2D3, which has high binding affinity to VDR. The conversion of precursor vitamin D into its active metabolite occurs in the presence of 1-α-hydroxylases. Immunohistochemistry and *in situ* hybridization studies indicated strong expression of 1α-hydroxylase protein and mRNA in the distal convoluted tubule, the cortical and medullary part of the collecting ducts and the papillary epithelia. Lower expression was observed along the thick ascending limb of the loop of Henle and Bowman's capsule. Weaker and more variable expression of 1α-hydroxylase protein and mRNA was seen in proximal convoluted tubules, and no expression was observed in glomeruli or vascular structures [36]. Whereas lesser expression of 1*α*–hydroxylase was also observed in non–renal cells including keratinocytes, macrophages, prostatic epithelium, colonocytes [37, 38] and breast epithelium [39] to lesser extent. Kidneys and non-renal 1-α-hydroxylases are

**2. Bio‐activation and metabolism of Vitamin D in normal breast**

are represented in yellow colour.

138 A Critical Evaluation of Vitamin D - Clinical Overview

The endocrine pathway is involved with the circulation of 1,25(OH)2D3, which reaches the mammary tissues and produces anti-neoplastic effects through genomic pathway.

#### *2.1.2. Autocrine/paracrine pathway*

The other pathway is the autocrine/paracrine pathway involved with the 25(OH)D3, which reaches the mammary gland and converts into 1,25(OH)2D3 [43] in the presence of 1-αhydroxylase to prevent breast cancer [41]. Most of the extra-renal tissues of the body have its own 1-α-hydroxylase enzyme needed for the production of active metabolite of vitamin D [37]. The circulating level of 25(OH)D3 seems to be the key regulator of tissue-specific synthesis of active vitamin D [37, 44]. The locally produced active vitamin D binds with VDRs of mammary epithelium in order to regulate the expression of more than 200 genes, which are involved in controlling cell proliferation, inhibit cell growth, stimulate cell differentiation, induce apoptosis and inhibit angiogenesis [45] and contribute in the prevention of breast tumourogenesis [46]. Moreover, mammary epithelial cells also contain 24-hydroxylase enzyme (CYP24), which converts active vitamin D into less active metabolites including 24,25-dihydrohydroxyvitamin D3 and 1,24,25-trihydroxyvitamin D3 [43]. For this reason, we can say that breast tissues contain all the elements of vitamin D signalling axis, which involve in the local synthesis as well as metabolism of vitamin D and its signal transduction through VDRs.