**ADVANCED GAS CHROMATOGRAPHY – PROGRESS IN AGRICULTURAL, BIOMEDICAL AND INDUSTRIAL APPLICATIONS**

Edited by **Mustafa Ali Mohd**

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http://dx.doi.org/10.5772/2518 Edited by Mustafa Ali Mohd

#### **Contributors**

Solomon Tesfalidet, Pascal Cardinaël, Auguste Bruchet, Valérie Peulon-Agasse, Hiroyuki Kataoka, Xinghua Guo, Ernst Lankmayr, Douglas Lane, Siwatt Pongpiachan, Lu Rong, Jian Hai Sun, Sukesh Sinha, Peter Kusch, Kasylda Milczewska, Adam Voelkel, Maria João Bastos Cabrita, Raquel Garcia, Marco Gomes Da Silva, Ana Maria Costa Freitas, Nuno Martins, Tetsuo Ohkuwa, Francis Orata, Samuel Mugo, Karl Ayton, Lauren Johanna Huybregts, Ting Zhou, Pranav Kumar Gutch, Jaya Shankar Tumuluru, Sokhansanj Shahab, Timothy G Kremer, Christopher T. Wright, Takeo Hama, Shigeki Wada, Julian Zuo, Huang Zeng, Fenglou Zou, Dan Zhang, Eric Lehne, Iulian Comanescu, Vasile Matei, Anca-Florentina Borcea, Grazia Masciandaro, Cristina Macci, Serena Doni, Eleonora Peruzzi, Brunello Ceccanti

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Advanced Gas Chromatography - Progress in Agricultural, Biomedical and Industrial Applications Edited by Mustafa Ali Mohd

p. cm. ISBN 978-953-51-0298-4 eBook (PDF) ISBN 978-953-51-4316-1


*Edited by P. Balasubramaniam,*

*Sathiyaraj Thambiayya, Kuru Ratnavelu*

*and JinRong Wang*

The portfolio diversification strategy study is useful to help investors to plan for the best investment strategy in maximizing return with the given level of risk or minimizing risk. Further, a new set of generalized sufficient conditions for the existence and uniqueness of the solution and finite-time stability has been achieved by using Generalized Gronwall-Bellman inequality. Moreover, a novel development is proposed to solve classical control theory's difference diagrams and transfer functions. Advanced TCP strategies and free parametrization for continuous-time LTI systems and quality of operation of control systems are presented.

ISBN 978-1-83969-788-3

Control Systems in Engineering and Optimization Techniques

Published in London, UK © 2022 IntechOpen © lena\_serditova / iStock


**Abstract**

Acute diverticulitis is one of the most common surgical causes of admission to Emergency Departments in Western Countries. Although most of the cases can be managed conservatively or electively, a number of them will require an emergency surgical treatment. Among these patients, an even smaller number of them will present with a full-blown catastrophic septic shock. These minorities of cases have accounted for a significant part of the overall mortality and morbidity of complicated acute diverticulitis itself. The implementation of Damage Control strategies has shown to be useful also in these septic catastrophes, where a profound derangement of physiology makes unsafe a classic approach. Damage Control, as we intend it, is not a surgical "technique." A close collaboration between different specialties brought forth a strategy of treatment. The Surgeon, the Anesthetist, and the Intensivist are the three most involved specialists in the treatment of these cases. It is paramount for them to learn how to work side by side and in harmony, since the patients will benefit from each-one's input in their care.

**Keywords:** acute diverticulitis, damage control, peritonitis, laparostomy, Sepsis


**6. References**

<sup>\*</sup> Corresponding Author

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**Chapter 22**


**The Energy Crisis in Parkinson's Disease: A Therapeutic Target**

Mhamad Abou-Hamdan, Emilie Cornille, Michel Khrestchatisky, Max de Reggi and Bouchra Gharib *NICN, UMR6184, CNRS, Aix-Marseille University, Marseille France*

### **1. Introduction**

272 Etiology and Pathophysiology of Parkinson's Disease

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fibers in the striatum and the substantia nigra pars reticulata in Parkinsonian model

locus coeruleus than nucleus basalis and substantia nigra in Alzheimer' and

The energy demand of the brain is very large: it accounts for 20% of the body's energy consumption, even though its weight is less than 2% of the total body mass. In the adult, brain energy comes primarily from glucose through oxidative glycolysis. The end product is acetyl-coenzyme A (acetyl-CoA), which enters the mitochondria and feeds into the tricarboxylic acid (TCA) cycle to produce energy in the form of reductants, such as NADH. The chemical energy of NADH is then used by the respiratory chain, or electron transport chain, to synthesize ATP (Fig. 1). Energy depletion is a major factor in the cascade of events culminating in dopaminergic neuronal death in Parkinson's disease (PD). There are two reasons for that. First, a frequent feature of the disease, as well as of other neurodegenerative diseases, is an alteration of glucose metabolism. Second, there is a decrease of mitochondrial respiratory chain activity due to, in particular, inhibition of the electron transport system complex I (NADH-ubiquinone oxidoreductase).

Complex I activity is redox-dependent and thiol-regulated; therefore its inhibition is associated with oxidative stress. Depletion of GSH, a major antioxidant and redox modulator, is observed in the substantia nigra of parkinsonian patients, as well as in the mouse MPTP model of the disease. Conversely, the restoration of GSH levels preserves complex I activity. Accordingly, the maintenance of cellular redox homeostasis by thiol agents protects against nigrostriatal toxicity.

In the case of the alteration of glucose metabolism, the brain has the ability to adapt its metabolism and to increase its reliance on lipids for energy production, through fatty acid βoxidation. The process involves a mitochondrial oxido-reductase superfamily with broad substrate specificity. The penultimate step of the process is catalyzed by L-3-hydroxyacyl-CoA dehydrogenase (HADH II) (EC <IP_ADDRESS>). HADH II overexpression protects against acute brain injury and chronic neurodegeneration. By-products of fatty acid β−oxidation are the ketone bodies β-hydroxybutyrate and acetoacetate. When injected into mice or rats, or administered in the form of a ketogenic diet, ketone bodies have a protective role in a broad spectrum of cerebral injuries and diseases.

In the present report, we examine the brain energy metabolism, its alterations associated with PD and how fatty acid β-oxidation can compensate such impairment. Energy store boosting agents have potential therapeutic properties. Pantethine, the precursor of vitamin

The Energy Crisis in Parkinson's Disease: A Therapeutic Target 275

Fig. 2. Pantethine forms the active moiety of CoA. Pantetheine, the reduced form of pantethine, is first 4'-phosphorylated by pantothenate kinase and then adenylated by phosphopantetheine adenylyl transferase (CoaD) to form dephospho-CoA; finally,

in the form of acyl-CoA thioesters.

**2. Brain energy metabolism**

dephospho-CoA is phosphorylated to coenzyme A by the enzyme dephosphocoenzyme A kinase (CoaE). Lipids are metabolized as fatty acids linked to the SH group of pantetheine,

Although the brain represents only 2% of the body weight, it receives 15% of the cardiac output and accounts for 20% of total body oxygen consumption as well as 25% of total body glucose utilization. Under physiological conditions, glycolysis is, by far, the major energetic pathway in the adult brain. Glucose is broken down in the presence of oxygen, yielding pyruvate and lactate. Evidence accumulated during the past decade supports the notion that astrocytes play a pivotal role in the regulation of brain-glucose metabolism, via the so-called neuron-astrocyte lactate shuttle (Escartin et al., 2006; Hertz, 2004; Schurr, 2006). Owing to their strategic location surrounding cerebral blood capillaries, astrocytes form the first cellular barrier encountered by glucose entering the brain parenchyma, which makes them a prevalent site of glucose uptake. Blood-borne glucose crosses the vascular endothelial cells and enters brain cells through specific hexose transporters of the glucose transporter family (GLUT) (McEwen and Reagan, 2004; Vannucci et al., 1997). When the supply of oxygen therefore does not match precisely the demand, e.g. during neuronal activation or under pathological conditions, glucose may be broken down anaerobically, to produce lactate in order to supply

The following step of energy production is the conversion of pyruvate to acetyl-CoA which is used by mitochondria, the power house of living cells. Mitochondria produce the reductant NADH via the tricarboxilic acid cycle; then the chemical energy of NADH is used by the electron transport chain (ETC) to synthesize ATP. Mammalian ETC is composed of least 49 individual polypeptides which constitute a series of electron carriers organized in four enzymatic complexes plus the ATP synthase machinery. Complex I (NADH ubiquinone oxidoreductase) (EC<IP_ADDRESS>) is a very large enzymatic set catalyzing the first step of the ETC (Saraste, 1999; Schultz and Chan, 2001). The enzyme oxidizes NADH, transferring electrons to Ubiquinone (Coenzyme Q, CoQ), a lipid soluble electron carrier

energy faster. This process has, however, low energetic efficiency.

B5, is one of them, with the advantage of targeting multiple pathways involved in disease process. By itself or by its constituents (Fig. 2), pantethine regulates lipid metabolism, in addition to its anti-oxidant and anti-inflammatory properties, giving rise to the promise of an original therapeutic strategy against PD.

Fig. 1. The energetic pathways. Glycolysis is the major energetic pathway in the adult brain. It is impaired in Parkinson's disease, leading to an energy crisis, which is compensated by fatty acidβ−oxidation. Solid symbols (red) indicate the injuries and alterations occurring in the processes leading to the disease; open symbols (green) indicate the protective effects of pantethine.

B5, is one of them, with the advantage of targeting multiple pathways involved in disease process. By itself or by its constituents (Fig. 2), pantethine regulates lipid metabolism, in addition to its anti-oxidant and anti-inflammatory properties, giving rise to the promise of

Fig. 1. The energetic pathways. Glycolysis is the major energetic pathway in the adult brain. It is impaired in Parkinson's disease, leading to an energy crisis, which is compensated by fatty acidβ−oxidation. Solid symbols (red) indicate the injuries and alterations occurring in the processes leading to the disease; open symbols (green) indicate the protective effects of pantethine.

an original therapeutic strategy against PD.

Fig. 2. Pantethine forms the active moiety of CoA. Pantetheine, the reduced form of pantethine, is first 4'-phosphorylated by pantothenate kinase and then adenylated by phosphopantetheine adenylyl transferase (CoaD) to form dephospho-CoA; finally, dephospho-CoA is phosphorylated to coenzyme A by the enzyme dephosphocoenzyme A kinase (CoaE). Lipids are metabolized as fatty acids linked to the SH group of pantetheine, in the form of acyl-CoA thioesters.

#### **2. Brain energy metabolism**

Although the brain represents only 2% of the body weight, it receives 15% of the cardiac output and accounts for 20% of total body oxygen consumption as well as 25% of total body glucose utilization. Under physiological conditions, glycolysis is, by far, the major energetic pathway in the adult brain. Glucose is broken down in the presence of oxygen, yielding pyruvate and lactate. Evidence accumulated during the past decade supports the notion that astrocytes play a pivotal role in the regulation of brain-glucose metabolism, via the so-called neuron-astrocyte lactate shuttle (Escartin et al., 2006; Hertz, 2004; Schurr, 2006). Owing to their strategic location surrounding cerebral blood capillaries, astrocytes form the first cellular barrier encountered by glucose entering the brain parenchyma, which makes them a prevalent site of glucose uptake. Blood-borne glucose crosses the vascular endothelial cells and enters brain cells through specific hexose transporters of the glucose transporter family (GLUT) (McEwen and Reagan, 2004; Vannucci et al., 1997). When the supply of oxygen therefore does not match precisely the demand, e.g. during neuronal activation or under pathological conditions, glucose may be broken down anaerobically, to produce lactate in order to supply energy faster. This process has, however, low energetic efficiency.

The following step of energy production is the conversion of pyruvate to acetyl-CoA which is used by mitochondria, the power house of living cells. Mitochondria produce the reductant NADH via the tricarboxilic acid cycle; then the chemical energy of NADH is used by the electron transport chain (ETC) to synthesize ATP. Mammalian ETC is composed of least 49 individual polypeptides which constitute a series of electron carriers organized in four enzymatic complexes plus the ATP synthase machinery. Complex I (NADH ubiquinone oxidoreductase) (EC<IP_ADDRESS>) is a very large enzymatic set catalyzing the first step of the ETC (Saraste, 1999; Schultz and Chan, 2001). The enzyme oxidizes NADH, transferring electrons to Ubiquinone (Coenzyme Q, CoQ), a lipid soluble electron carrier

The Energy Crisis in Parkinson's Disease: A Therapeutic Target 277

both PD platelet homogenates and mitochondria isolated from PD platelets, although the degree of its inhibition varied within a wide range. Other ETC complexes in PD platelets are also concerned: complex II (Yoshino et al., 1992), complex II + complex III (Haas et al., 1995), and complex IV (Benecke et al., 1993). Several studies showed impaired complex I, II+III, and IV activities in PD muscle (Bindoff et al., 1991; Blin et al., 1994; Cardellach et al., 1993); whereas no differences were observed in other studies (DiDonato et al., 1993; Mann et al., 1992; Reichmann et al., 1994). Similar conflicting results were reported in the ETC in PD lymphocytes (Martin et al., 1996; Yoshino et al., 1992). Such inconsistency in the experimental data may be explained by significant methodological differences in these studies, e.g. difficulties in obtaining the relevant tissue samples, individual variability of PD patients and

Complex I activity is reduced in mitochondria isolated from PD frontal cortex (Keeney et al., 2006; Parker et al., 2008); it is believed to be an early pathogenic event in PD. Ample data strongly suggest that MPTP-induced ETC disruption per se is sufficient to trigger the death of nigrostriatal neurons and to cause PD-like symptoms in animals and humans. Thus, despite some conflicting results, systemic complex I deficiency might be a predominant feature in PD pathogenesis (Banerjee et al., 2009). Accordingly, 1H and 31P magnetic resonance spectrometry demonstrated mitochondrial dysfunction in the putamen and midbrain of both early and advanced PD subjects, with a bilateral reduction of high-energy phosphates; the changes were associated with abnormally elevated lactate levels. In contrast, low-energy metabolites such as adenosine diphophosphate and inorganic phosphate were within normal ranges. These results provide strong in vivo evidence that mitochondrial dysfunction of mesostriatal neurons is a central and persistent phenomenon in the pathogenesis cascade of PD which occurs early in the course of the disease (Hattingen

Paraquat and rotenone are other neurotoxins that inhibit mitochondrial complex I activity, whereas there are substantial differences in their action (Richardson et al., 2005). Rotenone rat models of PD have been developed that reproduce essential biochemical and behavioral human PD features (Alam and Schmidt, 2002; Betarbet et al., 2000; Greenamyre et al., 2003;

Complex I activity is redox-dependent and thiol-regulated (Annepu and Ravindranath, 2000; Sriram et al., 1998). Since PD pathogenesis consistently involve reactive oxygen and nitrogen species (Bove et al., 2005; Li et al., 2003; Przedborski, 2005; Przedborski and Ischiropoulos, 2005) this may explain, at least in part, complex I inhibition. Thus, depletion of GSH, an antioxidant and redox modulator, may be one of the early events leading to the inhibition of complex I activity and loss of mitochondrial function (Chinta and Andersen,

In the past decade, a rapidly expanding list of Mendelian-inherited gene mutations has provided great insight into the mechanisms leading to loss of the nigrostriatal dopaminergic neurons in familial PD which constitutes less than 10% of the total number of PD cases. In recent years, a plethora of studies of the multifunctional consequences of these mutations point towards the disruption of mitochondrial function culminating in

**4. Mitochondrial dysfunction and the genetic causes of the disease**

many other factors, as was suggested (Parker et al., 2008).

et al., 2009; Henchcliffe et al., 2008).

Sherer et al., 2003).

2006; Jha et al., 2000).

neuronal dysfunction and death.

embedded in the lipid bilayer of the inner mitochondrial membrane. Complex II (succinateubiquinone oxidoreductase) (EC<IP_ADDRESS>)**,** bound to the inner mitochondrial membrane, catalyzes the oxidation of succinate to fumarate with the reduction of ubiquinone to ubiquinol. Complex III (ubiquinol-cytochrome C oxidoreductase; EC <IP_ADDRESS>) is the oligomeric protein complex that transfers electrons from ubiquinol to cytochrome C and links proton translocation to this electron transfer by the proton motive Q cycle mechanism (Trumpower, 1990). Complex IV (cytochrome C oxidase (EC <IP_ADDRESS>) is a transmembrane protein which receives electrons from cytochrome C and transfers them to one oxygen molecule, converting molecular oxygen to water. In the whole process, a transmembrane difference of proton electrochemical potential is established that the ATP synthase then uses to synthesize ATP. Mitochondrial dysfunction results in a dwindling supply of ATP, a failure in maintaining cellular homeostasis and activation of cell death pathways.

#### **3. Energy crisis in Parkinson's disease**

PD, Huntington's disease (HD) and Alzheimer's disease (AD) are age-related diseases of diverse etiologies, but energy crisis is a common factor. The link between PD and mitochondria was first established with the identification of a deficiency in the activity of complex I in the substantia nigra of PD patients (Schapira et al., 1989) and it has been then confirmed by several authors (see reviews in (Banerjee et al., 2009; Schapira, 2006)). Complex I deficiency was noticed not only in the brain but also in the peripheral tissues of PD patients (Krige et al., 1992; Wallace et al., 1992). Whether mitochondrial dysfunction is the cause or effect of PD pathogenesis is debatable. However, it is clear that dopaminergic neurons are especially susceptible to energy deficit, meaning that mitochondrial dysfunction may underlie selective dopaminergic neuro-degeneration in PD (Beal, 2005).

The seminal discovery that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) causes PDlike symptoms in humans (Langston et al., 1983) and the ensuing rapid unraveling of the molecular mechanism of its toxicity strongly stimulated the interest of the PD research community in the role of mitochondria in PD pathology. MPTP is metabolized to its toxic form MPP+ (1-methyl-4-phenylpyridinium ion) by mitochondrial monoamine oxidase (MAO) (Chiba et al., 1984), specifically by MAO B (Heikkila et al., 1984) and is rapidly concentrated in the mitochondria (Ramsay et al., 1986b). Once accumulated, MPP+ specifically inhibits the oxidation of NAD–linked substrates (Nicklas et al., 1985) by blocking the electron transfer through the ETC complex I (Ramsay et al., 1986a). It also inhibits the activity of a key TCA (tricarboxylic acid) enzyme KGDHC (α-ketoglutarate dehydrogenase complex) thereby impairing the ATP synthesis and inducing "**energy crisis**" *in vivo* (Mizuno et al., 1988b) and *in vitro* (Mizuno et al., 1988a). The rather selective toxicity of MPP+ to dopaminergic neurons in SN (substantia nigra) was explained by the fact that MPP+ is selectively accumulated by the dopamine uptake system involving the dopamine transporters (DAT) (Javitch et al., 1985). Platelets which also express DAT (Frankhauser et al., 2006) have been shown to accumulate MPP+ with high efficiency and suffer from mitochondrial failure as a result of MPP+ exposure (Buckman et al., 1988). Human platelets also contain high levels of MAO B and share a number of properties with aminergic neurons including receptors, uptake sites and storage granules for amine neurotransmitters. As platelets are more available for research than PD brain samples or muscle biopsy specimens, they were a natural choice for PD tissue samples in earlier studies on the status of complex I in PD. Low complex I activities have been reported in

embedded in the lipid bilayer of the inner mitochondrial membrane. Complex II (succinateubiquinone oxidoreductase) (EC<IP_ADDRESS>)**,** bound to the inner mitochondrial membrane, catalyzes the oxidation of succinate to fumarate with the reduction of ubiquinone to ubiquinol. Complex III (ubiquinol-cytochrome C oxidoreductase; EC <IP_ADDRESS>) is the oligomeric protein complex that transfers electrons from ubiquinol to cytochrome C and links proton translocation to this electron transfer by the proton motive Q cycle mechanism (Trumpower, 1990). Complex IV (cytochrome C oxidase (EC <IP_ADDRESS>) is a transmembrane protein which receives electrons from cytochrome C and transfers them to one oxygen molecule, converting molecular oxygen to water. In the whole process, a transmembrane difference of proton electrochemical potential is established that the ATP synthase then uses to synthesize ATP. Mitochondrial dysfunction results in a dwindling supply of ATP, a

failure in maintaining cellular homeostasis and activation of cell death pathways.

PD, Huntington's disease (HD) and Alzheimer's disease (AD) are age-related diseases of diverse etiologies, but energy crisis is a common factor. The link between PD and mitochondria was first established with the identification of a deficiency in the activity of complex I in the substantia nigra of PD patients (Schapira et al., 1989) and it has been then confirmed by several authors (see reviews in (Banerjee et al., 2009; Schapira, 2006)). Complex I deficiency was noticed not only in the brain but also in the peripheral tissues of PD patients (Krige et al., 1992; Wallace et al., 1992). Whether mitochondrial dysfunction is the cause or effect of PD pathogenesis is debatable. However, it is clear that dopaminergic neurons are especially susceptible to energy deficit, meaning that mitochondrial dysfunction may underlie

The seminal discovery that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) causes PDlike symptoms in humans (Langston et al., 1983) and the ensuing rapid unraveling of the molecular mechanism of its toxicity strongly stimulated the interest of the PD research community in the role of mitochondria in PD pathology. MPTP is metabolized to its toxic form MPP+ (1-methyl-4-phenylpyridinium ion) by mitochondrial monoamine oxidase (MAO) (Chiba et al., 1984), specifically by MAO B (Heikkila et al., 1984) and is rapidly concentrated in the mitochondria (Ramsay et al., 1986b). Once accumulated, MPP+ specifically inhibits the oxidation of NAD–linked substrates (Nicklas et al., 1985) by blocking the electron transfer through the ETC complex I (Ramsay et al., 1986a). It also inhibits the activity of a key TCA (tricarboxylic acid) enzyme KGDHC (α-ketoglutarate dehydrogenase complex) thereby impairing the ATP synthesis and inducing "**energy crisis**" *in vivo* (Mizuno et al., 1988b) and *in vitro* (Mizuno et al., 1988a). The rather selective toxicity of MPP+ to dopaminergic neurons in SN (substantia nigra) was explained by the fact that MPP+ is selectively accumulated by the dopamine uptake system involving the dopamine transporters (DAT) (Javitch et al., 1985). Platelets which also express DAT (Frankhauser et al., 2006) have been shown to accumulate MPP+ with high efficiency and suffer from mitochondrial failure as a result of MPP+ exposure (Buckman et al., 1988). Human platelets also contain high levels of MAO B and share a number of properties with aminergic neurons including receptors, uptake sites and storage granules for amine neurotransmitters. As platelets are more available for research than PD brain samples or muscle biopsy specimens, they were a natural choice for PD tissue samples in earlier studies on the status of complex I in PD. Low complex I activities have been reported in

**3. Energy crisis in Parkinson's disease**

selective dopaminergic neuro-degeneration in PD (Beal, 2005).

both PD platelet homogenates and mitochondria isolated from PD platelets, although the degree of its inhibition varied within a wide range. Other ETC complexes in PD platelets are also concerned: complex II (Yoshino et al., 1992), complex II + complex III (Haas et al., 1995), and complex IV (Benecke et al., 1993). Several studies showed impaired complex I, II+III, and IV activities in PD muscle (Bindoff et al., 1991; Blin et al., 1994; Cardellach et al., 1993); whereas no differences were observed in other studies (DiDonato et al., 1993; Mann et al., 1992; Reichmann et al., 1994). Similar conflicting results were reported in the ETC in PD lymphocytes (Martin et al., 1996; Yoshino et al., 1992). Such inconsistency in the experimental data may be explained by significant methodological differences in these studies, e.g. difficulties in obtaining the relevant tissue samples, individual variability of PD patients and many other factors, as was suggested (Parker et al., 2008).

Complex I activity is reduced in mitochondria isolated from PD frontal cortex (Keeney et al., 2006; Parker et al., 2008); it is believed to be an early pathogenic event in PD. Ample data strongly suggest that MPTP-induced ETC disruption per se is sufficient to trigger the death of nigrostriatal neurons and to cause PD-like symptoms in animals and humans. Thus, despite some conflicting results, systemic complex I deficiency might be a predominant feature in PD pathogenesis (Banerjee et al., 2009). Accordingly, 1H and 31P magnetic resonance spectrometry demonstrated mitochondrial dysfunction in the putamen and midbrain of both early and advanced PD subjects, with a bilateral reduction of high-energy phosphates; the changes were associated with abnormally elevated lactate levels. In contrast, low-energy metabolites such as adenosine diphophosphate and inorganic phosphate were within normal ranges. These results provide strong in vivo evidence that mitochondrial dysfunction of mesostriatal neurons is a central and persistent phenomenon in the pathogenesis cascade of PD which occurs early in the course of the disease (Hattingen et al., 2009; Henchcliffe et al., 2008).

Paraquat and rotenone are other neurotoxins that inhibit mitochondrial complex I activity, whereas there are substantial differences in their action (Richardson et al., 2005). Rotenone rat models of PD have been developed that reproduce essential biochemical and behavioral human PD features (Alam and Schmidt, 2002; Betarbet et al., 2000; Greenamyre et al., 2003; Sherer et al., 2003).

Complex I activity is redox-dependent and thiol-regulated (Annepu and Ravindranath, 2000; Sriram et al., 1998). Since PD pathogenesis consistently involve reactive oxygen and nitrogen species (Bove et al., 2005; Li et al., 2003; Przedborski, 2005; Przedborski and Ischiropoulos, 2005) this may explain, at least in part, complex I inhibition. Thus, depletion of GSH, an antioxidant and redox modulator, may be one of the early events leading to the inhibition of complex I activity and loss of mitochondrial function (Chinta and Andersen, 2006; Jha et al., 2000).


*3.2. Modeling Probiotics Viability Loss as a Function of Temperature and Pressure*

A single multi-parameter model was developed to describe the effect of pressure and temperature process conditions only on the D-value of Bifidobacteria;

$$D = D\_0 \cdot \left\{ \exp\left\{-\frac{2.303 \cdot T \cdot T\_{ref}}{Z\_T} \cdot \exp\left[-A\left(P - P\_{ref}\right)\right] \cdot \left(\frac{1}{T} - \frac{1}{T\_{ref}}\right) + \frac{2.303}{Z\_P} \cdot \left(P - P\_{ref}\right) \right\} \right\}^{-1} \tag{3}$$

where *D0* (min) is the decimal reduction time at the reference conditions of pressure (Pref, MPa) and temperature (Tref, ◦C), *A* is a constant parameter of the proposed model (MPa−1) and *zT* ( ◦C) and *zP* (MPa) are the thermal and pressure resistance constants, respectively.

This equation takes into account the effect of pressure on the zT value, while the zP value found not to be dependent on the process temperature. The parameters of the model were estimated (Table 2) using non-linear regression and, results indicated that the predicted D-values from the model were

well correlated with the corresponding D-values obtained from the experimental data (Figure 2, R2 0.97−0.99).

**Table 2.** Viability loss kinetic parameters of *Bifidobacterium bifidum.*

Values are means ± standard error of regression.

As detailed described above, considering that the survivability of *B. bifidum* was more sensitive to pressure and temperature conditions contrary to this of *L. casei*, we presumably deduce that the specific model can be a useful tool for estimating the survival of single or symbiotic bacterial cultures, comprising strains of the Bifidobacteria and Lactobacilli species, when exposed to HP processing conditions.

**Figure 2.** Correlation of experimental and predicted from the proposed model decimal reduction times (D) of *B. bifidum* tested in growth media of different pH values (Solid and dashed black lines represent the linear correlation of the data at pH of 4.8 and 6.5 respectively, while grey solid and dashed lines represent the corresponding 95% prediction bands).

### *3.3. Selection of Optimal HP Conditions-Application in Yoghurt Production*

Given that the application of HP processing at the pressure range of 100−300 MPa and temperature range of 20−25 ◦C for 10−15 min did not induce any significant lethality to the probiotic cells population under acidic conditions, we decided to assess the feasibility of these processing conditions when applied to a fermented probiotic dairy food. Treatment of yoghurt samples was also performed at 400 MPa, to explore possible positive effect on the rheological parameters at this higher pressure. The physicochemical, rheological and sensory properties as well as the probiotics cells survivability over a 28 days storage period were monitored.


**Author details**

Adebare Nurudeen Adewunmi1 \*, Sabejeje Akindeji Jerome1 , Su Huaneng2 and Lindiwe Eudora Khotseng1 \*

1 Faculty of Natural Sciences, Department of Chemistry, University of the Western Cape, Bellville, South Africa

2 Institute for Energy Research, Jiangsu University, Zhenjiang, China

\*Address all correspondence to<EMAIL_ADDRESS><EMAIL_ADDRESS>
© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


**2.4.5 L-Selectin ligand**

328 Endometriosis - Basic Concepts and Current Research Trends

ART procedure, clinicians can improve embryo formation considerably; however, no therapies are available to make the endometrium more receptive. Expression of various implantation markers and proteins lead to remodeling of the endometrial matrix thereby transforming the endometrium towards a receptive milieu. Several molecular repertoires expressed during the implantation window are considered to be useful markers of implantation. Expression of various markers including pinopodes αvβ3 integrin, LIF, Lselectin ligand and Mucin-1 throughout the different stages of implantation are considered

Pinopodes, also known as uterodomes, are large cytoplasmic protrusions from the endometrial epithelial surface and are several micrometers wide. These are specialized cell structures that are involved in adhesion and penetration of the blastocyst into the stroma. These structures project into the uterine lumen and are above the microvilli level. Their expression is limited to a maximum period of 2 days during the menstrual cycle corresponding to the presumed window of implantation (Stavreus-Evers et al., 2001). Endometrial pinopodes development is associated with the mid-luteal phase increased expression of leukaemia inhibitory factor (LIF) and its receptor (Aghajanova et al., 2003), progesterone (Stavreus-Evers et al., 2001) and integrin αVβ3 (Lessey et al., 1992). Advocated as a marker of uterine receptivity, their expression, has been investigated solely by means of

Integrins are surface ligands, usually glycoproteins, belonging to the class of cell adhesion molecules (CAM). An integrin molecule consists of two different, non-covalently linked α and β subunits that are paired to form various heterodimers with distinct function (Hynes, 2002). At least 20 types of integrin heterodimer have been defined, which form from 14α and 9β subunits (Lindhard 2002). Integrins are unusual cell surface receptors in that they bind with low affinity and are present in large numbers, allowing for ligand motility without loss of attachment. Endometrial epithelial cells constitutively express certain integrins, whereas others are cycle dependent (Lessey 1992). αvβ3, an example of the latter is present on the apical surface of both luminal endometrial cells and human embryos. 41 different aberrant expressions of this integrin are reported in women with endometriosis (Lessey et al., 1994).

LIF is a member of the IL-6 family and is secreted by the endometrial epithelium, CD16– CD56 natural killer cells and type 2 T-helper cells. Animal and human studies indicate that LIF plays an important role in implantation and for pregnancy to occur (Lass et al., 2001). LIF protein can be detected by immunohistochemistry in the luminal, glandular and stromal epithelium. There is very little LIF expression in proliferative endometrium, but levels increase during the secretory phase, reaching a maximum between days 19 and 25, which

Mucins are high molecular weight (MW) glycoproteins, which contain at least 50% of carbohydrate O-linked to a threonine/serine rich peptide core (Gendler et al., 1990). Among

to be responsible for endometrial receptivity.

scanning electron microscopy (SEM) (Develioglu et al., 2000).

coincides with the implantation window (Charnock-Jones 1994).

**2.4.1 Pinopodes**

**2.4.2 Integrins**

**2.4.3 LIF**

**2.4.4 Mucins**

Selectins are glycoproteins which also belong to the CAM family. The expression of selectin oligosaccharide-based ligands, such as MECA-79 or HECA-452, is up-regulated during the window of implantation (Genbacev et al., 2003). MECA-79 is immunolocalized in the luminal and glandular endometrial epithelium throughout the menstrual cycle, although the staining considerably intensifies during the mid-secretory phase. The physiological importance of the interaction between L-selectin and its oligosaccharide ligands has been investigated in the human endometrium (Genbacev et al., 2003).

Though several studies investigating endometrial receptivity during implantation window are documented, the mechanism responsible for implantation failure in endometriosis is still poorly understood. Expression of various cell adhesion molecules and pinopodes in women with endometriosis is explored in the present study. Since, COX-2 is reported to be physiologically involved in the process of angiogenesis (Matsumoto et al., 2002), and in view of the fact that angiogenesis is essential for endometrial remodeling, we were motivated to assess the expression of various angiogenic factors including VEGFR, MMP-2,-9 and their tissue inhibitors in women with endometriosis during the implantation window. Additionally, expression of COX-2 was studied to assess their associated regulatory role in the process of endometrial remodeling during implantation window.


**1. Introduction**

Film mulching technology has the advantages of increasing temperature and moisture; preventing plant diseases, insects and weeds; and promoting crop growth [1]. In 2019, the amount of plastic film used in China reached 1.379 × 106 t, and the area covered by plastic film reached 1.76281 × 107 hm2 [2], which ranked first in the world. However, the farmland residual film recycling technology in China started relatively late, and the long-term, large-scale use of ultra-thin and low-strength plastic film has caused a series of problems, such as soil compaction, a decreased seedling rate, and crop yield reduction [3].

At present, manual recycling is mainly adopted in the treatment of non-point source pollution of farmland residual film, mechanical recycling, and the use of degradable plastic

**Citation:** Liu, J.; Liu, X.; Jiang, Y.; Zhou, X.; Zhang, L.; Wang, X. Research on the Adaptability of High-Performance Film for Full Recycling to the Curl-Up Film Collecting Method. *Agriculture* **2022**, *12*, 1051. https://doi.org/10.3390/ agriculture12071051

Academic Editors: Jin Yuan, Wei Ji and Qingchun Feng

Received: 18 June 2022 Accepted: 16 July 2022 Published: 19 July 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/).

film. Manual recycling of residual film is time-consuming, laborious, and costly, and it is difficult to motivate farmers [4]. Residual film recycling is not required after laying degradable residual film, since the film can decompose through natural degradation [5], however, degradable plastic film is not yet mature in cost control and production technology; the high cost of use and the unpredictable degradation effect during use make it difficult to implement large-scale promotion and use [6,7]. Mechanical recycling of residual film is currently the most widely used method for its high operating efficiency and low operating cost. The mulch film widely used in China has two levels of thickness, 0.008 mm and 0.01 mm, and its tensile property is lower than the mulch film with a thickness of 0.025 mm or more, which is commonly used abroad. Residual plastic film collectors used abroad are mostly curl-up residual film recycling machines with a simple mechanical structure demanding a good tensile performance of plastic film [8], while development of the residual plastic film collectors used in China is restricted by the poor tensile properties of plastic film. According to the planting mode of crops, a variety of film collectors with different mechanical structures has been developed, mainly including drum type, spring tooth type, and tooth chain type [9], which are not only complex in structure but also have a lower film recycling rate than those developed in foreign countries. Marí et al. [10] studied the application of biodegradable plastic mulch films (BDMs) in strawberry planting, and the research results showed that BDMs are a viable alternative to PE mulch. However, Anunciado [6] pointed out in the study of BDMs that the extent of change to the physicochemical properties of BDMs, due to agricultural weathering, is greatly affected by the polymeric composition and is greater in warmer climates. Steinmetz [11] studied BDMs and mentioned that the high use cost restricted the popularization of BDM. Therefore, due to the high cost of agricultural weathering, the technology of BDMs cannot effectively solve the problem of non-point source pollution of residue film in fields. Zhang et al. [12] performed parameter optimization on the Arc-Shaped Nail-Tooth Roller-Type Recovery Machine for Sowing Layer Residual Film, and the field test results showed that this machine type could achieve a normal residual film collection rate of 66.8% on common polyethylene mulching film. Zhou et al. [13] developed a kind of film collector with a film-removing plate, and this device can achieve a film collection rate of 86.93% on common polyethylene mulching film in ideal conditions. However, in the process of collecting the polyethylene mulching film, there are still residue films uncollected in the field, thus, the film-collecting effect was not satisfactory. Qu et al. [14] replaced the traditional rheological processing of drag and shear on high polymer materials with plasticizing transport based on volume elongational rheology, which reduced the macromolecular chain breakage of high polymer materials and greatly improved the mechanical properties of film molded by processing extreme rheological plastics, such as polyethylene. Based on the complex blow-molding technology, through dynamic distribution, the film can be overlaid for 3–5 layers, and the macromolecules are oriented in different directions between the layers to achieve an interweaving effect; thus, the tensile performance of the film is greatly enhanced, and the "high-performance film for full recycling to the curl-up film recycling method" (which can be called "high-performance film") was developed [15,16]. Since the tensile performance of the high-performance film is better than that of common polyethylene film, laying the high-performance film for full recycling can greatly improve the film collecting rate, and the production cost of the high-performance film is very low compared with BDMs; therefore, this technology has become an effective means to solve non-point source pollution of residue films in agricultural fields.

A contrast test on the tensile property of high-performance film and ordinary polyethylene film under different test factors was carried out, and the variation rules of the tensile properties of both films during the film-laying period of 0–180 days, as well as the minimum tensile level for the 180-day film-laying period, were obtained. Moreover, the operation principles of the curl-up residual plastic film collector were analyzed, and the curl-up collecting of the film for the 180-day film-laying period was carried out. Through an analysis on overcoming the force between the soil and the film during curl-up collecting of the film, the tensile stresses on the film while the curl-up film collector pulled it up under different test factors were obtained. The field test on the curl-up collecting of film was carried out. By comparing the film recycling rate on the film laid in the same year and the working performance of the two residual plastic film collectors of different structures, the proper structure adaptable to the curl-up collecting of high-performance film was obtained. This research can provide theoretical support for simplifying the structure of residual plastic film collectors, enhancing the film recycling rate, and reducing the cost of film recycling.

### **2. Contrast Test on the Tensile Properties of High-Performance Film and Ordinary Polyethylene Film**

In order to obtain the variation law of the tensile properties of the high-performance film and the ordinary polyethylene film laid in a cotton field in Xinjiang within their service period and the minimum tensile level at the end of the service period, the film-laying period, the film thickness, sampling direction, and sampling position were used as test factors; the elongation at break and tensile yield stress were used as test indexes to carry out the contrast test on the two types of films.


**4. Conclusions**

In this paper, we extended our work of single-phase IBM for RANS simulations of fixed and moving objects in air–water two-phase turbulent flows. The VoF method with a compression term was used to simulate the air–water interface. Compared with the simulations of single-phase flows, the momentum equation for two-phase flows has the gradient of density term because of buoyancy. Due to the large ratio of density between air and water, a correct density distribution near the IB surface is necessary to represent the homogeneous Neumann wall condition of density on body-fitted boundaries. This is satisfied indirectly by setting the homogeneous Neumann boundary condition of the volume fraction *α*, and it corresponds to a neutral contact angle boundary condition *θ* = *π*/2. In the present work, the volume fraction *α* is extended into the solid domain by a field extension operation. The process involves interpolation of *α* one layer a time into the solid domain using the inverse square distance method. For turbulence modeling, the same methodology in our previous work is adopted, i.e., the Spalart–Allmaras turbulence model with an IB wall function.

A series of test cases are presented to evaluate the accuracy of the IBM. The cases consider both fixed and moving IB. Various aspects are carefully investigated, including the deformation of the air–water interface, the flow fields and the forces on the IB surfaces. Comparisons between the present results and other resourses demonstrate that the proposed IBM is capable of simulating the interaction between the air–water interface and the solid boundaries. Finally, we investigate the simulation of a KCS ship model advancing with a rotating rudder. The accuracy and flexibility of the IBM is fully demonstrated via the combined usage of the IB surfaces with unstructured body-fitted approach.

**Author Contributions:** Conceptualization, H.Y. and K.M.; methodology, H.Y.; software, H.Y. and Y.C.; validation, H.Y., Y.C. and K.M.; formal analysis, H.Y.; investigation, H.Y., Y.C., and K.M.; resources, H.Y. and K.M.; data curation, H.Y.; writing—original draft preparation, H.Y.; writing—review and editing, Y.C. and K.M.; visualization, H.Y.; supervision, K.M.; project administration, K.M.; funding acquisition, K.M. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by Ford Motor Company and the United States Office of Naval Research.

**Acknowledgments:** The authors gratefully acknowledge the financial support of Ford Motor Company and the United States Office of Naval Research.

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


Spirituality and Hansen's Disease: Spirituality' Conceptual Structure and Hansen's Disease History - Part One

*Makiko Kondo, Mikako Yamaberi, Hitomi Yamao, Masato Muguruma, Kayoko Furochi, Shiho Oka and Aiko Matsushita*