**4.2.2 Mirror neurons and the social robot**

One of the key requirements for Rob's robot is the ability to be social in the sense that it can interact with human beings in a sensible, autonomous manner. Such an interaction can take many forms. One example is *learning by imitation*, which would allow the robot to learn novel tasks by observing a human demonstrating the desired behavior. It could also take the form of *cooperation*, in which Rob's robot has to solve a task together with a human. Or it could be *verbal interaction*, which may be required in all social scenarios involving robots.

What is common to all these scenarios is first and foremost the requirement that Rob's robot be able to *understand* the actions of a human and related concepts, whether shown to the robot by demonstration or given via verbal labels. In other words, these scenarios can benefit from the embodied theories on sensory-motor grounding in order to facilitate this understanding.

Within this context, the discovery of mirror neurons –neurons that are active both when an agent executes a (goal-directed) action and when he observes the action being executed by another (Gallese et al., 1996) –is attracting Rob's attention. Indeed, one of the most prominent hypotheses on the functional role of mirror neurons is that they form the link between action perception and action understanding Bonini et al. (2010); Cattaneo et al. (2007); Fogassi et al. (2005); Rizzolatti & Sinigaglia (2010); Umiltà et al. (2008), which appears highly relevant for Rob's robot. Even so, it is always worthwhile to remember that this claim remains a *hypothesis*, not a proven fact, and does not come without criticism (Hickok, 2008).

It is further thought that mirror neurons may play a role in learning by imitation (Oztop et al., 2006) as well as in the sensory-motor grounding of language (see Chersi et al. (2010) for a discussion). Although these are again hypotheses rather than facts (, for instance rightly points out that most of the neurophysiologic data supporting the theories come from macaque monkeys, which neither imitate nor use language), they have inspired some robotics research (see for instance Yamashita & Tani (2008) for an example of learning by imitation and Wermter et al. (2005) for an example of language use). Overall, it thus comes as no surprise that mirror neurons are also of high interest to the field of humanoid robotics, since they may provide the key to grounding cognition in sensory-motor experiences. For this reason, Rob is interested in some of the work within the field of robotics that is based on insights learned from mirror neurons.

#### **4.2.3 Mirror neuron based robots**

Oztop et al. (2006) provides a general review of computational mirror neuron models (including models that can be seen to have components which function similarly to mirror neurons rather than being explicitly inspired by mirror neuron research), together with a proposed taxonomy. Not all of these are relevant to robotics, but we will briefly mention a few controllers that are examples of early mirror-neuron related work in robotics.

One of the first such examples is the recurrent neural network with parametric bias (RNNPB) by Tani et al. (2004), in which "parametric bias" units of a recurrent neural network are associated with actions, encoding each action with a specific vector. Then the system may then either be given a PB vector to generate the associated action, or it may be used to predict the PB vector associated with a given sensory-motor input. As such, these PB units can be understood as replicating some of the mirror functionality. Tani et al. (2004) demonstrate the 12 Will-be-set-by-IN-TECH

theories and computational models thereof (Pezzulo et al., 2011) while on the other hand, insights from embodied cognition can allow the better design of robots. For Rob's robot, the latter is clearly the most interesting aspect and hence the focus of the remainder of this section.

One of the key requirements for Rob's robot is the ability to be social in the sense that it can interact with human beings in a sensible, autonomous manner. Such an interaction can take many forms. One example is *learning by imitation*, which would allow the robot to learn novel tasks by observing a human demonstrating the desired behavior. It could also take the form of *cooperation*, in which Rob's robot has to solve a task together with a human. Or it could be

What is common to all these scenarios is first and foremost the requirement that Rob's robot be able to *understand* the actions of a human and related concepts, whether shown to the robot by demonstration or given via verbal labels. In other words, these scenarios can benefit from the embodied theories on sensory-motor grounding in order to facilitate this understanding. Within this context, the discovery of mirror neurons –neurons that are active both when an agent executes a (goal-directed) action and when he observes the action being executed by another (Gallese et al., 1996) –is attracting Rob's attention. Indeed, one of the most prominent hypotheses on the functional role of mirror neurons is that they form the link between action perception and action understanding Bonini et al. (2010); Cattaneo et al. (2007); Fogassi et al. (2005); Rizzolatti & Sinigaglia (2010); Umiltà et al. (2008), which appears highly relevant for Rob's robot. Even so, it is always worthwhile to remember that this claim remains a *hypothesis*,

It is further thought that mirror neurons may play a role in learning by imitation (Oztop et al., 2006) as well as in the sensory-motor grounding of language (see Chersi et al. (2010) for a discussion). Although these are again hypotheses rather than facts (, for instance rightly points out that most of the neurophysiologic data supporting the theories come from macaque monkeys, which neither imitate nor use language), they have inspired some robotics research (see for instance Yamashita & Tani (2008) for an example of learning by imitation and Wermter et al. (2005) for an example of language use). Overall, it thus comes as no surprise that mirror neurons are also of high interest to the field of humanoid robotics, since they may provide the key to grounding cognition in sensory-motor experiences. For this reason, Rob is interested in some of the work within the field of robotics that is based on insights learned from mirror

Oztop et al. (2006) provides a general review of computational mirror neuron models (including models that can be seen to have components which function similarly to mirror neurons rather than being explicitly inspired by mirror neuron research), together with a proposed taxonomy. Not all of these are relevant to robotics, but we will briefly mention a

One of the first such examples is the recurrent neural network with parametric bias (RNNPB) by Tani et al. (2004), in which "parametric bias" units of a recurrent neural network are associated with actions, encoding each action with a specific vector. Then the system may then either be given a PB vector to generate the associated action, or it may be used to predict the PB vector associated with a given sensory-motor input. As such, these PB units can be understood as replicating some of the mirror functionality. Tani et al. (2004) demonstrate the

few controllers that are examples of early mirror-neuron related work in robotics.

*verbal interaction*, which may be required in all social scenarios involving robots.

not a proven fact, and does not come without criticism (Hickok, 2008).

**4.2.2 Mirror neurons and the social robot**

neurons.

**4.2.3 Mirror neuron based robots**

utility of the overall architecture in three tasks. First, they show that the architecture enables a robot to learn hand movements by imitation. Second, they demonstrate that it can learn both end-point and cyclic movements. Finally, they illustrate the ability of the architecture to associate word sequences with the corresponding sensory-motor behaviors.

Yamashita & Tani (2008) similarly use a recurrent neural network at the heart of their robot controller but endow it with neurons that have two different timescales. The robot then learns repetitive movements and it is shown that the neurons with the faster timescale encode so-called movement primitives while the neurons with the slower timescale encode the sequencing of these primitives. This enables the robot to create novel behavior sequences by merely adapting the slower neurons. The encoding of different movement primitives within the neural structure also replicates the organization of parietal mirror neurons (Fogassi et al., 2005), which is at the core of other computational models of the mirror system (Chersi et al., 2010; Thill et al., In Press; Thill & Ziemke, 2010).

While the RNNPB architecture encodes behavior as different parametric bias vectors, Demiris & Hayes (2002); Demiris & Johnson (2003) propose an architecture in which every behavior is encoded by a separate module. This architecture combines inverse and forward models, leading to the ability to both recognize and execute actions with the same architecture. Learning is done by imitation, where the current state of the demonstrator is received and fed to all forward modules. These forward modules each predict the next state of the demonstrator based on the behavior they encode. The predicted states are compared with the actual states, resulting in confidence values that a certain behavior is being executed. If the behavior is known (a module produces a high confidence value), the motors are then actuated accordingly. If not, a new behavioral module is created to learn the novel behavior being demonstrated. A somewhat similar model of human motor control, also using multiple forward and inverse models has been proposed by Wolpert & Kawato (2001), with the main difference being that in this work, all models (rather than simply the one with the highest confidence value) contribute to the final motor command (albeit in different amounts).

Finally, Wermter et al. (2003; 2005; 2004) developed a self-organizing architecture which "takes as inputs language, vision and actions . . . [and] . . . is able to associate these so that it can produce or recognize the appropriate action. The architecture either takes a language instruction and produces the behavior or receives the visual input and action at the particular time-step and produces the language representation" (Wermter et al., 2005, cf. Wermter et al., 2004). This architecture was implemented in a wheeled (non-humanoid) robot based on the PeopleBot platform. This robot can thus be seen to "understand" actions by either observing them or from its stored representation related to observing the action. This is therefore an example of a robot control architecture that makes use of embodied representations of actions. In related work on understanding of concepts/language in mirror-neuron-like neural robotic controllers (Wermter et al., 2005) researchers use the insight that language can be grounded in semantic representations derived from sensory-motor input to construct multimodal neural network controllers for the PeopleBot platform that are capable of learning. The robot in this scenario is capable of locating a certain object, navigating towards it and picking it up. A modular associator-based architecture is used to perform these tasks. One module is used for vision, another one for the execution of the motor actions. A third module is used to process linguistic input while an overall associator network combines the inputs from each module. What all these examples illustrate is that insights from mirror neuron studies (in particular their potential role in grounding higher-level cognition in an agent's sensory-motor experiences) can be useful in robotics. In terms of using insights from embodied cognition,

for Humanoid Robots 15

Rob's Robot: Current and Future Challenges for Humanoid Robots 293

Dynamic Field Theory (DFT) is a mathematical framework based on the concepts of Dynamical Systems and the guidelines from Neurophysiology. A field represents a population of neurons and their activations follow continuous responses to external stimuli. Amari (1977) studied the properties of these networks as a model of the activation observed in cortical tissue. Fields have the same structure of a recurrent neural network since their connections can have, depending on the relative location within the network, a local excitation or a global

Fields are used to represent perceptual features, motion or cognitive decisions, e.g. position, orientation, color, speed. The dynamics of these fields allow the creation of peaks which are the units of representation in DFT (Schöner, 2008). Different configurations of one or more fields are possible, being the designer responsible for creating a proper connectivity and tuning of parameters. The result of activating this type of network is a continuously adaptive

Rob has learned about the different properties and potentials of dynamic fields for using it as part of a robust cognitive architecture. Some of the most attractive features of this approach include the possibility of having a hebbian-type of learning by exploiting the short-term memory features implicit in the dynamics of this algorithm. Long-term memory, decision making mechanism and noise robustness (also implicit in the dynamics of fields), and single-shot learning are all important tools that can and must be included in any cognitive architecture. Several applications modeling experiments on human behavior (Dineva (2005); Johnson et al. (2008); Lowe et al. (2010)) and robotic implementations (Bicho et al. (2000);

Nonetheless, from Rob's perspective, the current work with dynamic fields still needs to overcome a number of challenges. Dynamic field controllers are currently designed by hand, through elaborate parameter space explorations, to solve a very specific problem. Although these models nicely illustrate that decision-making can be grounded directly in sensory-motor experiences, their learning ability is limited and any particular model does not generalize well to other tasks, even though modular combinations of different models each solving a particular task seems possible (Johnson et al. (2008); Simmering et al. (2008); Simmering &

system that responds dynamically to any change coming from external stimuli.

Erlhagen et al. (2006); Zibner et al. (2011)) have demonstrated DFT's potential.

Fig. 4. Typical activations in a dynamics field, from Schöner (2008).

**4.2.5 Dynamic Field Theory**

inhibition, Fig. 4.

Spencer (2008)).

these are relatively simple examples since the main role of the body in these cases is to enable the grounding of concepts. For instance, a robot would "know" what a grasp is because it can relate it to its own grasping movements via the mirror neurons.

However, from Rob's perspective, there is still substantial work that needs to be done in this direction. In essence, what the field is currently missing are robots that can display higher-level cognition which goes beyond simple toy problems. For example, most of the examples above dealing with learning by imitation understand imitation as reproducing the trajectory of, for instance, the end-effector. However, imitation learning is more complex than that and involves decisions on whether it is really the trajectory that should be copied or the overall goal of the action (see *e.g.* Breazeal & Scassellati, 2002, for a discussion of such issues). Similarly, while there is work on endowing robots with embodied language skills (*e.g.* Wermter et al., 2005), it rarely goes beyond associating verbal labels to sensory-motor experiences (Although see Cangelosi & Riga (2006) for an attempt to build more abstract concepts using linguistic labels for such experiences). Again, while this is a worthwhile exercise, it is not really an example of a robot with true linguistic abilities.


**6. Conclusion**

**Figure 6.** Estimated annual number of dengue cases and hospitalizations in Indonesia following adjustment of

system and associated health system parameters, a study to estimate the proportion of dengue was conducted by Delphi panel in 2017. The iterative estimation was generated by calculating the expansion factors (EF), the ratio of total and reported cases during the presentation of medical and epidemiological data and subsequent discussions. The data revealed that from all of symptomatic Indonesian dengue episodes, 57.8% enter healthcare facilities to seek treatment but only 39.3% of them are diagnosed as dengue. Furthermore, only 20.3% of them are subsequently reported in the surveillance system. Public sector found dominating occurrence of hospitalizations and followed by private sector for ambulatory episodes (∼55%). Therefore, estimations gave an overall EF of 5.00; hospitalized EF of 1.66; and ambulatory EF of 34.01 which, when combined with passive surveillance data, equates to an annual average (2006–2015) of 612,005 dengue cases, and 183,297 hospitalizations (**Figure 6**.). The findings are lower than those similar estimations published elsewhere, perhaps due to case definitions,

The goal of WHO Global Strategy is to reduce the burden of dengue. Its specific objectives are: (1) to reduce dengue mortality by at least 50% by 2020, (2) to reduce dengue morbidity by at least 25% by 2020, and (3) to estimate true burden of the disease by 2015 (the year 2010 is used as the baseline). The implementing strategy is expected to pave the way for reducing dengue morbidity and mortality nationwide through strengthening local and national capabilities, as well as regional coordination. National Dengue Control Program in Indonesia

surveillance reports with EFs, and their 95% confidence intervals (CIs), 2006–2015.

88 Current Topics in Tropical Emerging Diseases and Travel Medicine

local clinical perceptions, and treatment-seeking behavior [34].

**5. Dengue fever prevention and control**

Given the wide area in the tropical temperature, high population density in urban area, and various geographic and biodiversity, putting Indonesia as a natural potential for the habitat of dengue viruses. The number of dengue fever cases reported dramatically increases since it was firstly found in 1968 and spread out almost in 80% cities and districts in Indonesia in 2016. Many of those cities and districts were very vulnerable and putting million people at risk to the disease in 2012. Some challenges are still heading in the front of the prevention and control implementation actions. However, keeping spirit for struggling to combat dengue fever in Indonesia along with full commitment and involvement of community are urgently needed as well as to revitalize dengue disease eradication programs at every stage with close monitoring implementation.

In addition, technical guidance and increased skills of health officers are indispensable. Socialization of a hands-on program activities in particular and increased capacity and active participation of community on the action could be a joint action in preventing the increase in dengue disease associated to climate change.


**3. Methodology**

### *3.1. Analysis Sources*

This study focused on using SOC reports and their qualitative data on WH management and conservation-related issues. The SOC reports, elaborated on a yearly basis, provided a brief analysis of the conservation threats to properties that both the WH Centre and advisory bodies considered as having high relevance for discussion by the WHCOM. These reports are requested when 'the values for which a property was inscribed on the WH List appear to be significantly threatened by either existing processes, or by potential processes with a high likelihood of taking place' [28] (e.g., climate change, development). Despite lacking quantitative information and analysis, SOC reports are the source of more objective discussions on WH issues such as the range of impacts on OUVs [12]. In their text format, reports include the viewpoints of the State party, advisory bodies, and the WH Centre in the form of concerns and recommendations that may differ from those of the national authorities or heritage managers [76]. Although SOC reports identify climate change and severe weather events among a list of 14 factors (https://whc.unesco.org/en/factors/) affecting the conservation of WH properties, the system does not systematically correlate extreme weather events (e.g., hurricane, drought) with climate change. Additionally, UNESCO's SOC database is not designed to provide systematic insights about the interactions between heritage management and the factors that both positively and negatively impact the conservation of WH properties. Nonetheless, it has proved valuable for the collation of information from numerous individual practices. Thus, SOC reports can be used to systematically assess patterns linked to the identification of threats to WH areas, management deficiencies, and conservation needs and developments [76]. For example, it has enabled the monitoring and quantification of the qualitative aspects of factors affecting the conservation of cultural and mixed heritage properties across time and geographical location [29].

### *3.2. Data Collection*

In this study, we focused on 'climate change' as a key term. The SOC reports were downloaded from the UNESCO website and gathered in PDF format in order to conduct an advanced search in Acrobat Reader DC v.2020 using 'climate' + 'change' as keywords. Through directed content analysis, we sought to explore insights on the situational and management context in which climate change was noted in SOC monitoring exercises. The aim was to understand commonalities and differences between the challenges and/or opportunities discussed by conservation practice in all categories of WH properties when confronted by climate change as a global phenomenon of systemic complexity. We selected reports online from 2000 up to 2019.

### *3.3. Data Analysis*

A coding system was applied to classify mentions of 'climate change' based on two pre-coding dimensions and two post-coding dimensions (Table 1). First, pre-coding identified mentions using the set of keywords 'climate change' and extracted all mentions found for analysis. The second pre-coding dimensions were SOC reports' general information, which was extracted and compiled in a Microsoft Excel spreadsheet in order to identify mentions according to the year of the SOC report, WH name, heritage category (i.e., natural, cultural, or mixed) and geographical location (country and region). The post-coding dimensions served to structure analysis involving advances in theory and practice. First, post-coding dimension three, context of references, identified the standard situational context in which mentions could be discussed, based on World Heritage Convention (WHC) protocols when elaborating on SOC reports. These included three viewpoints according to which debates on conservation issues revolved: (1) expression of concerns (C) by the WH Centre or advisory bodies on unresolved issues or possible negative outcomes of past and future measures; (2) recommendations (R) by both the WH Centre and advisory bodies to State Parties on prioritising actions; (3) implementations (I), which concerned the WHC's acknowledgement of efforts made by State Parties for dealing with a given threat or other conservation issues identified in previous WHC meetings. Viewpoints varied in order of appearance within reports. The second post-coding dimension, landscape-based conservation principles, comprised the operational definitions of landscape approaches identified through a taxonomic analysis of mentions. Four typologies were defined to formulate an initial framework for identifying landscape approaches related to climate change in WH conservation practices: (1) landscape scale, which refers to the upscaling of conservation activities in the wider context in which WH properties are located; (2) evidence of climate change impacts on OUV (lack or availability) to inform heritage management; (3) landscape governance, which includes the lack or existence of coherent planning and governance tools in collaboration with other sectors and actors (policies, management plans, and strategic actions); (4) adaptation measures addressing one of or the cumulative impacts of other identified factors that are exacerbated by climate change.

**Table 1.** Coding dimensions and definitions.

Collected qualitative data (mentions) were entered into an Excel spreadsheet and analysed using content analysis (Creswell, 2014). We calculated the frequency of each pre-coding and post-coding item, i.e., the number of times an item was coded across SOC reports. Next, relationships between pre and post-coding items were analysed based on their occurrence and following the hierarchical order of coding dimensions. The Excel COUNTIF function was used to count the number of extracted texts that met the criteria of coding dimensions. This allowed for interpretation of the meaning of mentions in the theoretical context of landscape conservation and the WH system. The key aspects of our analysis, which structured our results presented in the next section, were the following: (1) the complexity of discussion around climate change based on WH categories, regions (pre-coding dimensions one and two in Table 1) through the period 2000–2019; (2) the discussion of climate change drivers within the WH system (post-coding dimensions three and four in Table 1); (3) trends related to how WH conservation practice employed principles of landscape approaches to respond to climate change (relationships among all coding dimensions).


*2.2. Meshing*

Commercial ANSYS-ICEM17.0 software was utilized to mesh various computational domains. As the structured meshes only contained quadrilaterals or hexahedrons in this case, their topological structure was equivalent to a uniformly orthogonal mesh within a rectangular domain. Accordingly, the nodes on each layer of the mesh lines can be effectively adjusted to ensure a high quality [20–24]. The overall computational domain was structured and meshed and the boundary layer of the meshes in the vicinity of the near wall of the blade was refined. The quality of meshes within all computational domains was above 0.35 (Figure 2).

(**b**) Computational domain and structure grid.

**Figure 2.** Mesh of the pump.

The efficiency, head, and power of the rated point of the pump were considered indexes for mesh independence verification of the unslotted centrifugal pump model. The global maximum mesh size was used to control the mesh density of each computational domain. Local meshes within each computational domain were specifically refined to ensure the desired mesh quality. The meshing results are shown in Table 2.

**Table 2.** Analysis of the grid independent.

Figure 3 shows the effects of the number of meshes in different cases on the head, power, and efficiency of the simulated pump. A numerical calculation on a mesh with a global mesh size of 2 mm was conducted with both the computational cycle and computational accuracy taken into account.

**Figure 3.** Schematic diagram of the blade structure grid.

#### *2.3. Computational Cases and Boundary Conditions*

Numerical calculations were performed in ANSYS-CFX19.2 software (ANSYS CFX. 19.2" ANSYS CFX 19.2 Documentation. 2019). The turbulence model in this case was a standard *k-*ω turbulence model. The computational impeller domain was set to a rotational domain and all other computational domains were set to static. Data transfer at the interface between the static domains and the rotational domains was achieved by the frozen rotor method.

To consider the effects of the impeller cover plate on the flow, all other inner wall surfaces within the pump cavity excluding those in contact with the impeller outlet surface were set to a rotational wall surface. The roughness of each computational domain surface was set to 10 μm to observe the effects of the material on the internal flow characteristics of the pump. The boundary conditions were set to pressure inlet and mass outflow. The reference pressure was set to a standard atmospheric pressure, the wall surface was placed under a non-slip boundary condition, and a standard wall surface function was used with the convergence accuracy set to 10−4.

#### *2.4. Orthogonal Design of Blade Slots*

To explore the effects of blade-slotting on the medium specific speed pump systematically, four factors including the slotting position, slotting width, slotting depth, and slotting angles of the blades

were studied via the orthogonal design method. The orthogonal design method is a scientific design technique wherein test plans are reasonably arranged to determine the main factors that influence certain indexes within a brief testing time [25]. Many researchers have used orthogonal designs to study the performance of centrifugal pumps [26–29]. Considering the time and cost burdens of the test, the geometrical factors of the slots as they affect pump performance were observed in this study by combining CFD technology with an orthogonal design.

#### *2.5. Determining the Test Factors*

As discussed above, four sets of geometric parameters were taken as test factors: slot position *p* slot width *b*1, slot deflection angle β and slot depth *h* (Figure 4). Slot position *p* is the position of the slot on the blade. Based on the arc length of the blade profile, four uniform levels were taken from the inlet edge of the blade to the outlet edge of the blade: 20%*p*, 40%*p*, 60%*p*, and 80%*p*. Three levels of the slot width *b*1 were selected: 0.5 mm, 1 mm, and 1.5 mm. As shown in Figure 4, the angle β is the included angle between the slot and the tangent line of the blade in the slot position. The deflection angle of the slot relates to the effects of the slot jet on the liquid flow in the flow passage. Three angles were tested: 30◦, 45◦, and 60◦. The slot depth *h* is the axial distance from the inner surface of the front cover plate, relative to the blade outlet width *b*. Three depths were selected: 1/4 *b*, 2/4 *b*, and 3/4 *b*.

**Figure 4.** The schematic diagram of the gap geometry parameters.

As shown in Table 3, the L16 orthogonal table was selected for these four factors.

**Table 3.** Factor level table.

#### **3. Analysis of Numerical Simulation Results**

#### *3.1. Test Verification*

To validate the numerical simulation method used in this study, the original model was tested. As shown in Figure 5, the test rig is an open-type system, which is composed of two parts, namely, the data acquisition system and the water circulation system. The DN100 electromagnetic flowmeter whose maximum allowable error is ±0.5% was used to measure the flow rate *Q*. The valve of the pump inlet pipeline was fully opened during the test and the flow condition points were collected through the pump outlet pipeline valve. To secure a smooth external characteristic curve during the collection process, recording was performed at an interval of 5 m3/h from the shutoff point to the large flow condition point for a total of 17 operating points.

**Figure 5.** Schematic diagram of the test rig. 1. Motor; 2. torque meter; 3. centrifugal pump; 4. outlet pipeline pressure section; 5. DN100 electromagnetic flowmeter; 6. outlet pipeline valve; 7. water tank; 8. inlet pipeline valve and 9. inlet pipeline pressure section.

Table 4 shows the pump performance test results. As the rotational speed of the pump was not constant at 2850 r/min during actual operation, for an effective comparison against the numerical calculation results, the external characteristic data of the pump was converted to a rated speed of 2850 r/min according to the rules of similarity theory.

**Table 4.** Pump performance test results.

Figure 6 shows a comparison between the test-based and simulated pump performance indicators. To completely reflect the external characteristic variation curve from the shuto ff point to the maximum flow condition during the pump test, eight flow condition points were simulated from 0.1 *Q* to 1.4 *Q*. The numerical simulation results accurately predicted the external characteristic curve of the pump within the whole range of operating conditions as observed in the test. The relative errors in the head, efficiency, and power of the rated operating points were 4.4%, 2.95%, and 4%, respectively. All were smaller than 5%, which indicates that the numerical simulation method was accurate. Further, these results suggest that the orthogonal design case accurately reflects slotting e ffects numerically.

**Figure 6.** Comparison of test and numerical results.

#### *3.2. Direct Analysis of Orthogonal Design Case*

Sixteen sets of orthogonal design cases were used in this study. Prototyping all of them would be costly and time-consuming, so considering the accuracy of the numerical calculation method, the full flow field numerical simulation method was selected as the research tool for this orthogonal design. To observe the e ffects of slotting on the performance of the medium specific speed centrifugal pump, full flow field numerical simulations were conducted at four operating condition points: 0.6*Q,* 0.8 *Q*, 1.0 *Q*, 1.2 *Q*, and 1.4 *Q* for 16 sets of slotted impellers in conjunction with the volutes.

This study centers on the e ffects of di fferent slotting cases on pump performance. Tables 5–7 show the numerical simulation results of 0.6 *Q*, 1.0 *Q*, and 1.4 *Q*, respectively. The orthogonal test data was processed to assess the main factors influencing the pump head and e fficiency in the slotted blade case [18]. The range analysis method was used to observe the e ffects of the levels of the factors at 0.6 *Q*, 1.0 *Q*, and 1.4 *Q* operating conditions on the pump's performance.

**Table 5.** 0.6*Q* numerical simulation results.

**Table 6.** 1.0*Q* numerical simulation results.

**Table 7.** 1.4*Q* numerical simulation results.

In the case of a greater range, different levels of a given factor lead to a larger amplitude of variations in the test indicators. To this effect, the factor corresponding to the maximum range was the most important factor. *K*i(*i* = 1,2,3,4) denotes the sum of the tests of the same level in any of the columns in Table 3, where *i* corresponds to different levels of the same factor, *ki* = *Ki*/*n* denotes the arithmetic mean value of different levels of the same factor, *n* denotes the number of occurrence of the same level in any of the columns in the table, and *R* = *max(k*1, *k*2, *k*3, *k*4) − *min(k*1, *k*2, *k*3, *k*4) denotes the range. A range analysis of 0.6Q are shown in Tables 8 and 9.

**Table 8.** 0.6*Q* head analysis.

**Table 9.** 0.6*Q* efficiency analysis.

The primary and secondary geometric parameters of slots influencing the pump performance at 0.6*Q* were obtained as shown in Table 10.

**Table 10.** The order of influence of the gap geometry parameters on pump performance at 0.6*Q*.

A range analysis of 1.0*Q* are shown in Tables 11 and 12.

**Table 11.** 1.0*Q* head analysis.

**Table 12.** 1.0 *Q* efficiency analysis.

The primary and secondary geometric parameters of slots influencing the pump performance at 1.0 *Q* were obtained as shown in Table 13.

**Table 13.** The order of influence of the gap geometry parameters on pump performance at 1.0 *Q*.

A range analysis of 1.4 *Q* are shown in Tables 14 and 15.

**Table 14.** 1.4 *Q* head analysis.

**Table 15.** 1.4 *Q* efficiency analysis.

The primary and secondary geometric parameters of slots influencing the pump performance at 1.4 *Q* were obtained as shown in Table 16.

**Table 16.** The order of influence of the gap geometry parameters on pump performance at 1.4 *Q*.

Range analyses of the operating condition points, 0.6 *Q*, 1.0 *Q*, and 1.4 *Q* indicated that the slot width and depth under the small flow conditions and rated conditions have the greatest e ffects on the pump head and e fficiency among the parameters tested. The slot position appeared to have little e ffect on the performance of the pump under small flow conditions. In the case of large flow conditions, however, the slot position had a greater e ffect on pump performance than any other parameter.

To analyze the e ffects of the changes in factor levels on the pump performance more intuitively, a trend variation chart was plotted with the head and e fficiency of the pump as indicators. As shown in Figure 7, the head *h*0.6Q was the largest when the blade slotting position *p* was close to the outlet side and the slot deflection angle β was the smallest under the small flow condition 0.6 *Q*. The head *h*0.6Q decreased progressively as slot width *b*1 and the slot depth *h* increased, and an inflection point emerged on the curve of the head *h*0.6Q as slot position *p* varied. Based on the steepness of the curve variation trend, the primary and secondary factors influencing the head *h*0.6Q were slot width *b*1, slot deflection angle β, slot depth *h*, and slot position *p*, respectively. This result was consistent with the range analysis results. The e fficiency η0.6Q also increased as *b1* and *h* decreased. The e fficiency η0.6Q curve trend also presented an inflection point with the changes in the slot position. Based on the trend graph, in order of intensity, the factors influencing the e fficiency η0.6Q were slot depth *h*, slot width *b*1, slot deflection angle β, and slot position *p*.

**Figure 7.** 0.6 *Q* head (**left**) and e fficiency (**right**)-factor relationship.

As shown in Figures 8 and 9, under the conditions of 1.0 *Q* and 1.4 *Q*, the heads of *h*1.0Q and *h*1.4Q were the largest when the blade slot position *p* was in the vicinity of the inlet edge of the blade. Like 0.6 *Q*, the heads of *h*1.0Q and *h*1.4Q and the e fficiencies of η1.0Q and η1.4Q decreased progressively as slot width *b*1 and the slot depth *h* increased. *h*1.0Q, *h*1.4Q, η1.0Q, and η1.4Q also increased progressively as slot deflection angle β increased.

**Figure 8.** 1.0*Q* head (**left**) and efficiency (**right**)-factor relationship.

**Figure 9.** 1.4*Q* head (**left**) and efficiency (**right**)-factor relationship.

#### *3.3. Analysis of Internal Flow Field*

The orthogonal test results suggest that blade slotting improved the head at small flow condition points and the efficiency at large flow condition points, which is consistent with previously published results. Under the working condition of 0.6*Q*, the head of Case 1 was 39.3 m; in the original case the head was 38.5 m. The head and efficiency in Case 1 for the 1.4*Q* condition were 30.15 m and 77.86%, respectively, and in the original case were 30.05 m and 77.09%. To further explore the effects of the geometric slot parameters on pump performance, the distributions of performance curves of the original model and Case 1 were compared as shown in Figure 10.

**Figure 10.** Comparison of case 1 and original model.

Figures 11 and 12 show cloud diagrams of the static pressure distribution of the blade unfolding at the section of the pump impeller flow passage (the section value Span was 0.9) in the original model and Case 1 of slotted blades under the conditions of 0.6*Q* and 1.4*Q*, respectively. As shown in Figure 11, under the 0.6*Q* condition, the static pressure distributions of the blade unfolding in Case 1 and the original model differed significantly. The distribution of pressure in the impeller flow passage from the blade inlet to the outlet was characterized by a low-pressure region in the first half-section of the impeller flow passage and a high-pressure region in the second half-section of the passage. The pressure gradient in the second half-section of the impeller flow passage was large because the flow passage diffusion was severe, which might have created a secondary back flow at the outlet of the impeller under small flow conditions. This is also likely a cause of the low efficiency of the medium-low specific speed centrifugal pump at the small flow condition point.

**Figure 12.** Static pressure distributions on the cross section of the impeller channel at 1.4*Q*.

A significant low-pressure region was also observed in the position close to the inlet edge of the original model. Due to slotting in the position close to the inlet edge of the impeller, the distribution of blade unfolding static pressure disappears in the low-pressure region close to the inlet position of the blade in Case 1 and the pressure distribution is significantly more uniform than that in the original model. Vortexes and back flows are unlikely to form in the inlet position of the blade in this case, which is also one of the reasons why the head of the model in Case 1 is larger than that of the original model under the 0.6 *Q* condition.

Under the 1.4 *Q* large-flow condition, the diagram for the blade unfolding static pressure distribution in the case of the original model was similar to that in Case 1, however, the original model had a significant low-pressure region with considerable variations in the pressure gradient in the first half-section of the impeller flow passage inlet. This is mainly because the fluid flow angle of the incoming liquid increases with the flow rate while the inlet setting angle of the blade remains unchanged. As a result, the inlet setting angle is smaller than the liquid flow angle; a flow cuto ff forms at the working surface in the position of the blade inlet creating a low-pressure region. Similarly, the changes in pressure gradient in the static pressure distribution diagram of blade unfolding in Case 1 are smaller than those of the original model due to the fact that the blade is slotted near the inlet.

As shown in Figure 13, the pressure distribution is shown on the blade surface at the mean circumferential flow surface. Under 0.6 *Q*, the pressure distribution of the original model and the Case 1 model were quite di fferent (Figure 13). At the position near the inlet side, the pressure of the pressure surface and the suction surface of the Case 1 model were larger than the original model. This further illustrates that the Case 1 model improved the pressure distribution at the inlet edge of the blade due to slotting. The pressure near the inlet edge of the blade was higher than that of the original model under the 1.4Q large-flow condition.

**Figure 13.** Variation of the blade load with streamwise at 0.6 *Q* (**left**) and at 1.4 *Q* (**right**).

Figures 14 and 15 show the distribution of pressure clouds in the middle plane of the blade flow channel. The pressure gradient distribution of the Case 1 model is more uniform than the original model under the 0.6 *Q* condition (Figure 14); the original model shows a lower pressure than the Case 1 model near the blade inlet as well, which is consistent with the findings shown in Figures 11 and 12. The enlarged view in the figure shows where, due to the existence of a gap, the local low-pressure gradient distribution was more uniform in the original model. This gap jet made the streamline in the inlet low-pressure area closer to the profile of the blade airfoil, thereby improving the local flow field. Figure 15 shows that under the large flow rate of 1.4 *Q*, the impact of the gap on the local area was relatively small. The local enlarged view did not show similar phenomena to the small flow conditions. Generally speaking, the gap improved the local flow field under small flow conditions.

**Figure 14.** Static pressure distribution in the middle plane of the blade flow channel at 0.6*Q*.

**Figure 15.** Static pressure distribution in the middle plane of the blade flow channel at 1.4*Q*.

Figure 16 shows a diagram of the relative velocity distribution under the 1.4*Q* operating condition in the impeller calculation domain. This distribution was normal; the average velocity of the impeller calculation domain was basically 11 m/s. The velocity distribution amplitude of velocity in Case 1 was larger than that of the original model, which indicates that the velocity within the impeller was concentrated near the desired value and was uniform throughout the impeller calculation domain. This was also one of the reasons why the efficiency and head of Case 1 were larger than those of the original model.

**Figure 16.** Velocity distribution in the impeller calculation domain at 1.4*Q*.


*Review* **Textile-Based Sound Sensors (TSS): New Opportunities for Sound Monitoring in Smart Buildings**

**Andrea Giglio 1,\* , Karsten Neuwerk 2 , Michael Haupt 2 , Giovanni Maria Conti 1 and Ingrid Paoletti 1**

**Abstract:** Persistent poor acoustic conditions can imbalance humans' psychophysical capabilities. A good acoustic project starts with either correct measurements of the existing acoustic parameters or with the correct hypothesis of new sound conditions. International standards define invasive measurement conditions and procedures that can disturb user activities. For this reason, alternative methodologies have been developed by mounting real-time sound-monitoring devices. Most of the research on these aims to decrease their dimensions in order to be placed in the tight service spaces of modern architecture and to reduce their aesthetic impact on interiors design. In this perspective, this article explores the features and potentialities of textile-based sound sensors (TSS) as they can not only fulfill these needs but can also be used as architectural ornaments by partially wrapping interiors. The ubiquitous of e-textiles for wearable applications has led to increasing the performance of TSS. Therefore, a comparison of the sensitivity values, signal-to-noise ratio and noise floor of sound TSS with sound sensors is presented, which is still missing in the literature. The paper demonstrates how these can be exploited for sound monitoring and can provide valid opportunities for new smart acoustic textiles.

**Keywords:** e-textiles; textile-based sound sensors; sound monitoring; smart building


**2. Etiology and routes of transmission**

Tuberculosis (TB) is caused by the *Mtb* complex. The mycobacterium is nonmotile, Gram-positive, rod-shaped, obligate aerobic bacteria that belong to the order Actinomycetales and family Mycobacteriaceae. This *Mtb* complex includes (subspecies *M. canetti*), *M. bovis*, *M. microti, M. africanum*, *M. caprae*, *M. bovis* BCG, and *M. pinnipedii* [10]. The cough in a TB patient is caused by the infection of *Mtb* and distributed to air during coughing. The healthy persons who inhaled air droplets of TB infected person and make contact become infected [11].

#### **Tuberculosis-HIV Combination:**

The current opinion disclosed that one-third of the 42 million people living with HIV/AIDS all around the world are co-infected with TB. As per the WHO report, about 90% of the patients containing both TB and HIV died within only some months after clinical indications have arisen. Thus, WHO warned the world of the "even bigger TB-HIV crisis" and explained for extensive accessibility of free anti-TB drugs to individuals living with HIV. The HIV cases are spreading quickly in India with the biggest number of TB cases all around the world [12–15].

#### **3. Chemotherapy of tuberculosis**

#### **First-line anti-TB drugs:**

Treatment of TB is mainly dependent on first-line anti-TB drugs (**Figure 1**), which comprises SM, INH, RMP, EMB, and PZA, these are more effective and less toxic effects as compare to second-line anti-TB drugs [15].

**Drugs for HIV/TB**

*Structures of different antibiotics (second-line drugs).*

**Figure 2.**

**Figure 1.**

*Structures of first-line anti-TB drugs.*

HIV/AIDS [4, 15].

**33**

Clarithromycin (**Figure 5**) is a macrolide antibiotic drug used in HIV infected

erythromycin but is more efficient against certain Gram-negative bacteria, mainly *Legionella pneumophila*. Thioacetazone (**Figure 5**) is valuable in stopping resistance to more influential drugs like INH and RIF. It is not at all used on its own to treat TB. It uses is declining because it can originate severe skin reactions in HIV positive patients. It is also identified to kill MDR-TB. It is no longer suggested for treatment due to its adverse effects like urination-difficulties, dry mouth, glaucoma, and postural hypotension. The circumstances are further complex by the emergence of MDR-TB and XDR-TB by infections with lethal synergy with

TB patients to cure the *M. avium* complex (MAC). It has an analogous of

*Study of Various Chemically and Structurally Diverse Currently Clinically Used…*

*DOI: http://dx.doi.org/10.5772/intechopen.95538*

#### **Second-line anti-TB drugs:**

According to the WHO, there are six drugs of second-line anti-TB drugs. These drugs are categorized as second-line anti-TB drugs due to one of two potential reasons: 1) they are less active than the first-line anti-TB drugs or more toxic sideeffects or 2). These drugs involve different classes namely, aminoglycosides (**Figure 1**): (kanamycin, amikacin), polypeptide analogs (**Figure 2**): (viomycin, capreomycin), FQs (**Figure 3**): (CPX, MXF, OFX, etc), thioamides: (prothioamide, ethionamides), cycloserine and para-aminosalicylic acid (**Figure 4**) [2–4].

*Study of Various Chemically and Structurally Diverse Currently Clinically Used… DOI: http://dx.doi.org/10.5772/intechopen.95538*

#### **Figure 1.**

representation of the world TB threat. It was predictable that nearly 1 billion more people will be infected with TB in the coming 20 years. However, the number of new TB cases is still growing slowly, 95% occur in developing nations every year, and about one million young women per year are offended with this infectious disease in the developing world. The occurrence of TB is associated with a dense population, deprived sanitation, and, poor diet [6]. Directly observed treatment, short-course (DOTS), is the effective way of the control of TB. The three main anti-TB drugs, isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) are used. These drugs are hepatotoxic and may cause drug-related hepatitis. Despite the success of the DOTS therapy, the appearance of MDR-TB strains, persistently isolated from the sputum of pateints, darkens the future [7]. The expansion in TB incidence during current years is primarily due to the incidence of TB in synergy with the HIV pandemic, which increases the risk of growing the new TB cases were attributable to HIV co-infection, and as well as the emergence of MDR-TB strains [8, 9]. Therefore, the objective of this paper is to review the current status of antimycobacterial

*Molecular Epidemiology Study of Mycobacterium Tuberculosis Complex*

Tuberculosis (TB) is caused by the *Mtb* complex. The mycobacterium is nonmotile, Gram-positive, rod-shaped, obligate aerobic bacteria that belong to the order Actinomycetales and family Mycobacteriaceae. This *Mtb* complex includes (subspecies *M. canetti*), *M. bovis*, *M. microti, M. africanum*, *M. caprae*, *M. bovis* BCG, and *M. pinnipedii* [10]. The cough in a TB patient is caused by the infection of *Mtb* and distributed to air during coughing. The healthy persons who inhaled air

The current opinion disclosed that one-third of the 42 million people living with HIV/AIDS all around the world are co-infected with TB. As per the WHO report, about 90% of the patients containing both TB and HIV died within only some months after clinical indications have arisen. Thus, WHO warned the world of the "even bigger TB-HIV crisis" and explained for extensive accessibility of free anti-TB drugs to individuals living with HIV. The HIV cases are spreading quickly in

Treatment of TB is mainly dependent on first-line anti-TB drugs (**Figure 1**), which comprises SM, INH, RMP, EMB, and PZA, these are more effective and less

According to the WHO, there are six drugs of second-line anti-TB drugs. These

drugs are categorized as second-line anti-TB drugs due to one of two potential reasons: 1) they are less active than the first-line anti-TB drugs or more toxic sideeffects or 2). These drugs involve different classes namely, aminoglycosides (**Figure 1**): (kanamycin, amikacin), polypeptide analogs (**Figure 2**): (viomycin, capreomycin), FQs (**Figure 3**): (CPX, MXF, OFX, etc), thioamides: (prothioamide,

ethionamides), cycloserine and para-aminosalicylic acid (**Figure 4**) [2–4].

droplets of TB infected person and make contact become infected [11].

India with the biggest number of TB cases all around the world [12–15].

toxic effects as compare to second-line anti-TB drugs [15].

drugs.

**2. Etiology and routes of transmission**

**Tuberculosis-HIV Combination:**

**3. Chemotherapy of tuberculosis**

**First-line anti-TB drugs:**

**Second-line anti-TB drugs:**

**32**

*Structures of first-line anti-TB drugs.*

#### **Figure 2.**

*Structures of different antibiotics (second-line drugs).*

### **Drugs for HIV/TB**

Clarithromycin (**Figure 5**) is a macrolide antibiotic drug used in HIV infected TB patients to cure the *M. avium* complex (MAC). It has an analogous of erythromycin but is more efficient against certain Gram-negative bacteria, mainly *Legionella pneumophila*. Thioacetazone (**Figure 5**) is valuable in stopping resistance to more influential drugs like INH and RIF. It is not at all used on its own to treat TB. It uses is declining because it can originate severe skin reactions in HIV positive patients. It is also identified to kill MDR-TB. It is no longer suggested for treatment due to its adverse effects like urination-difficulties, dry mouth, glaucoma, and postural hypotension. The circumstances are further complex by the emergence of MDR-TB and XDR-TB by infections with lethal synergy with HIV/AIDS [4, 15].

IhhA needs metabolic activation. It is also utilized in combinations, INH and RIF

*Study of Various Chemically and Structurally Diverse Currently Clinically Used…*

inhibits the mycobacterial transcription by binds to the β-subunit of DNA-

formulation, it can access CNS and it is sensitive to moisture [2–4].

Rifamycins are natural products from *Amicolaptosis mediterranei* belong ansamycin family and are. These are active towards various bacteria but used

Rifapentine is a cyclopentyl analog of RIF. The benefit over rifampin is less repeated dosing. It inhibits bacterial DNA-dependent RNA polymerase and binds to the β subunit. The RIFs blocks the elongation of the RNA transcript and inhibits gene expression. It also acts as a CYP450 inducer. One remarkable side effect is the discoloration of body fluids. The RIFs are not suggested for use in HIV infected patients. Two RIF analogs are existing for indications other

a. **Rifabutin** (Mycobutin): It is used mostly in MAC infections [2–4].

an anti-TB drug in 1966. It obstructs polymerization of cell wall component lipoarabinomannan and arabinogalactan that interrupted biosynthesis of

arabinan and results in the addition of the lipid carrier deca-prenol

darabinofuranosyl-P-decaprenol and produced bacteriostatic effect [25, 26]. EMB (+) isomer is orally active, 16 times more potent than meso isomer, and 200 times more potent than () isomer. The EMB inhibits the polymerization of cell wall

phosphoarabinose. The EMB interferes with the transfer of arabinose to the cell wall acceptors. EMB is effective only towards energetically dividing cells and its action is synergistic with RIF. Arabinosyl transferase enzyme is a target for the action of EMB in both *Mtbs* and *M. avium*. The enzyme is encoded by the embCAB gene organized as an operon and engaged in the arabinogalactan synthesis [27, 28].

Pyrazinamide (PZA) is a pyrazine derivative of nicotinamide and its mechanism is assumed to be analogous to INH. It has to be metabolically activated and PZAresistant strains of *Mtb* contain a mutation in the hydrolase gene. PZA activity against *Mtb* depends on the anaerobic and acidic conditions. PZA is activated to pyrazine acid by the pyrazinamide/nicotinamidase that encoded by gene pncA [29]. Acidic condition favors the production of protonated pyrazinoic acid that collected in the *Mtb* cell membrane which interrupts cell membrane potential and altered membrane transport [30]. The new target of PZA', clpC1 (Rv3596c) that encodes an ATP-dependent ATPase is liable for protein degradation by the complex struc-

b. **Rifaximin** (Xifaxan): Indicated for the treatment of traveler's diarrhea [2–4].

Ethambutol (EMB) is a bacteriostatic, active against growing bacilli, and used as

Rifampin is a semisynthetic analog of rifamycin and the most effective anti-TB agent with MIC values as low as 0.005 μg/mL. It is used as an oral or parenteral

Rifampicin (RIF) was isolated from *Streptomyces mediterranei* from the soil sample and used as an anti-TB since 1972 [21]. It is still utilized as the best choice of anti-TB drugs. RIF diffuses across *Mtb* cell membrane due its lipophilic nature. RIF

and INH, RIF, and PZA. **Rifampicin**

**Rifamycins**

than TB [2–4].

dependent-RNA polymerase [22–24].

*DOI: http://dx.doi.org/10.5772/intechopen.95538*

almost exclusively against TB [2–4].

**Rifampin (Rifadin)**

**Rifapentine (Priftin)**

**Ethambutol (Myambutol):**

**Pyrazinamide (Aldinamide)**

ture with protease clpP1 and clpP2 [31, 32].

**35**

**Figure 3.**

*Structures of different fluoroquinolones (second-line anti-TB drugs).*

**Figure 4.**

*Structures of different second-line anti-TB drugs.*

**Figure 5.** *Structures of drugs for HIV/TB.*

#### **4. Properties and mechanism of currently used common anti-TB drugs**

#### **4.1 Primary agents**

#### **Isoniazid (Nydrazid, Laniazid)**

It is a bacteriostatic drug against resting cells and bactericidal against dividing microorganisms. Isoniazid (INH) is an anti-TB drug since 1952 and acts as a bactericidal and bacteriostatic for rapidly and slowly growing bacilli. It diffuses across the *Mtb* cell membrane [16]. The INH targets KatG and inhA gene. KatG gene encodes catalase/peroxidase enzyme that activates prodrug and peroxynitrite that are involved in pathways of reactive nitrogen and oxygen intermediates [17, 18]. InhA gene encodes NADH dependent enoyl-Acyl Carrier Protein (ACP)-reductase that causes inhibition of mycolic acid synthesis [19, 20]. The INH is a close to ideal antibiotic and very selective (MIC value 0.025–0.05 μg/mL and other bacteria MIC vale >500 μg/mL). The INH has good oral availability and low toxicity. It Inhibits mycolic acid biosynthesis and targets the enoyl-acyl carrier protein reductase enzyme (InhA) engaged in mycolic acid synthesis. The INH inactivation of

*Study of Various Chemically and Structurally Diverse Currently Clinically Used… DOI: http://dx.doi.org/10.5772/intechopen.95538*

IhhA needs metabolic activation. It is also utilized in combinations, INH and RIF and INH, RIF, and PZA.

#### **Rifampicin**

Rifampicin (RIF) was isolated from *Streptomyces mediterranei* from the soil sample and used as an anti-TB since 1972 [21]. It is still utilized as the best choice of anti-TB drugs. RIF diffuses across *Mtb* cell membrane due its lipophilic nature. RIF inhibits the mycobacterial transcription by binds to the β-subunit of DNAdependent-RNA polymerase [22–24].

#### **Rifamycins**

Rifamycins are natural products from *Amicolaptosis mediterranei* belong ansamycin family and are. These are active towards various bacteria but used almost exclusively against TB [2–4].

#### **Rifampin (Rifadin)**

Rifampin is a semisynthetic analog of rifamycin and the most effective anti-TB agent with MIC values as low as 0.005 μg/mL. It is used as an oral or parenteral formulation, it can access CNS and it is sensitive to moisture [2–4].

#### **Rifapentine (Priftin)**

Rifapentine is a cyclopentyl analog of RIF. The benefit over rifampin is less repeated dosing. It inhibits bacterial DNA-dependent RNA polymerase and binds to the β subunit. The RIFs blocks the elongation of the RNA transcript and inhibits gene expression. It also acts as a CYP450 inducer. One remarkable side effect is the discoloration of body fluids. The RIFs are not suggested for use in HIV infected patients. Two RIF analogs are existing for indications other than TB [2–4].

a. **Rifabutin** (Mycobutin): It is used mostly in MAC infections [2–4].

b. **Rifaximin** (Xifaxan): Indicated for the treatment of traveler's diarrhea [2–4].

#### **Ethambutol (Myambutol):**

Ethambutol (EMB) is a bacteriostatic, active against growing bacilli, and used as an anti-TB drug in 1966. It obstructs polymerization of cell wall component lipoarabinomannan and arabinogalactan that interrupted biosynthesis of darabinofuranosyl-P-decaprenol and produced bacteriostatic effect [25, 26]. EMB (+) isomer is orally active, 16 times more potent than meso isomer, and 200 times more potent than () isomer. The EMB inhibits the polymerization of cell wall arabinan and results in the addition of the lipid carrier deca-prenol phosphoarabinose. The EMB interferes with the transfer of arabinose to the cell wall acceptors. EMB is effective only towards energetically dividing cells and its action is synergistic with RIF. Arabinosyl transferase enzyme is a target for the action of EMB in both *Mtbs* and *M. avium*. The enzyme is encoded by the embCAB gene organized as an operon and engaged in the arabinogalactan synthesis [27, 28].

#### **Pyrazinamide (Aldinamide)**

Pyrazinamide (PZA) is a pyrazine derivative of nicotinamide and its mechanism is assumed to be analogous to INH. It has to be metabolically activated and PZAresistant strains of *Mtb* contain a mutation in the hydrolase gene. PZA activity against *Mtb* depends on the anaerobic and acidic conditions. PZA is activated to pyrazine acid by the pyrazinamide/nicotinamidase that encoded by gene pncA [29]. Acidic condition favors the production of protonated pyrazinoic acid that collected in the *Mtb* cell membrane which interrupts cell membrane potential and altered membrane transport [30]. The new target of PZA', clpC1 (Rv3596c) that encodes an ATP-dependent ATPase is liable for protein degradation by the complex structure with protease clpP1 and clpP2 [31, 32].

**4. Properties and mechanism of currently used common anti-TB drugs**

It is a bacteriostatic drug against resting cells and bactericidal against dividing microorganisms. Isoniazid (INH) is an anti-TB drug since 1952 and acts as a bactericidal and bacteriostatic for rapidly and slowly growing bacilli. It diffuses across the *Mtb* cell membrane [16]. The INH targets KatG and inhA gene. KatG gene encodes catalase/peroxidase enzyme that activates prodrug and peroxynitrite that are involved in pathways of reactive nitrogen and oxygen intermediates [17, 18]. InhA gene encodes NADH dependent enoyl-Acyl Carrier Protein (ACP)-reductase that causes inhibition of mycolic acid synthesis [19, 20]. The INH is a close to ideal antibiotic and very selective (MIC value 0.025–0.05 μg/mL and other bacteria MIC vale >500 μg/mL). The INH has good oral availability and low toxicity. It Inhibits mycolic acid biosynthesis and targets the enoyl-acyl carrier protein reductase enzyme (InhA) engaged in mycolic acid synthesis. The INH inactivation of

**4.1 Primary agents**

*Structures of drugs for HIV/TB.*

**Figure 3.**

**Figure 4.**

**Figure 5.**

**34**

**Isoniazid (Nydrazid, Laniazid)**

*Structures of different second-line anti-TB drugs.*

*Structures of different fluoroquinolones (second-line anti-TB drugs).*

*Molecular Epidemiology Study of Mycobacterium Tuberculosis Complex*