**6. Conclusions**

In this paper, we surveyed the literature on mathematical programming with fuzzy numbers from a perspective that emphasizes the necessity of using the extension principle within the whole optimization process, not only within the fuzzy arithmetic evaluation.

Since our review showed that the extension principle was widely present through the fuzzy arithmetic, but much less involved in the foundations of the solution concepts, we advanced the idea that the rehabilitation of the extension principle when deriving relevant fuzzy descriptions to optimal solutions is highly needed. Our opinion was supported by several recent studies showing that better and more effective solutions can be obtained when the algebraic aggregation of the fuzzy quantities and optimization are unified and together conduce to a solution concept that complies to the extension principle.

We discussed the similarities between optimization problems with fuzzy coefficients and full fuzzy optimization problems, and concluded about the unification of their subclass of optimization problems with fuzzy coefficients that assume fuzzy decision variables but with a priori unknown shapes. The solution approaches to this subclass of optimization problems with fuzzy numbers are expected to follow the extension principle, and a posteriori disclose the shapes of the decision variables.

We believe that this study advances relevant ideas to initiate the revitalization of the extension principle in mathematical optimization with fuzzy numbers. Due to its critical view on the basis of the methodology used to solve certain classes of fuzzy optimization problems, and since its implementation in various fields is able to provide more accurate and reliable optimal solutions, we expect that our conclusions will have an impact on solving practical industrial problems. As it has been said, the impact should be effective on the methodology level, and could be seen as a subtle attempt to filling the gap between the academic researches with their theoretical results and the relevant solutions needed in practice.

Our future research will be focused on deriving analytic solutions to full fuzzy optimization problems that are in accordance to the extension principle, and also simple enough to be able to replace the existing solution approaches. We will follow the research directions proposed in the previous section in order to enlarge the class of problems approachable via the extension principle.

**Author Contributions:** Conceptualization and methodology, B.S. and M.S.; writing—original draft and visualization, B.S.; writing—review and editing, validation, S.N.; supervision, M.S. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** The authors wish to record their sincere gratitude to professor I. Dzitac for his generous help in the preparation of this paper, and also for many valuable and constructive suggestions that guided them for years. This work was partly supported by the Serbian Ministry of Education, Science and Technological Development through Mathematical Institute of the Serbian Academy of Sciences and Arts and Faculty of Organizational Sciences of the University of Belgrade.

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


**4. Antigenic structure**

known which cause a wide range of illnesses, from mild respiratory infections in young chil-

This family includes two genera designated based on genetic criteria (*Atadenovirus* and *Siadenovirus*) as well as three genera, in which adenoviruses are combined according to the type of host (*Aviadenovirus*, *Ichtadenovirus*, and *Mastadenovirus*) (https://talk.ictvonline.org/

Genus *Atadenovirus* presents the newly formed genus which combines adenoviruses with a high relative content of AT-pairs in genomic DNA. This genus includes also adenoviruses of

Genus *Siadenovirus* combines adenoviruses containing at the 5′ end which contains a gene of an enzyme sialidase that cuts off sialic acid residues from the surface glycoproteins of the host

Genus *Aviadenovirus* includes adenoviruses of turkeys, quail, chickens, and a number of other birds. The type species causes the death of embryos and respiratory disease in quails and chickens. Other members of this genus are pathogens of the egg drop syndrome, hemorrhagic

Genus *Ichtadenovirus* has the only characterized representative which infects white sturgeon—

Genus *Mastadenovirus* includes various viruses of mammals: viruses of cows, sheep, deer,

Adenoviruses are non-enveloped viruses, 80–90 nm in diameter. The icosahedral capsid of adenoviruses consists of hexones carrying group-specific and type-specific antigens and pentones containing mainly group-specific antigens at each apex. From each pentone there is a

Structural proteins of adenoviruses are designated by Roman numerals in descending order of molecular weight. The adenovirus capsid consists of seven structural proteins; three major capsid proteins hexon, fiber, and penton; and four minor proteins protein IIIa (pIIIa), VI, VIII, and protein IX [5]. Fibers provide binding to cellular receptors and participate in the discrimination of infected cells, causing inhibition of the synthesis of cellular macromolecules [6]. Soluble proteins of pentone cause a cytopathic effect similar to the action of infectious adenoviruses,

In humans, 57 adenoviruses are known, which are divided into 7 groups (A–G).

dren to life-threatening multi-organ disease in immunocompromised people.

**2. Adenoviruses' nomenclature**

snakes, possums, calves, chameleon, ducks, and lizard.

cells. These adenoviruses infect frogs and birds.

pigs, dogs along with all human adenoviruses.

fiber with a head at the end (**Figure 1**).

taxonomy).

2 Adenoviruses

enteritis, and hepatitis.

*Sturgeon ichtadenovirus A.*

**3. Structure**

Antigenic structure of *Mastadenovirus* is represented by three soluble antigens: the hexone A-antigen is common for all serotypes; pentone antigen (B-antigen) is a toxic antigen, it inhibits the action of interferon and increases the severity of associated respiratory infections; and fibril C-antigen is a type-specific which promotes the adsorption of adenoviruses on monkey or rat erythrocytes and causes their agglutination. Manifest forms of the disease cause epidemic serotypes (3, 4, 7, 14, 21) of subgroups B and E. Serotypes 1, 2, 5, and 6 subgroups C cause a latent current, contributing to the formation of chronic tonsillitis and adenoiditis. Clinical forms of adenovirus infection presented in **Table 1**.

of virus particles occurs in the nucleus, where crystal-like inclusions are formed. Several hundred viral particles are synthesized in each cell. The release of adenoviruses is accompanied by the destruction of the host cell. The cycle of reproduction of adenoviruses in the cell lasts

Introductory Chapter: Human Adenoviruses http://dx.doi.org/10.5772/intechopen.82554 5

Adenoviruses can multiply in different cells, including airway epithelial cells and lymphocytes. Virus-infected cells become targets for immunity effectors. However, adenoviruses impose such properties on cells that allow them to avoid destruction or at least reduce this possibility. Adenoviruses produce factors that block the synthesis and expression of HLA-I molecules on the cell surface and thereby inhibit the presentation of viral antigens attacked by CD8+T-lymphocytes. Cells infected with adenoviruses acquire increased resistance to interferons and TNF-a, a potent cytotoxic cytokine. In both cases, adenoviral proteins interfere with molecular mechanisms that determine antiviral effects. Among the products of early adenoviral genes are factors that delay the development of apoptosis. In general, this reflects a strategy aimed at improving the survival

From the pathogenetic point of view, adenoviruses damage the respiratory tract and belong to the "respiratory" viruses. However, adenoviruses also can cause lesions of the intestine and conjunctiva, as well as the central nervous system, bladder, and genitals. Adenoviruses multiply in the mucous membrane with a gradual, consistent involvement in the pathological process of the descending parts of the respiratory tract. Reproduction of adenoviruses also can occur in the intestinal tissue or lymph nodes which is accompanied by a multiple increase in lymph nodes. In addition to local changes, adenoviruses have a general toxic effect which appears as a fever and symptoms of general intoxication (weakness, lethargy, loss of appetite, headache, and nausea). The ability of adenoviruses to reproduce in the epithelial cells of the respiratory tract, conjunctiva, and intestine with the occurrence in some cases of hematogenous dissemination creates a wide range of clinical manifestations of this infection, including the appearance of generalized lymphadenopathy and widespread exanthema. In addition to adenoviruses in the genesis of acute pneumonia, the attachment of a secondary bacterial flora

is important, which is facilitated by the suppression of the immune system [23–24].

The term "adenoviruses" has an ecological coloration, reflecting the tendency to persistence in the lymphoid tissue, so that adenoviruses can be isolated from the tonsils, adenoids, appen-

After acute infections, many serotypes are not eliminated from the body for a long time. Most of the latent viruses belong to subgroups B2 and C. They can persist for years in the lymphoid tissue of the pharyngeal ring and, apparently, other localizations (e.g., in the mesenteric lymph

of infected cells and creating conditions for viral persistence [22].

14–24 h.

**7. Pathogenesis**

**8. Adenoviral latency**

dix, and lymph nodes of practically healthy people.

**Table 1.** Clinical forms of adenovirus infection.

The WHO have reported that data on the incidence and ramp prevalence of adenoviral infections are not exact, since in many cases, adenoviruses cause mild forms and therefore remain unregistered, according to general practitioners [16]. However, in recent years, adenoviruses caused widespread outbreaks in Asia [17–19] in which adenoviral infection was accompanied by the development of acute respiratory distress syndrome (ARDS) in Malaysia [18], China [16, 19], and South Korea [19].


**1. Introduction**

The benefits of regular physical exercise are widely debated and include reducing the risk of obesity [1] or cardiovascular diseases [2]. On the other hand, improperly performed training with excessive intensity may negatively affect the organism's homeostasis and increase the risk of injury [3].

**Citation:** Wiecha, S.; Kasiak, P.S.; Cie´sli ´nski, I.; Maciejczyk, M.; Mamcarz, A.; Sli ´ z, D. Modeling ˙ Physiological Predictors of Running Velocity for Endurance Athletes. *J. Clin. Med.* **2022**, *11*, 6688. https:// doi.org/10.3390/jcm11226688

Academic Editor: Birna Bjarnason-Wehrens

Received: 26 September 2022 Accepted: 9 November 2022 Published: 11 November 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

The concept of anaerobic threshold (AT) is widely discussed in exercise physiology [4]. As envisioned by Karlman Wasserman, the AT linked the increase in blood lactate concentration ([La−]b), during a strenuous incremental cardiopulmonary exercise test (CPET), with an excess arterial CO2 accumulation and its further pulmonary output [5]. Above the AT, [La−]b increase leads to temporary acidosis. The endurance capacity of the whole system is usually sufficiently high to cope with the incoming state [6]. During steady-state exercise with intensity above the AT, an equilibrium in [La−]b appearance and its elimination is observed [6]. Thus, AT is a useful practical indicator to provide personalized training recommendations (with the aim of adjusting exercise intensity to set goals) and load monitoring [7].

The respiratory compensation point (RCP) is the intensity at which arterial CO2 begins to decrease during demanding activity due to breathing capacity [8]. Above the RCP, the intensity of acidic ion accumulation exceeds their systemic or respiratory elimination abilities and indicates reduced endurance capacity. This leads to an over-decrease in the serum pH during graded exercise. This threshold indicates how long a high-intensity effort can be sustained [9].

The velocity at the anaerobic threshold (VAT), at the respiratory compensation point (VRCP), and at its maximum (Vmax) play an essential position in the endurance performance assessment, both for professional and recreational endurance athletes (EA), as well as for the general population under clinical conditions [10,11].

These variables are the shift points of aerobic exercise to anaerobic metabolism and can be used as one of the parameters to evaluate the maximum endurance capacity [7]. Moreover, they closely positively correlate with exercise abilities [4]. They could be incorporated into the prescription for the advancement of training plans [7] or competition strategies [12] for special and narrow populations (e.g., EA), and in sports diagnostics whenever controlled running intensity is required (i.e., in clinical CPET) [7]. Furthermore, currently, these variables most closely correspond to the EA critical power sustainability [13,14].

Apart from Vmax, maximal aerobic speed (MAS), which is directly related to VO2max, is another important aspect of overall performance evaluation. However, as the aim of this research is to predict Vmax, we recommend that further studies should be performed to analyze the MAS.

Numerous parameters, such as heart rate (HR), oxygen uptake (VO2), or anthropometric data (i.e., height, age, and gender), are widely discussed in the development of multivariable prediction models that provide an increasingly more suitable alternatives to direct CPET measurements [15].

Several studies have attempted to develop and validate various non-invasive prediction equations for different sports performance measurements (i.e., for HR, VO2, and others) [11,15,16]. However, they were mostly conducted on general populations or on small athletic samples, and thus, they can only be extrapolated to a low degree [17]. In addition, their methodology is widely variable, and only a few of them fulfilled recommended TRIPOD guidelines [18]. Thus, the actual number of VAT, VRCP, and Vmax predictive models is limited, despite being significant measures of endurance capacity [19,20]. Moreover, although the variables influencing the running performance are well researched, the authors have not yet assessed how accurately they can be used to estimate running velocity by further including them in prediction models.

The aims of this study were: (1) to find the somatic and CPET variables that are the most responsible for running velocity, (2) to develop a prediction method for VAT, VRCP, and Vmax, in accordance with TRIPOD recommendations [18], (3) to internally validate the obtained formulae, (4) to assess the accuracy of the current machine-learning abilities to predict running velocity based on the primarily determined variables, and (5) to evaluate practical applications of such an approach in sports or clinical conditions based on actual knowledge regarding exercise physiology.


**10. References**

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Fig. 2. Alcoholism Treatment: A Treatment approach to use a trio of Pharmacotherapy using pharmacological agents, where a traditional approach of "One dose for all" is used and Psychotherapy – an important part of treatment in alcoholism and Pharmacogenetics based on Genetic makeup of the Individual for better and effective treatment in alcoholism

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**9. Conclusion**

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**13**

*Spain*

**Pharmacological**

**Approaches to Improve Ageing**

*Department of Physiology, University of Extremadura, Cáceres,*

Pedro J. Camello, Cristina Camello-Almaraz and Maria J. Pozo

Aging is generally considered as a progressive and irreversible set of structural and functional changes, due both to the genetic background of the individual and the oxidative damage and modifications of intracellular signaling mechanisms. Although the anatomical and physiological alterations associated to aging (e.g. sarcopenia, cognitive and sensorial decline, functional loss in cardiovascular system…) are not a disease, they reduce the functional reserve of the organism, ultimately leading to pathological alterations and death. Improvements of nutrition, hygiene and public health, and medical diagnosis and treatments have dramatically extended life expectancy in the last decades. However, the rate of human aging is to the moment an elusive target in biomedical interventions. The achievement of a slowing of human age is not necessarily linked to an increase of morbid, unhealthy population, but is likely to postpone the onset of age-related pathologies (Blagosklonny, 2010). Pharmacological intervention to decelerate aging and age-related diseases is highly attractive because it would target all the population during many years. If successful, antiaging therapy will be more efficient in reducing mortality than to fight separately each age-related disease (Olshansky *et al.*, 2007). Research on anti-aging interventions has evolved along the main theories of aging. We describe here the available

explanations for aging before presenting the updated status of each approach.

After formulation of the "rate of living" hypothesis at the beginning of the last century, proposing that longevity is determined by the metabolic rate (Pearl, 1928), the main explanation for aging has been oxidative damage due to free radicals, especially when comparative studies made clear that metabolic rate alone could not explain longevity (see Speakman & Selman, 2011). The oxidative theory of aging (Harman, 1956) proposes that aging is driven by the damage inflicted to cellular components by reactive oxygen species (ROS) produced by mitochondria in the course of respiration, and has evolved into the mitochondrial free radicals theory of aging pointing to this organelle as a key factor in aging (Harman, 1972;Miquel *et al.*, 1980), including some refinement (de Grey, 2004). Briefly, endogenous ROS (and some nitrogen reactive species derived from them) modify lipids, DNA and proteins,

**2. Oxidative stress, aging and antioxidant treatments**

**2.1 Mitochondrial free radicals theory of aging**

**1. Introduction**


**4.6 Dabrafenib and trametinib**

Dabrafenib (also known as GSK2118436) is a BRAF kinase inhibitor, which has been tested *in vitro* and has demonstrated antiproliferative effects in human colon cancer xenografts and BRAFV600E positive melanoma [83]. It has also been tested in clinical trials in BRAF-positive cancers. In this case, BRAF-positive cancers become resistant to dabrafenib in 6–7 months. To prevent this therapeutic failure dabrafenib was administered with trametinib, a MEK inhibitor, and this combination was approved by the FDA for the treatment of BRAFV600E positive metastatic melanoma. Dabrafenib and trametinib were administered to anaplastic cancer patients with BRAFV600E mutation with promising results [55, 84–87].