*3.2. Kaumaha-Chiefly Obligation to Steward in Perpetuity*

As we (re)understood the relationship ali'i had with 'a¯ina and maka'a¯inana, we thought more about the vast responsibility that the ali'i shouldered to ensure the functioning of the socio-ecological system. We enlisted Ka¯naka 'O¯ iwi scholars at the indigenous organization, the Edith Kanaka'ole Foundation (EKF) to assist us in understanding these profound concepts. We describe the weighty or heavy burden of ali'i to safeguard and perpetuate resources in perpetuity for his or her people as kaumaha [47,57]. We use kaumaha to describe a deep, imperative responsibility that one cannot easily relinquish, such as that of landscape-level 'aina stewardship. ¯

The word kaumaha is colloquially most often understood as the feeling of sadness, grief and sorrow, and contemporarily, students often learn this word early in 'olelo Hawai'i classroom training as ¯ an example stative verb in sentences like: "Kaumaha au, I am sad." However, connotations of grief and sadness are not what we wish to convey in this context of 'a¯ina stewardship. Pukui, Haertig and Lee (2002) explain that kaumaha as grief and sorrow is derived from the "*original use of kaumaha meaning weight or heavy weight and from use of the separate syllables, kau (place, put, set) and maha (relief or rest). From the most literal connotation, that holding a physical weight is followed with relief when it is set down,* *came the abstract idea that grief is a heavy weight followed by relief.*" [56] (p. 132). The literal and figurative kaumaha is somewhat like the English word burden, which refers to a heavy load that one carries, but figuratively and colloquially is understood as misfortune or hardship. In our context describing the perpetual duty to maintain and steward 'a¯ina, we refer to the original meanings of kaumaha: heavy, weighty, profound, deep and significant, and not its subsequent often cited figurative definitions.

Furthermore, we contrast the concept of kaumaha—an ali'i obligation of stewardship, with the more familiar term kuleana, meaning right, privilege, responsibility [42]. Traditionally, when a new Ali'i Nui ascended to power, all of the lands of the Island would be redistributed to the various ali'i allies under him or her. The rights and responsibilities (or kuleana) that maka'a¯inana had on those lands would not change through these conversions. On the other hand, the rights and obligations (or kaumaha) that individual ali'i had to steward lands given to him or her could change drastically [59]. We view the right and responsibility maka'a¯inana had to live on and care for their lands and seas as a kuleana, and indeed this is the name given to the lands that maka'a¯inana claimed during the land privatization process of the 1840's [45]. Both kaumaha and kuleana are inherited responsibilities through land and mo'oku'auhau, however, we argue that because of the intimate interdependence that ¯ ali'i had with akua and maka'a¯inana across various landscape scales, they carried a different obligation to maintain critical 'aina functions for all (i.e., water cycling—discussed below). ¯

### **'O ke akua ke komo, 'a'oe komo kanaka** ¯

*The gods may enter, man cannot enter*

#### **'O ke kane huawai, he akua k** ¯ **en¯ a**¯

*Man with the water gourd, he is the god*

Kumulipo, Lines 111–112 [48]

In the Kumulipo lines above, the man with the ka¯ne huawai (water gourd) is refered to as an akua. Why does this ka¯ne huawai elevate this man to akua status? We understand this passage to be about the maintenance of the water cycle, and that the man who perpetuates the sources and driving forces of water is not a merely a man but is an ali'i and god-like [57]. The ali'i as the principle land steward had the kaumaha or imperative duty to maintain the water cycle that sustains all life—the streams, the groundwater, the forested watershed, evaporation, condensation, precipitation [57]. The maintenance of the function of the watershed ensured that all lifeforms in the Hawaiian realm would be supported, including people. This involved the protection of the geologic formations that drive weather systems, the large trees that interact with the atmosphere to produce rain and cloudfall, the multi-layered forest that slows the force of descending raindrops, the groundcovers that absorb moisture and prevent erosion, as well as the aquifers and conduits that hold and distribute fresh water throughout the landscape.

In order to fulfill the kaumaha to ensure maintenance of 'a¯ina in perpetuity, the ali'i imposed rules for resource interaction, which included ka¯na¯wai (laws, rules, or protocols) and kapu (sacred, prohibitions, taboos) at different scales [42,60,61]. Ka¯na¯wai and kapu are both essential elements of 'O¯ iwi religion more broadly. Ka¯na¯wai and kapu indicate the relationship between natural phenomenon and natural phenomenon, Ka¯naka and natural phenomenon, and Ka¯naka to Ka¯naka", [47] (p. 45), meaning these concepts tell us (1) how different elements of the environment will interact, (2) how we as people and the environment should interact, and (3) how we as people should interact with one another. All three relationships are vital for biocultural resource health. The ali'i, as the institutors of kapu and ka¯na¯wai in traditional Hawai'i, governed through these relationships. First, they understood environmental element interactions and cycles through careful observation over generations. Second, using this expert scientific understanding of their environments, they understood resources had specific kapu or a sacredness which prohibited ka¯naka to access those resources at specific times. Ali'i enacted ka¯na¯wai of how ka¯naka should access those kapu resources. For example, seasonal ka¯nawai were put upon many kapu fish according to observations of their spawning times, knowledge of their maturity rates, food abundance and availability, and other information [49,50,62]. And third, ali'i created and

enforce rules of how people should interact with one another, an example being Kamehameha I's famous Ka¯na¯wai Ma¯malahoe, or Law of the Splintered paddle, which declared protections for all people, young and old, from violent assault [63].


**1. Introduction**

The growing prevalence of type 2 diabetes worldwide is particularly alarming. Based on recent world statistics [1], 352 million adults aged from 20 to 79 years old were glucose intolerant (7.3%), and 425 million (8.8%) had type 2 diabetes in 2017 [1]. The association between the dramatic increase of the disease and the rising prevalence of obesity is often highlighted [2]. Obesity and overweight initiate several metabolic disorders [3] that include insulin resistance, which is considered to be the central feature leading to type 2 diabetes [4].

**Citation:** Vodouhè, M.; Marois, J.; Guay, V.; Leblanc, N.; Weisnagel, S.J.; Bilodeau, J.-F.; Jacques, H. Marginal Impact of Brown Seaweed *Ascophyllum nodosum* and *Fucus vesiculosus* Extract on Metabolic and Inflammatory Response in Overweight and Obese Prediabetic Subjects. *Mar. Drugs* **2022**, *20*, 174. https://doi.org/10.3390/md20030174

Academic Editors: Donatella Degl'Innocenti and Marzia Vasarri

Received: 14 January 2022 Accepted: 24 February 2022 Published: 26 February 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/).

Prediabetes is an intermediate stage in the development of type 2 diabetes and is characterized by abnormal high fasting glucose, impaired glucose tolerance, and/or high-fasting insulin [5]. A number of other metabolic dysfunctions are linked to prediabetes and type 2 diabetes, such as chronic systemic low-grade inflammation [6,7], oxidative stress, endothelial dysfunction [8], and impaired gut integrity [9]. The extent to which these phenomena are observed differs with respect to diet composition, among other environmental factors. These disorders may be reversible at the prediabetes stage when nutritional interventions are implemented.

In a clinical setting, the implementation of a weight-loss approach is generally the first-line intervention in the prevention and management of type 2 diabetes among overweight or obese people. The main recommended nutritional treatment to lose weight and prevent type 2 diabetes is the reduction of energy intake [10]. Caloric restriction and weight loss have been shown to improve insulin sensitivity and reduce hyperglycemia [11,12]. A moderate caloric intake restriction of approximately 2093 KJ (500 kcal) per day is recommended [10,13] for a weight loss of 2 to 4 kg/month as suggested by the 2006 Canadian Obesity Guidelines [14].

Marine organisms are rich sources of compounds with diverse biological activities [15]. Among the most promising bioactive molecules in preventing type 2 diabetes are the phlorotannins, a class of polyphenols exclusively produced by brown seaweeds [16]. In vitro and in vivo studies [17,18] show that phlorotannin-rich extracts of brown seaweed *Ascophyllum nodosum* and *Fucus vesiculosus* reduce the α-amylase and α-glucosidase activities involved in the digestion of carbohydrates, resulting in a 90% reduction of glucose 30 min after a meal and a 40% decrease in peak insulin secretion in mice, as reported by Roy et al. [17]. In humans, it has been demonstrated that a single acute dose of 500 mg of a polyphenol-rich extract of *Ascophyllum nodosum* and *Fucus vesiculosus* had no significant effect on glycemia but induced a 12% reduction in the insulin incremental area under the curve (IAUC) following consumption of 50 g of bread compared with a placebo in healthy adults [19]. Fucoidan, a polysaccharide found in brown seaweeds, has also been recognized as a promising bioactive molecule with glucose-lowering potential [20,21], via a reduction of α-amylase and α-glucosidase activities, and therefore a diminution of intestinal absorption of glucose, and an enhancement of cellular glucose uptake via insulin through modulation of cellular glucose transporter GLUT-4 and AMP-activated protein kinase (AMPK). However, there are few studies addressing the chronic physiological effects of brown seaweed extract on metabolic and inflammatory markers in humans and particularly in people at high risk of type 2 diabetes.

Achieving normal blood glucose levels is one of the major goals in diabetes prevention, and it can be reached by different means, such as weight loss or an improvement of glucose homeostasis through a nutritional supplement [22]. From a biological perspective, the response to an energy-restricted diet varies between individuals [23], and this strategy alone is somewhat less effective in the long term [24]. Therefore, a nutritional supplement is often necessary in adjunction to energy restriction [25]. In this context, a brown seaweed extract, which has been shown to reduce waist circumference [26], could be administered in addition to a reduced-calorie diet to obtain additional effects.

The present study was thus undertaken to evaluate the effect of daily consumption of 500 mg of brown seaweed (*Ascophyllum nodosum* and *Fucus vesiculosus*) capsules rich in polyphenols associated with a reduced-energy diet on body weight and blood glucose homeostasis (glucose, insulin, and C-peptide in the fasting state and duringa2h oral glucose tolerance test) for 12 weeks in overweight prediabetic subjects. Lipid profile, heart rate, markers of inflammation, oxidative stress, and integrity of the intestinal barrier were measured as secondary outcomes. We expect that brown seaweed extract lowers body weight and improves glucose homeostasis and metabolic and inflammatory markers in the context of moderate weight loss in this 12-week clinical trial.


2.2.5. Statistical Analysis

Statistical differences were evaluated using a non-parametric test: the Mann–Whitney (Wilcoxon) W test, (Statgraphics Centurion XV, Statistical Graphics Corporation, MD, USA). Differences were considered significant at *p* < 0.05.


*2.9. Cell Viability Assay*

The viable cells were assayed using the MTT Cell Growth Assay Kit (Sigma-Alderich, Temecula, CA, USA). The trypsinized cells were appropriately diluted to adjust the cell number range of 1000–50,000 cells/well with growth medium. An amount of 0.2 mL of cell dilution was plated into each well in a 96-well format. The cells were incubated at 37 °C overnight. The medium was changed to make the final volume of each well 0.1 mL. We added 0.01 mL AB Solution (MTT) to each well. We incubated the cells at 37 ◦C for 4 h for cleavage of MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, Thiazolyl Blue Tetrazolium Bromide). We added 0.1 mL isopropanol with 0.04 N HCl to each well. The absorbance was measured on an ELISA plate reader (Bio-rad, Hercules, CA, USA) with a test wavelength of 570 nm and a reference wavelength of 630 nm within 1 h.


**1. Introduction**

Obesity is becoming increasingly common, with at least 400 million obese adults worldwide and the World Health Organization (WHO) projecting that this statistic will reach 700 million in another five years [1]. The body, which is altered by excessive weight, has its biological process modified. This results in several diseases. Different diseases such as heart disease and strokes, high blood pressure, type 2 diabetes, cancer, asthma, sleep apnea, osteoarthritis are all related to obesity [2].

According to a recent survey by the Brazilian Society of Endocrinology and Metabolism (SBEM) obesity in Brazil has increased, on average, 240% over the past 20 years. Today, methods of treatment for obesity are: a) diets; b) non-pharmacological treatments; c) pharmacological treatments; d) surgeries. All the aforementioned methods have the same principle –an energy deficit is necessary to cause weight loss.

Among the techniques available for treating obesity, surgical techniques are more efficient. It is known that surgical methods offer effective results, maintaining 50% weight loss for 10 years. Two types of surgical treatments are practiced: a reduction of the stomach volume to diminish food ingestion and the use of a stomach-intestine bypass to produce practically no absorption of nutrients [3].

In type 2 diabetes mellitus (T2DM), treatment with pharmacologic therapies in order to control blood sugar only slows progression of the disease. Bariatric surgery has been implicated in the complete resolution of type 2 diabetes mellitus in several clinical studies [4].

Multidisciplinary studies for treating obesity and type 2 diabetes mellitus have been developed. Doctors and Engineers are working together to deal with the problem and find

solutions. This is being carried out especially with biomaterials and in biomedical engineering where new devices are being developed.

Prosthesis for Flow Control in the Esophagus as a New Technique for the Treatment of Obesity 171

for treating ischemic leg ulcers. Here, the goal is for the biomembrane to act as an inducing agent for healing tissues [9]. In [10], this membrane was employed in recurrent umbilical

In orthopaedic research aimed at more effective bone regeneration, latex was efficient in repairing tibial fractures in a rabbit, demonstrating great potential for this kind of application. In skull fractures in rats, the results were similar and the researchers believe that new investigations indicate its use in osteoporosis, odontology and facial bone reconstruction [11]. In [12], they developed a new microperforated vascular prosthesis model, made of tissue covered with a compound derived from rubber tree natural latex (*Heveabrasiliensis*) and used an expanded a polytetrafluoroethylene prosthesis as control in the contralateral pelvic limb in the same animal. The study was done applying two prostheses in 15 dogs. The microperforated latex and fabric graft showed satisfactory structural qualities (adaptability, elasticity, impermeability and possibility of suture) as a vascular substitute. It stimulated endothelial growth, beyond contact regions with the artery in anastomoses and was bicompatible with the dog's arterial system, showing adequate tissue integration. In [13], they evaluated using a natural latex mould in the postoperative surgical preparation of the neovagina with the objective of inducing healing and to keep the cavity functional in nine patients with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. The results confirmed the properties of tissue replacement and regeneration of natural latex derived from *Hevea brasiliensis* and acceleration of the healing process with no rejection. In [14], they developed a topical latex membrane for controlled drug release. In other medical areas, latex has been studied and successfully utilized in the healing process of ulcers, and in burned areas on the body's surface and in conjunctiva reconstruction [8]. Due to these promising results, using latex was the basis for making the new device

A study was conducted concerning esophageal diseases in order to propose a device and its placement technique. It was found that patients with obstructive diseases of the esophagus (caustic stenosis, chagasic megaesophagus and esophageal cancer) have high weight loss as a result of reducing the flow of food,which can be seen in [15,16,17,18]. Because these esophageal diseases cause a reduction of the esophageal lumen or obstruct the emptying of the organ, they lead to the patient losing weight. In this context, the CFE® module was developed for helping in the treatment of obesity and it also can be used for diabetes treatment due to the significant weight loss achieved with its use. This chapter describes the engineering and design used in the development of the device and the tests already carried on it aiming at its efficacy and security evaluation in order to offer to the global community

Whereas a decrease in food consumption may be secondary to esophageal obstruction and considering that there is the possibility for inserting devices that may alter its diameter (which takes place in the treatment of bleeding due to esophageal varices), it was plausible

hernias and its effectiveness was established in twelve dairy cows.

proposed here for treating and controlling diabetes and obesity.

a new option for obesity and diabetes treatments.

**2. Materials and methods**

GI Dynamics® is developing a novel endoscopic treatment for obesity and T2DM. The EndoBarrier™ gastrointestinal liner is a removable implant that resides in the proximal intestine [3]. Toga, from Satiety, Inc., still in its trial stages, inserts flexible stapling devices through the mouth and into the stomach, and then uses suction to gather stomach tissue and staple it together, creating a small stomach pouch near the esophageal junction and thereby increasing satiety [1]. Furthermore, the methods used neuroregulation activation and gastric implants for activation of the vagus nerve as a way to control hunger [1,4].Thus, it is worth noting that there are difficulties in proposing an efficient obesity treatment. In other words, the control and cure of the multiple causes of obesity associated with eating habits is a difficult problem.

In this study, we designed an esophageal flow control module (CFE) made from a biosynthetic material based on natural latex (extracted from the rubber tree *Hevea brasiliens*). The intended purpose of the CFE is to help to control the speed and the volume of food ingested, and, as a result, to help in treatments to reduce weight.

The CFE proposed is classified as a restrictive surgical procedure. It is inserted into the esophagus (3 cm after the passage of the upper sphincter) and filled with gas. Experimental animal research has shown satisfactory results. The device has the mechanical characteristics necessary for use inside the esophagus. Furthermore, the animals did not have problems with gastric and behavioral changes, nutrition, blood disorders or irritation because of the CFE. Therefore, this unprecedented technique, which can solve the obesity problem, allows a decreased food intake by decreasing the flow through the esophagus.

Therefore, even though the device needs to be tested on humans, the efficiency of this procedure has been ratified, especially given the success of the evaluation in dogs. Weight loss was confirmed (and validated) between two groups of animals tested. One group had the module and the other did not (however both maintained the same dietary and environmental routine). A biomaterial, latex, is used in its development, given its prominence (in Brazil). There are non-gummy, rubber, hydrocarbon particles in the composition of natural latex. The particles are suspended in an aqueous solution phase in which there is on average 36% hydrocarbons, 1,4% proteins, 1,6% carbohydrates, 1% neutral lipids, 0,6% glycolipids plus phospholipids, 0,5% inorganic components, 58,5% water and 0,4% of other substances. For this reason, *Hevea brasiliensis* latex is a complex cytoplasmic system in which the rubber particles and the nonrubbery particles (also called non-gummy) are dispersed in an aqueous cytosolic phase. It is a national low-cost product, which is also easy to handle. Latex, plus other substances, was initially used as a material that induces healing in damaged esophageal walls. Results showed that a natural latex biomembrane with polylysine has biochemical characteristics that make it capable of interfering in the process of tissue repair thus promoting the rapid and regular formation of new tissue. It is also easy to handle, dispensing with complex techniques for manufacturing and use [5, 6, 7]. Based on these data, other studies utilizing latex have been done, such as using latex for myringoplasty in humans [8] and applying latex biomembranes for treating ischemic leg ulcers. Here, the goal is for the biomembrane to act as an inducing agent for healing tissues [9]. In [10], this membrane was employed in recurrent umbilical hernias and its effectiveness was established in twelve dairy cows.

In orthopaedic research aimed at more effective bone regeneration, latex was efficient in repairing tibial fractures in a rabbit, demonstrating great potential for this kind of application. In skull fractures in rats, the results were similar and the researchers believe that new investigations indicate its use in osteoporosis, odontology and facial bone reconstruction [11]. In [12], they developed a new microperforated vascular prosthesis model, made of tissue covered with a compound derived from rubber tree natural latex (*Heveabrasiliensis*) and used an expanded a polytetrafluoroethylene prosthesis as control in the contralateral pelvic limb in the same animal. The study was done applying two prostheses in 15 dogs. The microperforated latex and fabric graft showed satisfactory structural qualities (adaptability, elasticity, impermeability and possibility of suture) as a vascular substitute. It stimulated endothelial growth, beyond contact regions with the artery in anastomoses and was bicompatible with the dog's arterial system, showing adequate tissue integration. In [13], they evaluated using a natural latex mould in the postoperative surgical preparation of the neovagina with the objective of inducing healing and to keep the cavity functional in nine patients with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. The results confirmed the properties of tissue replacement and regeneration of natural latex derived from *Hevea brasiliensis* and acceleration of the healing process with no rejection. In [14], they developed a topical latex membrane for controlled drug release. In other medical areas, latex has been studied and successfully utilized in the healing process of ulcers, and in burned areas on the body's surface and in conjunctiva reconstruction [8]. Due to these promising results, using latex was the basis for making the new device proposed here for treating and controlling diabetes and obesity.

A study was conducted concerning esophageal diseases in order to propose a device and its placement technique. It was found that patients with obstructive diseases of the esophagus (caustic stenosis, chagasic megaesophagus and esophageal cancer) have high weight loss as a result of reducing the flow of food,which can be seen in [15,16,17,18]. Because these esophageal diseases cause a reduction of the esophageal lumen or obstruct the emptying of the organ, they lead to the patient losing weight. In this context, the CFE® module was developed for helping in the treatment of obesity and it also can be used for diabetes treatment due to the significant weight loss achieved with its use. This chapter describes the engineering and design used in the development of the device and the tests already carried on it aiming at its efficacy and security evaluation in order to offer to the global community a new option for obesity and diabetes treatments.

#### **2. Materials and methods**

170 Practical Applications in Biomedical Engineering

difficult problem.

engineering where new devices are being developed.

ingested, and, as a result, to help in treatments to reduce weight.

a decreased food intake by decreasing the flow through the esophagus.

solutions. This is being carried out especially with biomaterials and in biomedical

GI Dynamics® is developing a novel endoscopic treatment for obesity and T2DM. The EndoBarrier™ gastrointestinal liner is a removable implant that resides in the proximal intestine [3]. Toga, from Satiety, Inc., still in its trial stages, inserts flexible stapling devices through the mouth and into the stomach, and then uses suction to gather stomach tissue and staple it together, creating a small stomach pouch near the esophageal junction and thereby increasing satiety [1]. Furthermore, the methods used neuroregulation activation and gastric implants for activation of the vagus nerve as a way to control hunger [1,4].Thus, it is worth noting that there are difficulties in proposing an efficient obesity treatment. In other words, the control and cure of the multiple causes of obesity associated with eating habits is a

In this study, we designed an esophageal flow control module (CFE) made from a biosynthetic material based on natural latex (extracted from the rubber tree *Hevea brasiliens*). The intended purpose of the CFE is to help to control the speed and the volume of food

The CFE proposed is classified as a restrictive surgical procedure. It is inserted into the esophagus (3 cm after the passage of the upper sphincter) and filled with gas. Experimental animal research has shown satisfactory results. The device has the mechanical characteristics necessary for use inside the esophagus. Furthermore, the animals did not have problems with gastric and behavioral changes, nutrition, blood disorders or irritation because of the CFE. Therefore, this unprecedented technique, which can solve the obesity problem, allows

Therefore, even though the device needs to be tested on humans, the efficiency of this procedure has been ratified, especially given the success of the evaluation in dogs. Weight loss was confirmed (and validated) between two groups of animals tested. One group had the module and the other did not (however both maintained the same dietary and environmental routine). A biomaterial, latex, is used in its development, given its prominence (in Brazil). There are non-gummy, rubber, hydrocarbon particles in the composition of natural latex. The particles are suspended in an aqueous solution phase in which there is on average 36% hydrocarbons, 1,4% proteins, 1,6% carbohydrates, 1% neutral lipids, 0,6% glycolipids plus phospholipids, 0,5% inorganic components, 58,5% water and 0,4% of other substances. For this reason, *Hevea brasiliensis* latex is a complex cytoplasmic system in which the rubber particles and the nonrubbery particles (also called non-gummy) are dispersed in an aqueous cytosolic phase. It is a national low-cost product, which is also easy to handle. Latex, plus other substances, was initially used as a material that induces healing in damaged esophageal walls. Results showed that a natural latex biomembrane with polylysine has biochemical characteristics that make it capable of interfering in the process of tissue repair thus promoting the rapid and regular formation of new tissue. It is also easy to handle, dispensing with complex techniques for manufacturing and use [5, 6, 7]. Based on these data, other studies utilizing latex have been done, such as using latex for myringoplasty in humans [8] and applying latex biomembranes

Whereas a decrease in food consumption may be secondary to esophageal obstruction and considering that there is the possibility for inserting devices that may alter its diameter (which takes place in the treatment of bleeding due to esophageal varices), it was plausible

to suppose that developing the CFE® module may lead to reducing food intake.The objective is to evaluate the possibility of CFE® insertion into the esophagus which causes, during its use, resistance to the passage of food bolus. This makes food ingestion slower due to a reduction in the lumen of the esophagus, resulting in the need for prolonged chewing.

Prosthesis for Flow Control in the Esophagus as a New Technique for the Treatment of Obesity 173

With the objective of estimating the minimal time to carry out an intervention, in the event that it descends to the stomach and in order that it not cause intestinal obstruction, an experiment was conducted in the Laboratory of Engineering and Innovation – LEI at the Gama Campus of the University of Brasília. This experiment compared the volume of BIB (400 ml to 700 ml) and (CFE 146 ml) with the goal of comparing its volumes and its emptying capacity in the case it is punctured. The calculation employed for obtaining the CFE volume used a technique based on solids of revolution and the time was obtained from simple arithmetic means. There were four CFE modules used as samples and these were immersed into an environment similar to the stomach. The method utilized was to inflate the CFEs with the same pressure to be applied in humans (60 mmHg – minimum), withdrawal of the scalp1 number 27, immersion of the CFE in the environment with the hole made in the sample by the scalp on the upper part of the module thereby forcing partial emptying, since if it were not punctured, it would not empty as in the test done in [7].

The choice for using a dog – as an animal for testing and for weight loss and/or as a validator of the CFE module – was made in light of findings raised with medical veterinarians. It was verified that the animal would be an excellent subject for analysis in this study keeping in mind the anatomical-physiological similarity between human and canine esophagi. Allied with this, above all, factors that denote affability with such animals and also, the facility of controlling their eating routine, as well as the food ingestion speed of the animal, associated with little chewing and the absence of psychological pressure (as opposed to what a human develops when the goal is losing weight). To conduct the experimental procedure, eight adult dogs, of no specific breed, males and females, with body weights varying between 9.2 and 17.8 kg were selected. Before the experiment, the animals were kept at the Veterinarian Hospital kennel at the Federal University of Goiás to be submitted to quarantine procedures that include: vaccination (Duramune Max, single dosage), application of ecto and endoparasiticides (administered through 100 mg of mebendazole, twice a day for three days), in addition to laboratory exams like blood count, urinalysis, hormonal and blood biochemical evaluations. Furthermore, improvements in the nutritional conditions of the animals was sought, through the implementation of a daily diet of dry dog food, supplemented with semi-moist dog food rich in nutrients (Dudog®). The animals were vaccinated against rabies and DHLPPC (distemper, hepatitis and adenovirus, leptospirosis, parainfluenza, parvovirus, and coronavirus) and dewormed with a broad spectrum dewormer. Ectoparasites were eliminated with a two-dose application of pour-on parasiticide. Blood was taken from all the animals and when hemoparasitoses was present, doxycycline was applied for 21 days, and diminazene in

1 The scalps peripheral intravenous comprise: siliconized needle stainless steel bezel with thin walls and biangular and three faceted; wings malleable and flexible, adjustable anatomically as handling (known as "butterfly"); transparent

**2.4.** *In-vitro* **study**

**2.5. Preparation for clinical trial**

two applications with an interval of 15 days.

vinyl tube.

#### **2.1. Latex preparation**

The latex used here had already been through the centrifuging process, with sulfur and resin suspensions, having the objective of providing elasticity and the necessary strength for the final compound. From this preparation process, the latex is configured as a compound which upon contact with the skin, vulcanizes, making it adhesive. To be removed, however, just pure water is used. On glass surfaces, its removal is facilitated due to the low friction that glass provides.

When handling the latex, glass rods were used for mixing, as well as a glass container for storage, plastic wrap to protect it from contact with the air and cotton flannel for cleaning. An important point for any application that uses raw latex is the uniformity of its properties, since this is an essential characteristic. To obtain this characteristic, the latex source should be the same, i.e. the latex should come from trees of the same clone.


**5.9. Low-pressure plasma spraying process**

The TBC must exhibit high thickness (100–300 μm), vertical cracks should be present in the TBC in order to be a strain tolerant layer, and it must have high porosity to decrease the thermal conductivity. Rousseau et al. [39] prepared a Y-PSZ layer using low-pressure plasma spraying technique by introducing a solution of nitrate salt into a low-pressure plasma discharge. The characteristics and stability of the Y-PSZ layers were analyzed by several techniques. Optical emission spectroscopy indicated that the oxidant chemistry of the plasma caused oxide formation and the nitrate elimination at low temperature (T<300°C). Effects of the several parameters such as power of the plasma discharge, post-treatment and heat treatment on structure, morphology, and stability of the Y-PSZ coatings was studied by X-ray diffraction (XRD), scanning electron microscopy (SEM), water porosimetry, and thermal diffusivity measurement. It was observed that Y-PSZ coating (porosity-50%) had good thermal barrier property at high temperatures [39].

### **5.10. Thermal plasma process**

Superior properties such as high-melting point, high phase stability, low sintering ability, low thermal conductivity, and low oxygen permeability of lanthanum zirconate (LZ) have made it one of the most promising TBC materials for high-temperature applications. However, the production methods used to synthesize lanthanum zirconate are highly time-consuming and the powder is not commercially available. Hence, the thermal plasma process was utilized to synthesize, spheroidize, and spray deposits of lanthanum zirconate material by Ramachan‐ dran et al. [40]. They demonstrated the effectiveness of thermal plasma as a major materials processing technique. Suitable characterization techniques were used to study the material modifications after respective plasma processing exposures [40].


**15. Graphic notations**

258 Semantics – Advances in Theories and Mathematical Models

Analysis is deemed essential for providing information and critical skills for interface

Informs about a text, its underlying assumptions and its various dimensions of

Context with a operating-cultural structures and entities (human-machine) motivations

Unmasks the deep-seated rhetorical forms and underlying codes that fundamentally

Essentially C3 semantics modeling—dynamics mapping is based on 'reasoning' and 'understanding' using dynamic information and knowledge domains in the context of Ackoff system of filters. An example may be a mobile machine cognitive map that may "*contains, in addition to spatial information about the environment, assignments of mapping features*

The semantic process serves another purpose to facilitate the 'resource description framework' (RDF) which is drawn from the traditional project management processes. If this is the commonality then C3 'semantic project management mapping' (SPMM) stresses the 'semantics' core meaning of really 'itself' using knowledge—information—learning

In the SPMM context there is a reliance on meaningful communication with and within dependant or independent domains that interact with various entities and events. This

**13. Semiotic mapping**

Sign: "representation"

and media literacy.

interpretation.

**14. Guiding parameter**

therefore leads to a continuum:

domains.

In summary Semiotic mapping comprises:

Semiotics Themes (Fig 6) are inclined to be:

Interpretation: "Immediate; dynamic; logical"

that underlie perceptual representations.

Fig. 6. Semiotoc model (Ryder, 2004; Lemke, 2001).

*to entities of known classes*" (Uschold, 2001).

 Offers a lens into entities (human-machine) communication. Sharpens the entities consciousness surrounding a given text.

shape entities realities (Ryder, 2004; Lemke, 2001).

Rejects the possibility that can represent the world in a neutral fashion.

Object: "Immediate; dynamic"

A graphic notation tends to be cognitive by nature and as such is a feature of a semantic network or network*.* As an enabler, what is suggested is representing information– knowledge domains with patterns and symbols. By doing so the various management and learning styles are able to be accommodated. Additionally, what are highlighted are interconnected nodes and threads with alignments with philosophy, psychology, and linguistics (Sowa, 2006).

So what should it be F–semantics, I–semantics or a hybrid? F–semantics that is, the semantics is deterministic: no stable models or well-founded model is empty, but is meaningful. I–semantics namely lexical semantics: no principled reason to restrict being an ad hoc stipulation or satisfying declaratives for agent programs or a hybrid? (Phan Luong, 1999; Tancredi, 2007; Eiter et al., 1999).


*3.5. Sample Preparation*

In the establishment of the ELISA method, sample pretreatment is very important and is directly determined the accuracy of detection results. In recent years, the existing ELISA methods for PAHs detection have mainly concentrated on environmental samples, such as water (lake water, tap water, drinking water) and air [15,32,33]. However, there is no report on the detection of PAHs in aquatic products by ELISA. As a large country of aquatic products, it is imperative for China to detect PAHs in aquatic products. The ELISA method sensitivity is according to the specific binding ability of antigen and mAb, however, the

sensitivity is susceptible to interference by fat and protein in the sample. Therefore, the samples usually need to be pretreated (extracted, purified, concentrated or diluted) before analysis to reduce matrix interference. To improve the precision of detection, according to the chemical properties, the extraction method of PYR and BaP in aquatic products was explored.

First, the matrix effect was evaluated, and blank samples were directly pretreated with PBS as previously reported [33]. The results showed that the matrix effect was very severe, even false-positive. When organic solvent extraction was performed during sample pretreatment, the matrix effect problem was solved. In this study, several extraction buffers, including acetonitrile, ethyl acetate and ethyl acetate-acetonitrile (4:1; v:v), were used to investigate the extraction effect. It can be seen that a higher recovery rate was obtained by ethyl acetate-acetonitrile (4:1; v:v). Acetonitrile could not extract the drug, and the recovery of ethyl acetate was less than 70%. Therefore, ethyl acetate-acetonitrile (4:1; v:v) was selected as the extraction solvent for sample pretreatment.

### *3.6. IC-ELISA Performance for Aquatic Products*

Based on the optimization of ic-ELISA conditions and sample pretreatment described above, 20 negative samples were collected for ELISA performance measurement. The LODs of the method for PYR and BaP in fish, shrimp and crab ranged from 0.43 to 0.54 μg/kg and 0.92 to 0.98 μg/kg, respectively. Meanwhile, the recoveries of PYR and BaP in fish, shrimp and crab were 81.5–101.9% and 84.9–94.0%, respectively, and the CV was less than 11.7% (Table 2). The minimum detection levels of PYR and BaP in aquatic products were far below the MRLs.

**Table 2.** The LODs, LOQs, CV and recoveries of PYR and BaP in aquatic products.

To validate the reliability of this experimental method, the ic-ELISA and HPLC-FLD methods were used to detect positive fish samples contaminated with PYR. The liquid chromatogram of PYR in the fish sample is shown in Figure S3. The results from the ic-ELISA were consistent with the results of HPLC-FLD, and the correlation coefficient was R2 = 0.9961 (Figure 5). The results indicated that ic-ELISA can be used as an available tool for the detection of PYR and BaP in aquatic products samples.

**Figure 5.** Correlation between ic-ELISA and HPLC-FLD for PYR determination of positive fish sample.


**1. Introduction**

The simplicity of the design of memristor based circuits and the possibility of manufacturing memristors [1–3] using integrated technology make them promising for use in a variety of information storage and processing systems. The construction of neuromorphic systems [4–8] is one of the most important memristor applications where the memristors provide the function of nonvolatile analog memory.

Due to memristor capabilities the wide implementation of memristors is predicted in different circuit application spheres including analog circuits. The properties of memristors [3, 9] open up new possibilities of constructing the memristor based oscillators (MBO) of different types [10–14]. The complex behavior of MBOs is analyzed in some papers (see for instance [15–18]). The inertial property of memristors provides the elimination from oscillator circuits the reactive elements (inductors and capacitors) which are poorly compatible with the requirements of the integrated implementation of neuromorphic systems. By the present time the various types of reactance-less MBO have been proposed [19–28]. This class of oscillators is considered below in the paper.

The neuromorphic systems including artificial neurons (AN) and networks become promising area where the analog memory plays the important role [29–39]. The memory elements are located between neurons and provide restructuring the coupling weight coefficients. Memristors are well suited to the requirements for artificial synapses [9, 40, 41]. The memristor resistance determines the value of the weight coefficients. The change in resistance under the action of current determines the possibility of restructuring the connections.

However, it should be noted that the properties of memristors allow them to be used not only as synaptic elements but also in the artificial neurons themselves. It can be mentioned that the reactance-less MBO consisting of memristor device and an active element, for instance comparator, can be also considered as simple AN model. Such an oscillator element can be inhibited or excited similarly to AN behavior. Its state can be specified by the phase of periodic oscillation.

Advanced AN models [8] that more accurately describe the behavior of biological neurons have high complexity to represent essentially more complex and various dynamical processes. The response of oscillatory AN to the input excitation involves not only changing the state but also changing the character of generation of output pulse train. In this case the number of the pulses and position of the pulses in pulse train depend on input amplitude and transient prehistory.

The complex mathematical model is required to represent such a behavior. This is usually achieved by increasing the order of the model. The complexity of circuits of corresponding oscillatory AN is also must be increased [42, 43] and strict requirements for the precision of circuit parameters must be met.

We present the alternative approach in this paper. We demonstrate that coupled memristor-based reactance-less oscillators have the set of modes with dynamical processes that is enough to provide the desired complex behavior. To support these capabilities at circuit level the approach to MBO construction is presented that based on controlling the comparator threshold. Some advantages of this approach are demonstrated.

Among the advantages of controlling threshold approach in MBO it is essential to point out the opportunity to construct piecewise constant (PWC) oscillators. Recently AN models based on piecewise constant (PWC) oscillators have appeared [44–46]. Such AN models are convenient in practice. PWC oscillators are the oscillators with mathematical models which are systems of ordinary differential equations (ODE) with piecewise constant coefficients. The signals generated by AN in this case are piecewise linear functions of time. PWC oscillators are developed on the base of standard electronic components including amplifiers, logic gates, resistors, capacitors. The transient processes occur in these circuits under constant excitation, for example the charge or discharge of the capacitor at constant current. The analysis of AN behavior of such type and networks based on them is given in papers [47, 48]. The nonlinearity of the memristor characteristics due to the change in its resistance when current flows through device limits the development of PWC memristor based oscillators [49, 50]. Application of the considered approach to control threshold in MBO avoids this restriction because it provides use only changing the sign of the current through the memristor while generation process.

Application in binary oscillator networks is other important capability of the considered coupled reactance-less MBOs. Oscillatory neural networks are promising candidates for solving a number of complex computational problems [51–55]. The most suitable circuit elements for such networks are binary generators with binary output signals [56–58]. In binary oscillator networks (BON) binary signals are exchanged and information is represented by binary streams. The considered coupled reactance-less MBOs can be applied as elementary binary oscillators.

The rest of the paper is organized as follows. Section 2 presents the principle of controlling thresholds in MBO circuits. The circuit version of coupled MBOs with positive couplings and its functionalities are discussed in Section 3. In Section 4 the *Functional Capabilities of Coupled Memristor-Based Reactance-Less Oscillators DOI: http://dx.doi.org/10.5772/intechopen.97808*

functional capabilities of coupled MBOs with inverting connections are given. The main properties of coupled MBO for use in binary generator networks are considered in Section 5. The technique of using phase planes to analyze the behavior of MBOs is widely used in sections.


**5. Treatment**

252 Social and Psychological Aspects of HIV/AIDS and Their Ramifications

Several common diseases such as tuberculosis, malaria, influenza, measles malnutrition and stress temporarily suppress immune response, but once infection subside immune system returns to normal but in AIDS it does not. Antibodies to HIV form in 1 – 4 months after infection but symptoms may not appear for up to 5 years and beyond in some cases and

Perhaps the most important fact about AIDS is that it is a preventable disease. Ideally, this can be achieved by development of a vaccine, although much effort and money have been directed towards production of a vaccine. However, presently, there is none yet, and, it is unlikely that one will be available within the next five years (National Institute of Allergy and Infections Diseases (NIAID) 2009). In the absence of a vaccine, health education and counselling to create a sense of awareness and to reduce the risk of transmission by employing safe sex practices and other high risk behaviours, should become imperative (Centers for Disease Control & Prevention (CDCP), 2002). Other factors that may prevent the spread of AIDS includes ensuring a supply of safe blood and blood products, no sharing of needles and syringes and deferment of pregnancy among high risk subjects. Surveillance to monitor the size of the problem and how it changes, is an important component of

In most developing countries, many people are not aware of their HIV status. Less than 1% of sexually active persons in urban Nigeria have been tested for HIV and this proportion is even lower within rural populations (Akande, 2001). Furthermore, a mere 0.5% of pregnant women who attend urban health facilities are counselled, tested or receive their test results. In fact, this proportion is even lower in rural health facilities. Hence, donor blood and blood products that are used in medicine and medical research, are screened for HIV (Nunn, *et al.*, 2004). A typical HIV test, including the HIV Enzyme Immunoassay (EI) and the Western Blot Assay (WBA), detects HIV antibodies in serum, plasma, oral fluid, dried blood spot and urine of patients. However, the window period (the time between initial infection and the development of detectable antibodies against the infection), can vary. This is why it can take 3-6 months to seroconvert, test and detect other HIV antigens, HIV-RNA, and HIV-DNA (Scripps Research Institute, n.d). In order to detect HIV infection these assays are not

Three main transmission routes of HIV include sexual contact, exposure to infected body fluids or tissues and from mother to child during the prenatal period. It is possible to find HIV in the saliva, tears and urine of individuals but there have not been recorded cases of infection from these secretions (WHO, 2006). Therefore, the risk of infection through saliva,

A majority of HIV infections are acquired through unprotected sexual contact between partners, one of whom has HIV (UNAID, 2004; Ojukwu, 2004). Sexual intercourse is a

officially approved, but are nonetheless routinely used in some countries.

during these years, a person can transmit the virus to others without knowing.

**4. Prevention**

prevention (ibid).

**4.2 Transmission**

**4.3 Sexual contact**

tears and urine is negligible.

**4.1 HIV test**

WHO (2004) reported that there is currently no vaccine or cure for HIV/AIDS. The only known methods of prevention are based on avoiding exposure to the virus and an antiretroviral treatment, which, when taken directly after a highly significant exposure, called post-exposure prophylaxis (PEP), has a demanding four week schedule of dosage. Current treatments for HIV infection consist of highly active antiretroviral therapy (HAART). This has been highly beneficial to several HIV-infected individuals since its introduction in 1996 (UNAIDS, 2009).

In the first decade of the epidemic when no useful conventional treatment was available, a large number of people who have AIDS experimented with alternative therapies (Nomcebo, 2005). The definition of "alternative therapies" in AIDS has changed since then. During that time, the phrase often referred to community-driven treatments, were untested by government or pharmaceutical company research, and which most people hoped would directly suppress the virus or stimulate immunity against it. Despite widespread use of complementary and alternative medicines by people who live with HIV/AIDS, effectiveness of these therapies has not been established (UNAIDS, 2004).

Treatment of AIDS consists of treatment of the HIV infection and complications, which result from the immune deficiency. A number of chemotherapeutic agents such as Zidovudine or AZT, Ribavirin, Suramin, Foscarnet and HPA- 23 have been used as antiviral agents, with limited success. Thus far, only Zidovudine has been approved for use in several countries, since it has been shown to cross the blood brain barrier. However, it is expensive and toxic to bone marrow.

HIV/AIDS and the Productivity of Selected Sub-Saharan African Regions 255

The population of study comprises countries that have the highest prevalence of HIV/AIDS epidemic in sub-Saharan Africa. These countries are Botswana, Kenya, Uganda, South

Data for the research was obtained from secondary sources such as textbooks, journal articles and the internet. The data collected was analyzed by use of the T-test, which is used when comparing two population means. The formula for finding significant differences

( )( )

Ns N S N N

1 22 1 2

+ +

1 2 2 2

tx x

= −

( )( )

At the end, if the value of the critical value is less than the calculated value, the null

The essence of this presentation and analysis is to ensure that the collected data is meaningful for decision-making. Therefore, this section is the critical aspect of the research, which provides the background upon which the results and conclusion of the study will

(in 000)

Population with HIV/AIDS

Population without HIV/AIDS (in 000)

N N 2 NN

+ −

1 2 12

Africa and Zimbabwe, and were used to reflect rising trends of the epidemic.

**6.1 Population of study**

**6.2 Method of data collection and analysis**

Where 1 x = mean of the first group 2 x = means of the second group N1 = number of cases in the first group N2 =number of cases in the second group S1 =standard deviation of the first group S2 =standard deviation of the second group

**6.3 Data presentation and analysis**

Countries Total Population

Source: Field survey data, 2007.

(in 000)

rest.

Botswana Kenya Zimbabwe South Africa Uganda Total

between two independent means is stated as follows:

In using this formula, the degree of freedom (d.f) is noted.

hypothesis is rejected and the alternative hypothesis is accepted.

Table 1.1 Countries that have the highest prevalence of HIV/AIDS

#### **5.1 Economic impact**

HIV/AIDS retards economic growth by destroying human capital. According to a UN report, HIV/AIDS epidemics will have devastating consequences in decades to come for virtually every sector of society ranging from households, farms and other economic activities (Nomcebo, 2005). The epidemic is predicted to hinder possibility of achieving UN millennium development goals within most affected regions, particularly sub Saharan Africa (Todaro, 1992).


**7. Therapeutic perspectives of TLR targeting in periodontal inflammation**

Usual practical approaches to reduce bacterial levels to proportions manageable by the host innate immune system and limit the aggression of oral pathogens on periodontal tissues (scaling, root planning and meticulous oral hygiene techniques) [95] are often inefficient and for this reason adjunctive therapeutic strategies have been proposed in order to modulate host response.

Since their discovery, TLRs have emerged as pivotal mediators of innate host immune and inflammatory response. Due to their role in the recognition of PAMPS and DAMPS of various origins and the triggering of a proinflammatory response, TLR-signalling is regarded as a novel therapeutic target. That is why research was conducted to develop drugs that exploit TLRs signalling in immune therapy, drugs which are already tried to treat diseases, such as asthma and chronic obstructive pulmonary disease [96], AIDS [97], hepatitis B [98, 99], cancer [100, 101].

To date, several directions for targeting TLR-signalling pathways are discussed:

Despite the potential of TLRs to activate the synthesis of protective molecules against infection, they can also induce serious immunopathological reactions in case of overstimulation or insufficient control due to the limited action of some negative regulators. An increased number of negative regulators able to dampen the degree and duration of TLR-mediated inflammatory host response were proposed.

**Negative regulation** of TLR signalling can be exerted extracellularly (inhibition of receptor function) or intracellularly (inhibition of downstream signalling).

Negative regulation occurs through different mechanisms:

Negative regulators fail to control TLRs signalling because requiring a combination of effects, their loss leads to hyperactivation and pathogens develop strategies to evade TLR signalling [104]. TLRs may be novel therapeutic targets in periodontitis since manipulation of their signalling pathways contribute to the control of infection and inflammation and TLR agonists could be tested as vaccine adjuvants in treating periodontal inflammation [105].

**Vaccine adjuvants** exert their action by increasing antigen delivery to APCs, activating them to produce cytokines and by triggering T lymphocytes response [102, 106]. TLRs can function as adjuvant receptors for the recognition of certain antigens produced by microorganisms, the stimulation and maturation of APCs and the alerting of the immune system [24].

TLR agonists, similar but less toxic than PAMPS, are able to cause DCs maturation [102]. They are small molecules that mimic natural TLR ligands and could have improved pharmacological effects.

TLRs agonists are already clinically tested as vaccine adjuvants for cancer, allergic and infectious diseases [107].

#### **8. Conclusion**

Innate immune receptors are critical in maintaining periodontal health as well as in the progression of gingival inflammation by acting on the commensal microbiome and as a link to the activation of adaptive immunity. Due to the fact that TLRs are important in preserving the periodontium state in healthy conditions and TLR-inflammation is responsible for the destructive host reactions in periodontal diseases, the development of drugs that target TLR signalling and promote beneficial local effects would be of great success in such diseases.


Gate-All-Around FETs: Nanowire and Nanosheet Structure

*Jun-Sik Yoon, Jinsu Jeong, Seunghwan Lee, Junjong Lee and Rock-Hyun Baek*

### **Abstract**

DC/AC performances of 3-nm-node gate-all-around (GAA) FETs having different widths and the number of channels (Nch) from 1 to 5 were investigated thoroughly using fully-calibrated TCAD. There are two types of GAAFETs: nanowire (NW) FETs having the same width (WNW) and thickness of the channels, and nanosheet (NS) FETs having wide width (WNS) but the fixed thickness of the channels as 5 nm. Compared to FinFETs, GAAFETs can maintain good short channel characteristics as the WNW is smaller than 9 nm but irrespective of the WNS. DC performances of the GAAFETs improve as the Nch increases but at decreasing rate because of the parasitic resistances at the source/drain epi. On the other hand, gate capacitances of the GAAFETs increase constantly as the Nch increases. Therefore, the GAAFETs have minimum RC delay at the Nch near 3. For low power applications, NWFETs outperform FinFETs and NSFETs due to their excellent short channel characteristics by 2-D structural confinement. For standard and high performance applications, NSFETs outperform FinFETs and NWFETs by showing superior DC performances arising from larger effective widths per footprint. Overall, GAAFETs are great candidates to substitute FinFETs in the 3-nm technology node for all the applications.

**Keywords:** gate-all-around, nanowire, nanosheet, field-effect transistors, fin, RC delay, parasitic resistance, parasitic capacitance

#### **1. Introduction**

Gate-all-around (GAA) is a widely-using structure such as logic field-effect transistor (FET) due to its excellent short channel characteristics [1–6] or its high surface-to-volume ratio [7, 8], 3-D NAND flash memory for bit-cost scalability [9, 10], photodiode due to its waveguide effect [11, 12], and gas sensor due to its high physical fill factor or surface-to-volume ratio [13, 14]. Especially for logic applications, GAAFETs have been introduced by attaining good gate electronics and increasing current drivability under the same active area.

Currently, fin-shaped FETs (FinFETs) have been scaled down to 10-nm node [15] and further to 5-nm node [16] by forming ultra-sharp fin for high current drivability while maintaining gate-to-channel controllability. GAAFETs are possibly showing great potential to substitute FinFETs in the following technology node, and the performance comparisons between FinFETs and GAAFETs have been investigated [3–6, 17]. But more detailed analysis between FinFETs and GAAFETs

is needed to set the device guideline by considering fine TCAD calibration and middle-of-line levels.

Therefore, in this work, DC/AC performances of 3-nm-node GAAFETs were investigated using fully-calibrated TCAD platform. By changing the GAA geometries, we found optimal GAA structure to minimize the RC delay for three different applications such as low power (LP), standard performance (SP), and high performance (HP) applications.


**3.3 Facial expressions**

The face is informative in several ways. For example, humans get clues about people's health through skin color [34]. Nonetheless, the main source of information is the activity of the facial muscles. Their contraction, in specific combinations, produces skin movements, namely, *facial expressions*. Moreover, they assume complex patterns according to the movement of the head and eyes.

The muscles of the face include two large groups. First, the *mastication muscles* (i.e., temporalis, masseter, and pterygoid muscles) have the primary task of moving the jaws and chewing. However, they can even participate in emotional expression. It is the trigeminal nerve that innervates these muscles (**Figure 1**).

The *expressive* or *mimetic* muscles are the second group. The facial nerve innervates these muscles. Indeed, their function is to configure the expression of the face. The temporofacial division of this nerve connects the muscles of the upper part of the face to both cerebral hemispheres. Instead, the cervicofacial facial nerve links the lower face only to the contralateral hemisphere (**Figure 2**).

The cerebral cortex controls voluntary movements through the corticospinal (or pyramidal) tract [23]. Two-thirds of this tract receives input from the motor cortex and the rest from the somatosensory areas, such as the parietal lobe [9]. For these reasons, emotional facial expressions seem to depend on the other trait, the extrapyramidal one.

The right side of the face could be dominant for emotional expressions. That is the idea of some scholars, based on some clinical evidence. For example, several people show a left bias during posed expressions [23]. Nevertheless, the empirical results are ambiguous, and academic speculations are divergent [35]. For instance, the approachwithdrawal model hypothesizes that emotions of "approach" (e.g., joy) coincide with more activity of the left frontal brain, and the "withdrawal" ones (e.g., fear) activate the right frontal brain to a superior extent [36].

Moreover, humans can exhibit brief, local contractions (i.e., *microexpressions*). Their duration varies from about 40 to 335 ms [37]. Microexpressions mainly involve

**Figure 1.** *Schematic representation of the motor pathways of mastication*.

#### **Figure 2.**

*Schematic representation of the pathways of human facial expressive muscles.*

the upper face muscles (e.g., the frontalis) and occur unconsciously, at least in part. Indeed, it is the extrapyramidal tract that mediates their production [23]. However, their alleged unintentional nature has stretched their informative potential. In particular, several scholars believe that microexpressions are reliable signals of spontaneous emotions and lies. For example, law enforcement and airport security use microexpressions as lie-detecting clues. All this despite the experimental data being inconclusive and practical applications ineffective [38]. However, microexpressions could be functional in other fields (e.g., to survey the quality of the patient-therapist relationship) [39]. Noteworthy, only a few microexpressions seem unmanageable. For example, the eyebrow flash and contempt expression are more controllable [38].

Although the prototypical patterns are well known, there is a low coherence between facial displays and emotions. Specifically, the likelihood of a person showing an expression (e.g., the Duchenne smile) when feeling the corresponding emotion (e.g., joy) is often lower than chance, in the both laboratory [40] and naturalistic settings [41]. One of the determinants of this low emotion-expression coherence lies in *display rules*. In brief, they are laws of expression management based on various factors (e.g., context, roles, gender, and age). Learning these rules usually takes place in the first years of life. Thereby, humans learn to repeat, amplify, and inhibit the expression of emotions [42]. It is the cerebral cortex that mediates the voluntary inhibition of facial movements [23].

#### **3.4 Neurovegetative signals**

Despite limitations and still open questions, there are enough data to state that physiological changes accompany emotions (see Section 2).

Activities of the autonomic nervous system can induce appearance variations. For example, vasodilation can cause blood vessels to bulge and alter the color of the skin. Blushing (i.e., in embarrassment) and reddering (e.g., in anger) are two typical neurovegetative signals of an increase in the caliber of blood vessels. Conversely, vasoconstriction (e.g., in fear) produces blanching.

The body can also secrete various substances. For example, tear glands provoke crying [43] related to some types of sadness [44]. Similarly, the sweat glands produce sweat (e.g., in fear), and the salivary ones are responsible for the secretion of saliva, which is typical of certain emotional states, such as disgust and anger.

Other neurovegetative signals are piloerection and the change in pupil diameter. They can be cues to emotions (e.g., anger and fear) or other states (e.g., sexual appetite) [43].

At the central level, these ANS activities are outcomes of a neural network that involves the hypothalamus (Hy), which is essential for homeostasis. The Hy links with periaqueductal gray, the reticular formation, parabrachial nucleus, ventral tegmental area (VTA), and the raphe nuclei [45].


**Author details**

Lovro Sinkovič1 and Dragan Žnidarčič2\*

\*Address all correspondence to<EMAIL_ADDRESS>
1 Crop Science Department, Agricultural Institute of Slovenia, Ljubljana, Slovenia

2 Department of Agronomy, Biotechnical Faculty, University of Ljubljana, Ljubljana, Sloven‐ ia


**2. Myocardial infarction: What it entails**

In Cardiology, the etiology of congestive heart failure (CHF) is coronary artery disease in approximately two-thirds of cases. The majority of these patients have hearts with myocardial infarcted segments. This infarcted myocardial wall mitigates adequate contraction of the wall. So, the end-result of an infarcted left ventricle (LV) is poor intra-LV velocity distribution and pressure-gradient distribution, causing impaired outflow from the LV into the aorta.

In the infarcted myocardial segments, the myocardial infrastructure of actin and myosin filaments (and their cross – bridges) is disrupted, and hence there is no contraction within these infarcted myocardial segments. The below figure 1 illustrates a myocardial sarcomere segment's bioengineering model, composed of two symmetrical myocardial structural units (MSUs). In these MSU(s), the contractile elements represent the actin-myosin contractile components of the sarcomere segment. The disruptions of these contractile elements impair the contractile capability of that sarcomere segment. Hence, a LV with infarcted myocardial segments will have diminished contractility, inadequate and improper intra-LV flow, and poor ejection.


**5.4 Levenberg-Marquardt algorithm**

This type of algorithm is used for curve fitting or non-linear least-squares problems. This algorithm is also called as deep least-square; these kinds of issues arise usually in the least-squares curve fitting. It was first introduced by Kenneth Levenberg in 1944, although it was rediscovered by statistician called Donald Marquardt in 1963.