**3. Gaucher's and Parkinson's disease: Theories of a link**

Parkinson's disease (PD) is the one of the common movement disorders and the second most common human neurodegenerative disease. The major diagnostic neuropathological

Role of Lysosomal Enzymes in Parkinson's Disease: Lesson from Gaucher's Disease 465

intracellular components (Levine & Klionsky, 2004). It can be induced also by hypoxia, neurotrophic factor deprivation, excitotoxins and accumulation of protein aggregates through PI3K and ERK-mediated pathways (Zhu t al., 2007; Boland & Nixon, 2006). Macroautophagy is described as the sequestration of complete regions of the cytosol, including not only soluble proteins, but also complete organelles, into a double membrane vescicle known as autophagosome, which is considered an immature form of autophagic vacuole (AV) (Seglen et al., 1996; Mortimore et al., 1996). The limiting double membrane is thought to arise from the endoplasmatic reticulum, although the Golgi complex has also been indicated as a source (Levine & Klionsky, 2004; Mijaljica et al., 2006). Because these vesicles lack any enzyme, the trapped contents are not degradated until the autophagosome

Macroautophagy is regulated by the action of a family of molecules, known as autophagyrelated proteins (Atg), which participates in each of the different steps of this process (Klionsky et al., 2003). A series of conjugation events (protein-to-lipid and protein-toprotein) and several members of intracellular kinase families are involved (Klionsky, 2005;

One hypotheses has been proposed to explain the role of dysregulated autophagy in PD pathogenesis, in patients affected to Gaucher's disease. This theory ("offensive metabolite theory") is based on the ceramide activity in the process of autophagic pathway modulation (Scarlatti et al., 2004). Ceramide is a sphingolipid mediator with an essential role in different situations correlated with authophagic system, such as cell growth, cell death, proliferation and stress response (Klionsky & Emr, 2000). Studies have shown as ceramide interferes with the inhibitory class I PI3K signaling pathway and induces the expression of a

It's possible that the lack of β-glucocerebrosidase activity and the accumulation of glucocerebroside may interfere with the ceramide modulation system, destroing cellular pathways necessary for autophagic-lysosomal degradation and leading to the LB formation. The other types of described autophagy are microautophagy and CMA. The first one consists of direct engulfment of small volumes of cytosol (constituted by soluble proteins but also by complete organelles) by lysosomes (Ahlberg et al., 1982) through invaginations or tabulations that "pinch off" from the membrane into the lysosomal lumen where they are rapidly degraded (Marzella et al., 1981). Microautophagy participates in the continuous turnover of long-lived proteins inside many types of cells (Mortimore et al., 1988); in addition a number of studies have shown as a particular form of microautophagy can lead to preferential degradation of peroxisomes (micropexophagy) (Farre and Subramani, 2004;

Chaperon-mediated autophagy is characterized by selectivity; about 30% of cytosolic proteins are degraded by this pathway. Through CMA particular cytosolic proteins are recognized by a chaperone in the cytosol, which delivers the proteins directly to the surface of the lysosome (Dice, 1990; Majeski & Dice, 2004, Massey et al., 2006). A distinctive feature of this pathway is that all substrate proteins contain in their amino acid sequence a motif, biochemically related to the pentapeptide KFERQ, required for targeting to the lysosomal compartment (Dice, 1990). A heat shock protein, hsc73 (Chiang et al., 1989) , recognizes the substrates containing the motif, and brings them to the lysosome membrane, where it binds to the receptor protein, lamp2 (lysosome-associated membrane protein type 2a) (Cuervo & Dice, 1996). The substrate interacts direcly with lamp2, and once unfolded, it is transported

founds with a lysosome, forming a single membrane autophagolysosome.

autophagy-related gene beclin 1, stimuling the autophagyc process.

in the lysosome lumen (Salvador et al., 2000) where it is degraded.

Mukaiyama et al., 2002; Veenhuis et al., 2000).

Ohsumi, 2001).

features of the pathologiy are loss of dopaminergic neurons and the appearance of Lewy bodies (LB), which are intraneuronal inclusions composed by α-synuclein and abnormal ubiquitinated proteins aggregates.

The first associations of the glucocerebrosidase enzyme with parkinsonism were discovered through careful clinical observation of people affecting by GD, who in several cases developed Parkinson's disease. Although in recent years GBA mutations were found to be a major risk factor for the development of Parkinson's disease (Sidransky et al., 2009), it is not clear how these are related. However many findings suggest that GBA protein and αsynuclein are implicated in a common cellular pathway and different hypothesis have been created to explain the linkage between them.

Recent studies have shown as some mutations in the GBA gene can lead to the misfolded protein formation (Sawkar et al., 2005), contributing to parkinsonism by leading to lysosomal insufficiency, as a result of impairing autophagic pathways necessary to prevent the synucleopathies, or by crushing the ubiquitin-proteasome system.

During the life span of a protein, cellular systems continuously check on the quality of the protein and take care of its repair or removal from the cell if there is any abnormality. The advancement during the past decades in understanding the quality control system of cellular proteins has allowed the identification of unequivocal links between malfunctioning of these systems and some severe human pathologies, including major neurodegenerative disease as Parkinson's (PD) and Alzheimer's (AD).

Many newly synthesized proteins are incorrectly translated or wrongly folded as a result of errors in their sequence due to either genetic mutations or alterations during the synthesis process (Wheatley & Inglis, 1980; Vabulas & Hartl, 2005; Shubert et al., 2000; Yewdell, 2005). The role of protein catabolism in protecting cells from defective, misfolded proteins is essential to avoid the risk of long term accumulation of proteins which frequently develop abnormal intermolecular interaction, forming insoluble aggregates toxic for the cells (Squier, 2001; Kourie & Henry, 2001). So it is evident the involvement of the quality control system in maintaining cell homeostasis as well as the association between the alteration of the protein turnover and many disease states (Kundu & Thompson, 2008). The autophagy-lysosome and the ubiquitin-proteasome pathways are the two main routes of the quality control system in eukaryotic.

Autophagy-lysosomal degradation pathway is a complex system tightly regulated by series of signaling events that promote the efficient delivery of macronutrients and organelles to lysosomes for degradation by acidic hydrolases (Levine & Klionsky, 2004). It is implicated in the catabolism and recycling of long-lived proteins and organelles and it is thought to be involved in many physiological processes, including the response to starvation, cell growth control, antiaging mechanisms and innate immunity. Some years ago the authophagylysosome pathway was considered as a non selective form of catabolism, while now the view is changed and it is thought as a specialized system that distinguishes the substrates and chooses the route by which they reach the lysosomes. Three types of autophagy have been described: macroautophagy, microautophagy and chaperon mediated autophagy (CMA) (Cuervo, 2004). They share a common endpoint, the lysosome, but differ in substrates targeted, their regulation and the conditions in which each of them is preferentially activated.

Macroautophagy process is activated to generate essential macromolecules and energy in condition of nutritional scarcity (Mizushima, 2005) or as a mechanism to remove the altered

features of the pathologiy are loss of dopaminergic neurons and the appearance of Lewy bodies (LB), which are intraneuronal inclusions composed by α-synuclein and abnormal

The first associations of the glucocerebrosidase enzyme with parkinsonism were discovered through careful clinical observation of people affecting by GD, who in several cases developed Parkinson's disease. Although in recent years GBA mutations were found to be a major risk factor for the development of Parkinson's disease (Sidransky et al., 2009), it is not clear how these are related. However many findings suggest that GBA protein and αsynuclein are implicated in a common cellular pathway and different hypothesis have been

Recent studies have shown as some mutations in the GBA gene can lead to the misfolded protein formation (Sawkar et al., 2005), contributing to parkinsonism by leading to lysosomal insufficiency, as a result of impairing autophagic pathways necessary to prevent

During the life span of a protein, cellular systems continuously check on the quality of the protein and take care of its repair or removal from the cell if there is any abnormality. The advancement during the past decades in understanding the quality control system of cellular proteins has allowed the identification of unequivocal links between malfunctioning of these systems and some severe human pathologies, including major neurodegenerative

Many newly synthesized proteins are incorrectly translated or wrongly folded as a result of errors in their sequence due to either genetic mutations or alterations during the synthesis process (Wheatley & Inglis, 1980; Vabulas & Hartl, 2005; Shubert et al., 2000; Yewdell, 2005). The role of protein catabolism in protecting cells from defective, misfolded proteins is essential to avoid the risk of long term accumulation of proteins which frequently develop abnormal intermolecular interaction, forming insoluble aggregates toxic for the cells (Squier, 2001; Kourie & Henry, 2001). So it is evident the involvement of the quality control system in maintaining cell homeostasis as well as the association between the alteration of the protein turnover and many disease states (Kundu & Thompson, 2008). The autophagy-lysosome and the ubiquitin-proteasome pathways are the two main routes of the quality control

Autophagy-lysosomal degradation pathway is a complex system tightly regulated by series of signaling events that promote the efficient delivery of macronutrients and organelles to lysosomes for degradation by acidic hydrolases (Levine & Klionsky, 2004). It is implicated in the catabolism and recycling of long-lived proteins and organelles and it is thought to be involved in many physiological processes, including the response to starvation, cell growth control, antiaging mechanisms and innate immunity. Some years ago the authophagylysosome pathway was considered as a non selective form of catabolism, while now the view is changed and it is thought as a specialized system that distinguishes the substrates and chooses the route by which they reach the lysosomes. Three types of autophagy have been described: macroautophagy, microautophagy and chaperon mediated autophagy (CMA) (Cuervo, 2004). They share a common endpoint, the lysosome, but differ in substrates targeted, their regulation and the conditions in which each of them is

Macroautophagy process is activated to generate essential macromolecules and energy in condition of nutritional scarcity (Mizushima, 2005) or as a mechanism to remove the altered

the synucleopathies, or by crushing the ubiquitin-proteasome system.

ubiquitinated proteins aggregates.

created to explain the linkage between them.

disease as Parkinson's (PD) and Alzheimer's (AD).

system in eukaryotic.

preferentially activated.

intracellular components (Levine & Klionsky, 2004). It can be induced also by hypoxia, neurotrophic factor deprivation, excitotoxins and accumulation of protein aggregates through PI3K and ERK-mediated pathways (Zhu t al., 2007; Boland & Nixon, 2006). Macroautophagy is described as the sequestration of complete regions of the cytosol, including not only soluble proteins, but also complete organelles, into a double membrane vescicle known as autophagosome, which is considered an immature form of autophagic vacuole (AV) (Seglen et al., 1996; Mortimore et al., 1996). The limiting double membrane is thought to arise from the endoplasmatic reticulum, although the Golgi complex has also been indicated as a source (Levine & Klionsky, 2004; Mijaljica et al., 2006). Because these vesicles lack any enzyme, the trapped contents are not degradated until the autophagosome founds with a lysosome, forming a single membrane autophagolysosome.

Macroautophagy is regulated by the action of a family of molecules, known as autophagyrelated proteins (Atg), which participates in each of the different steps of this process (Klionsky et al., 2003). A series of conjugation events (protein-to-lipid and protein-toprotein) and several members of intracellular kinase families are involved (Klionsky, 2005; Ohsumi, 2001).

One hypotheses has been proposed to explain the role of dysregulated autophagy in PD pathogenesis, in patients affected to Gaucher's disease. This theory ("offensive metabolite theory") is based on the ceramide activity in the process of autophagic pathway modulation (Scarlatti et al., 2004). Ceramide is a sphingolipid mediator with an essential role in different situations correlated with authophagic system, such as cell growth, cell death, proliferation and stress response (Klionsky & Emr, 2000). Studies have shown as ceramide interferes with the inhibitory class I PI3K signaling pathway and induces the expression of a autophagy-related gene beclin 1, stimuling the autophagyc process.

It's possible that the lack of β-glucocerebrosidase activity and the accumulation of glucocerebroside may interfere with the ceramide modulation system, destroing cellular pathways necessary for autophagic-lysosomal degradation and leading to the LB formation. The other types of described autophagy are microautophagy and CMA. The first one consists of direct engulfment of small volumes of cytosol (constituted by soluble proteins but also by complete organelles) by lysosomes (Ahlberg et al., 1982) through invaginations or tabulations that "pinch off" from the membrane into the lysosomal lumen where they are rapidly degraded (Marzella et al., 1981). Microautophagy participates in the continuous turnover of long-lived proteins inside many types of cells (Mortimore et al., 1988); in addition a number of studies have shown as a particular form of microautophagy can lead to preferential degradation of peroxisomes (micropexophagy) (Farre and Subramani, 2004; Mukaiyama et al., 2002; Veenhuis et al., 2000).

Chaperon-mediated autophagy is characterized by selectivity; about 30% of cytosolic proteins are degraded by this pathway. Through CMA particular cytosolic proteins are recognized by a chaperone in the cytosol, which delivers the proteins directly to the surface of the lysosome (Dice, 1990; Majeski & Dice, 2004, Massey et al., 2006). A distinctive feature of this pathway is that all substrate proteins contain in their amino acid sequence a motif, biochemically related to the pentapeptide KFERQ, required for targeting to the lysosomal compartment (Dice, 1990). A heat shock protein, hsc73 (Chiang et al., 1989) , recognizes the substrates containing the motif, and brings them to the lysosome membrane, where it binds to the receptor protein, lamp2 (lysosome-associated membrane protein type 2a) (Cuervo & Dice, 1996). The substrate interacts direcly with lamp2, and once unfolded, it is transported in the lysosome lumen (Salvador et al., 2000) where it is degraded.

Role of Lysosomal Enzymes in Parkinson's Disease: Lesson from Gaucher's Disease 467

The UPS can only degrade proteins when they are in a soluble state or as a part of reversible protein complexes that can be disassembled into single protein units (Finkbeiner et al., 2006; Kopito, 2000). So any type of irreversible oligomeric structures, preaggregates, and protein aggregates cannot be handled by UPS, instead they can be degraded by the autophagic-

A different theory ("misfolded protein theory") to explain the linkage between Gaucher's and Parkinson's disease, is that mutant misfolded glucocerebrosidase might overwhelm the UPS, causing a delay in the degradation of accumulated proteins, including α-synuclein (Dawson, 2006). Ron et al. have shown that misfolded GCase endures endoplasmatic reticulum associated degradation (ERAD) (Ron and Horowitz, 2005). In this process, mutant proteins are identified as misfolded by the ER quality control system and retrotraslocated from ER to cytosol, ubiquitinated and eliminated by the ubiquitin-proteasome system. The same authors proposed that mutated GBA protein (but not WT GBA) undergoes parkin (E3-ligase)-mediated ubiquitination, creating an imbalance in protein degradation resulting in secondary toxicity. It is likely that, since GCase is not a natural substrate of parkin, the enduringly ER retention and proteasomal degradation of mutant β-glucosidase, mediated by parkin, affect its activity toward its natural substrates. Accumulation during the years of these proteins can lead to the

The theories described above, cannot explain completely the correlation between the diseases. In the "offensive metabolite theory" the reducing of the released ceramide inhibits the autophagic-lysosomal functions. This can explain the development of LB and

Moreover in Gaucher patients where mutations in GBA result in no protein product (i.e. c.84dupG and IVS2+1G>A) the risk to develop PD is high. So the "misfolded protein theory" also cannot clear fully the question, even if it is probably that very truncated forms of the mutant protein still might induce endoplasmic reticulum stress and guide to crashing

The first indication of a relationship between parkinsonism and GD was due to sporadic case reports in the literarture (Neudorfer et al., 1996; Machaczka et al., 1999; Tayebi et al., 2001). In these papers it was highlighted how in some GD patients the enzyme deficiency

These observations of occurrence of Parkinson's disease in some patients with nonneuropathic type 1 Gaucher disease and in their first degree relatives has led to the identification of GBA1 heterozigous mutations as a genetic risk factor for idiopathic

In these subjects the mean age at onset of parkinsonian symptoms is lower than in patients without GD1, becoming evident at an average age of 48 years compared with 71 years in the

These early observations led to several studies which revealed that patients with idiopathic PD had a higher probability of harboring GBA1 mutations compared to the general

The first large study was conducted by Lwin et al. (2004), using sequence analyses on brain samples from 57 subjects of different nationality, GBA alterations were detected in 12

death of cells in substantia nigra and eventually, to the development of PD.

parkinsonism in Gaucher patients, but not in GBA mutations carriers.

**4. Genetic studies and neuropathological data**

itself could predisposed to the susceptibility to parkinsonisms.

lysosomal pathway.

of UPS.

Parkinson's disease.

population.

sample (21%).

general population (Elbaz et al., 2003).

Substrates for CMA consist of a very heterogeneous pool of cytosolic proteins, different for structure and function, but having all the same KFERQ motif. CMA acts in the degradation of many different substrates (i.e. several glycolitic enzymes, glutathione transferase, ribonuclease A) and damaged proteins: its selective role allows removal of the altered proteins without affecting neighbouring healty ones (Kiffin et al., 2004; Cuervo et al., 1999). Many studies have shown as this autophagic pathway is activated when stress condition occurs in the cells, such as prolonged nutrient deprivation or exposure to toxic compounds (Cuervo & Dice, 1998).

Independently of the autophagic pathway, all substrates are brought to the lysosome lumen where several different lysosomal hydrolases rapidly degrade them. These enzymes are synthesized in the endoplasmatic reticulum, sorted to the trans-Golgi network by mannose-6-phosphate receptors, transported through the endosome to arrive to their lysosomal destination, where they are activated upon the exposure to the acid environment (Jadot et al., 1997). The proteolytic capacity of lysosomes comprises a mixture of endo- and exopeptidases, called cathepsins, which act in concert to degrade proteins to a mixture of amino acids and dipeptides. Expression, activation and inhibition of these cathepsins are differentially regulated, and individual cathepsins often have non-redundant functions in normal and disease states (Kroemer & Jaattela, 2005). In addition to peptidases activity, intralysosomal conditions and other lysosomal components (i.e. glycosidase, lipases, phospholipases, solphatases, nucleases and phosphatases) are designed to favor the complete degradation of the internalized products.

One route of degradation of the α-synuclein is via CMA pathway (Cuervo et al., 2004). Studies have revealed as impaired lysosomal function seems to be involved in familial forms of PD, as consequence of reduced α-synuclein degradation. So one theory is that disturbances in the lysosome (i.e. the alteration in the GCase function) contribute to reduce α-synuclein degradation and consequently promote its aggregation. This may be possible since ceramide can activate cathepsin D (aspartate protease), which in turn is responsible for the proteolytic activation of other lysosomal proteins (Heinrich et al., 1999). So the reduced activity of one protease can spark off the decremented action of other acid hydrolases causing an α-synuclein accumulation and contributing in LB formation.

The other α-synuclein degradation pathway is the ubiquitin-proteasome system (UPS). It serves as the primary route for the degradation of thousands of short-lived proteins and provides the specificity and temporal control needed for tuning the stady-state levels of many regulatory proteins (Ciechanover et al., 2000). UPS-mediated catabolism is also essential to preserve amino acid pools in acute starvation and contributes significantly to the degradation of defective proteins (Ciechanover & Brudin, 2003; Whealtley & Inglis, 1980; Vabulas & Hartl, 2005). UPS contributes also to diverse cellular processes, such as protein quality control, cellcycle progression, signal transduction, and development (Kerscher et al., 2006).

Substrates of the ubiquitin/proteasome system (UPS) get post-translationally modified by covalent attachment of multiple ubiquitin molecules at internal lysine residues. This polyubiquitylation of substrate proteins involves three enzymes: ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin protein ligases (E3). E1 hydrolyses ATP and forms a thioester-linked conjugate between itself and ubiquitin; E2 receives ubiquitin from E1 and forms a similar thioester intermediate with ubiquitin; and E3 binds both E2 and the substrate, and transfers the ubiquitin to the substrate. A chain made of four to six ubiquitin moieties targets the conjugated substrate for degradation by the 26S proteasome (Richly et al., 2005; Zhang et al., 2009).

Substrates for CMA consist of a very heterogeneous pool of cytosolic proteins, different for structure and function, but having all the same KFERQ motif. CMA acts in the degradation of many different substrates (i.e. several glycolitic enzymes, glutathione transferase, ribonuclease A) and damaged proteins: its selective role allows removal of the altered proteins without affecting neighbouring healty ones (Kiffin et al., 2004; Cuervo et al., 1999). Many studies have shown as this autophagic pathway is activated when stress condition occurs in the cells, such as prolonged nutrient deprivation or exposure to toxic compounds

Independently of the autophagic pathway, all substrates are brought to the lysosome lumen where several different lysosomal hydrolases rapidly degrade them. These enzymes are synthesized in the endoplasmatic reticulum, sorted to the trans-Golgi network by mannose-6-phosphate receptors, transported through the endosome to arrive to their lysosomal destination, where they are activated upon the exposure to the acid environment (Jadot et al., 1997). The proteolytic capacity of lysosomes comprises a mixture of endo- and exopeptidases, called cathepsins, which act in concert to degrade proteins to a mixture of amino acids and dipeptides. Expression, activation and inhibition of these cathepsins are differentially regulated, and individual cathepsins often have non-redundant functions in normal and disease states (Kroemer & Jaattela, 2005). In addition to peptidases activity, intralysosomal conditions and other lysosomal components (i.e. glycosidase, lipases, phospholipases, solphatases, nucleases and phosphatases) are designed to favor the

One route of degradation of the α-synuclein is via CMA pathway (Cuervo et al., 2004). Studies have revealed as impaired lysosomal function seems to be involved in familial forms of PD, as consequence of reduced α-synuclein degradation. So one theory is that disturbances in the lysosome (i.e. the alteration in the GCase function) contribute to reduce α-synuclein degradation and consequently promote its aggregation. This may be possible since ceramide can activate cathepsin D (aspartate protease), which in turn is responsible for the proteolytic activation of other lysosomal proteins (Heinrich et al., 1999). So the reduced activity of one protease can spark off the decremented action of other acid hydrolases

The other α-synuclein degradation pathway is the ubiquitin-proteasome system (UPS). It serves as the primary route for the degradation of thousands of short-lived proteins and provides the specificity and temporal control needed for tuning the stady-state levels of many regulatory proteins (Ciechanover et al., 2000). UPS-mediated catabolism is also essential to preserve amino acid pools in acute starvation and contributes significantly to the degradation of defective proteins (Ciechanover & Brudin, 2003; Whealtley & Inglis, 1980; Vabulas & Hartl, 2005). UPS contributes also to diverse cellular processes, such as protein quality control, cell-

Substrates of the ubiquitin/proteasome system (UPS) get post-translationally modified by covalent attachment of multiple ubiquitin molecules at internal lysine residues. This polyubiquitylation of substrate proteins involves three enzymes: ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin protein ligases (E3). E1 hydrolyses ATP and forms a thioester-linked conjugate between itself and ubiquitin; E2 receives ubiquitin from E1 and forms a similar thioester intermediate with ubiquitin; and E3 binds both E2 and the substrate, and transfers the ubiquitin to the substrate. A chain made of four to six ubiquitin moieties targets the conjugated substrate for degradation by the 26S

causing an α-synuclein accumulation and contributing in LB formation.

cycle progression, signal transduction, and development (Kerscher et al., 2006).

(Cuervo & Dice, 1998).

complete degradation of the internalized products.

proteasome (Richly et al., 2005; Zhang et al., 2009).

The UPS can only degrade proteins when they are in a soluble state or as a part of reversible protein complexes that can be disassembled into single protein units (Finkbeiner et al., 2006; Kopito, 2000). So any type of irreversible oligomeric structures, preaggregates, and protein aggregates cannot be handled by UPS, instead they can be degraded by the autophagiclysosomal pathway.

A different theory ("misfolded protein theory") to explain the linkage between Gaucher's and Parkinson's disease, is that mutant misfolded glucocerebrosidase might overwhelm the UPS, causing a delay in the degradation of accumulated proteins, including α-synuclein (Dawson, 2006). Ron et al. have shown that misfolded GCase endures endoplasmatic reticulum associated degradation (ERAD) (Ron and Horowitz, 2005). In this process, mutant proteins are identified as misfolded by the ER quality control system and retrotraslocated from ER to cytosol, ubiquitinated and eliminated by the ubiquitin-proteasome system. The same authors proposed that mutated GBA protein (but not WT GBA) undergoes parkin (E3-ligase)-mediated ubiquitination, creating an imbalance in protein degradation resulting in secondary toxicity. It is likely that, since GCase is not a natural substrate of parkin, the enduringly ER retention and proteasomal degradation of mutant β-glucosidase, mediated by parkin, affect its activity toward its natural substrates. Accumulation during the years of these proteins can lead to the death of cells in substantia nigra and eventually, to the development of PD.

The theories described above, cannot explain completely the correlation between the diseases. In the "offensive metabolite theory" the reducing of the released ceramide inhibits the autophagic-lysosomal functions. This can explain the development of LB and parkinsonism in Gaucher patients, but not in GBA mutations carriers.

Moreover in Gaucher patients where mutations in GBA result in no protein product (i.e. c.84dupG and IVS2+1G>A) the risk to develop PD is high. So the "misfolded protein theory" also cannot clear fully the question, even if it is probably that very truncated forms of the mutant protein still might induce endoplasmic reticulum stress and guide to crashing of UPS.


**5. Conclusions**

In this document, we have implemented and investigated an HAPF with a backstepping control technique. This control technique allows to ensure the stability of the closed loop system with better speed and accuracy compared to the classical PI controller and fuzzy logic controller. It is able to maintain the THD of the current within the limits indicated by the IEEE-519 standard, and to require a desired dynamic attitude.

The simulation results obtained illustrate the high performance of the HAPF using the backstepping controller for harmonic compensation. The proposed control strategy applied to the HAPF therefore has an important theoretical impact to improve the THD in a typical way, and to strengthen the power quality of the grid, by improving the stability, speed and precision of the system. The proposed backstepping controller has an advantage that does not require a mathematical model and achieves the desired performance, but the PI controller requires a precise mathematical model, and has a significant response time, which implies a degradation of speed. Also the fuzzy logic controller has a degraded speed and precision. The HAPF can also be spread to other electronic power converter topologies.

Taking into account the above methods, the proposed controller, which is applied on a hybrid HAPF filter, is an appropriate choice for improving the quality of electrical energy in the transmission and distribution of energy. An additional experimental test bench is being developed for the realization and testing of the proposed control scheme in our laboratory.

**Author Contributions:** Conceptualization, N.D.; Methodology, N.D.; Software, N.D.; Validation, N.D., F.G.M. and Y.D.; Formal analysis, N.D.; Investigation, N.D.; Resources, N.D.; Data curation, N.D.; Writing—Original draft preparation, N.D.; Writing—Review and editing, N.D. and F.G.M.; Visualization, N.D.; Supervision, N.D., F.G.M., N.A. and Y.D.; Project administration, N.D.; Funding acquisition, F.G.M.

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

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


2. Oil-jet cooling mechanism and experimental setup

Lubrication and cooling are important for the rolling bearing fatigue life extension. It is good for the bearing temperature control. The fluid jet is an effective cooling method which has been used widely in heat dissipation. In the rolling bearing operation, the oil-jet method is used for very high-speed conditions. The number of nozzles, the jet velocity, and the oil flow rate are significant to satisfy the bearing lubrication requirement. In order to overcome the detrimental centrifugal effects in high-speed applications, the lubricant oil under pressure is directed at the side of the bearing. The jet velocity should be sufficiently high since the air surrounding the bearing causes the oil to be deflected from the inner ring. Further, a sufficient amount of lubricant oil should be supplied to the bearing. However, an excessive amount of lubricant oil will increase the bearing temperature unnecessarily.

Figure 1(a) shows the schematic configuration of the oil-jet lubrication ball bearing under investigation. The cooling oil is injected into the bearing raceway through a small-diameter nozzle to lubricate and cool the bearing and ensure the safe and reliable operation of the rolling bearing. The high-speed oil-jet atomizes into droplets which then mix with the surrounding air to from a two-phase mixture. Besides, the two-phase mixture is working in an open space environment that has a direct contact with air of the outlets. In this way, coexistence of oil and air twophase flow is formed inside the ball bearing.

In the high-speed operation of bearings, a large amount of heat generated by friction between moving pairs will lead to bearings and their adjacent parts. A sharp increase of friction heat will lead to a significant increase in the working temperature. If the heat not effective discharged, it will inevitably lead to the failure of bearings, which will damage the service life of the bearings. The three major heat dissipation methods inside the ball bearing are shown in Figure 1(b), including the conduction through solid structures, the convection from solid structures to fluids, and the radiation to surrounding media. The latter one is not taken into consideration since it dissipates a negligible part of heat in the bearing case. When the bearing is in a state of thermal equilibrium, the main factors that impact the bearing temperature are bearing load, speed, oil-in temperature, and oil volume fraction inside the bearing, which indicates that the flow field and heat transfer characteristics between the two-phase flow and solid components have a considerable influence in the bearing temperature. Thus, it is essential to clarify the correlations between the fluid flow and thermal behaviors in oil-jet cooling bearing, in order to

Figure 1.

Configuration of the oil-jet cooling ball bearing and heat transfer method: (a) configuration of jet cooling mechanism and (b) heat dissipation methods.

make precise assessment of cooling method and optimize the design of cooling devices.

Experiment apparatuses for testing the flow pattern and temperature distribution of the ball bearing have been built up, as shown in Figure 2. No load is applied in the flow pattern test, as shown in Figure 2(a). The shaft of the tested ball bearing is horizontal. The maximum tested speed is 4500 r/min which is the rated speed of the driving motor. The parameters of the tested ball bearing are given in Table 1. The exact value of the oil volume fraction distribution is difficult to process, since the flow field inside the bearing is compact. Thus, the photograph of the flow pattern is presented to validate the simulated results.

Further, a tested apparatus for temperature test of ball bearing has been built up, as shown in Figure 2(b). The outer ring temperatures of different positions are measured by three temperature sensors. r is the radial coordinates and ω is the circumferential azimuth angle. The technical data of the experimental apparatus is presented in Table 2. The measured bearing temperature distribution can be used for computational model validation.

#### Figure 2.

Test apparatuses: (a) rolling bearing flow pattern test apparatus and (b) rolling bearing temperature distribution test apparatus.

#### Table 1. Specifications of the test ball bearing.

Flow and Heat Transfer in Jet Cooling Rolling Bearing DOI: http://dx.doi.org/10.5772/intechopen.84702

Table 2.

Technical data of the test apparatus.

### 3. Mathematical modeling

Since the two-phase flow changes constantly in high-speed rotating rolling bearings, the development of a computational fluid dynamics (CFD) model with a two-phase flow method to determine the amount of lubricant oil is of practical value as a substitution of empirical correlations. The volume of fluid (VOF) model is selected to model the two-phase interactions inside the bearing for its recognized ability in tracking the air-oil interface. The two-phase coexistence of the bearing is in the turbulent state. The RNG k-ε model is an economical turbulent model for the rotating or swirling flows, so it is chosen as the turbulent governing equations.

#### 3.1 Governing equations

The oil is defined as the primary phase in the two-phase calculation, and its volume fraction in each cell is denoted as φoil, with φoil = 1 representing a pure oil phase and φoil = 0 representing a pure air phase. If 0 < φoil < 1, the cell of interest is in the air-oil two-phase state. If the air volume fraction is similarly denoted as φair, then the sum of the volume fractions of the two phases in the flow domain should meet the follow the constraint:

$$
\rho\_{\rm oil} + \rho\_{\rm air} = \mathbf{1} \tag{1}
$$

The properties of an air-oil two-phase flow in the VOF method are treated as the volumetric average of that of the individual phase. Thus, the density, dynamic viscosity, and thermal conductivity are expressed as

$$
\rho = \rho\_{\text{oil}} \rho\_{\text{oil}} + \rho\_{\text{air}} \rho\_{\text{air}} \tag{2}
$$

$$
\mu = \varphi\_{\rm oil} \mu\_{\rm oil} + \varphi\_{\rm air} \mu\_{\rm air} \tag{3}
$$

$$k = k\_{\text{oil}} a\_{\text{oil}} + k\_{\text{air}} \mu\_{\text{air}} \tag{4}$$

where ρoil is the oil density, ρair is the air density, μoil is the oil dynamic viscosity, μair is the air dynamic viscosity, koil is the oil thermal conductivity, kair is the air thermal conductivity, and kf represents the effective thermal conductivity of the two-phase flow.

The governing equations for the entire computational domain are as follows: Continuity equation

$$\nabla \cdot \left(\rho \overrightarrow{\nu}\right) = \mathbf{0} \tag{5}$$

Momentum equation

$$\nabla \cdot \left( \rho \stackrel{\rightarrow}{\nu} \vec{\nu} \vec{\nu} \right) = \nabla \cdot \left( \mu \left( \nabla \vec{\nu} + \left( \nabla \vec{\nu} \right)^{T} \right) \right) - \nabla \cdot p + \rho \vec{\mathbf{g}} + \vec{F} \tag{6}$$

Energy equation for the fluid

$$\nabla \cdot \left[ \overrightarrow{\nu} \left( \rho E \right) \right] = \nabla \cdot \left( k\_f \nabla T \right) \tag{7}$$

where

$$E = \frac{\alpha\_{\rm oil} \rho\_{\rm oil} E\_{\rm oil} + \alpha\_{\rm air} \rho\_{\rm air} E\_{\rm air}}{\alpha\_{\rm oil} \rho\_{\rm oil} + \alpha\_{\rm air} \rho\_{\rm air}} \tag{8}$$

Energy equation for the solid

$$\nabla \cdot (\mathbf{k}\_\sharp \nabla T) = \mathbf{0} \tag{9}$$

! ! ! where υ is the velocity vector, p is the pressure, F is the external force, g is the gravity acceleration, T is the temperature, E is the energy, and ks is the thermal conductivity of the solid structure which varies with different material types.

In order to model fluid turbulence of high-speed swirl inside the bearing, the RNG k-ε model is selected for it is a recognizable model for rotating or swirling flow. The RNG k-ε turbulence model is a model derived from the transient N-S equation using the renormalization group method. Its k equation and ε equation have the similar form with the standard k-ε turbulence model but are more accurate in calculating the flow field with larger velocity gradient and strong rotational flow by increasing an additional term that is more responsive to the rapid curvature of strain and streamlines.

The transport equation of the turbulence kinetic energy k is

$$\frac{\partial(\rho k)}{\partial t} + \frac{\partial(\rho k u\_i)}{\partial \mathbf{x}\_i} = \frac{\partial}{\partial \mathbf{x}\_i} \left[ a\_k \mu \frac{\partial k}{\partial \mathbf{x}\_i} \right] + G\_k + \rho \varepsilon \tag{10}$$

The transport equation of the turbulence dissipation rate equation ε is

$$\frac{\partial(\rho\varepsilon)}{\partial t} + \frac{\partial(\rho\varepsilon u\_i)}{\partial \mathbf{x}\_i} = \frac{\partial}{\partial \mathbf{x}\_i} \left[ a\_e \mu \frac{\partial \varepsilon}{\partial \mathbf{x}\_i} \right] + \frac{\mathbf{C}\_{1x}\varepsilon}{k} \mathbf{G}\_k - \mathbf{C}\_{2x}\rho \frac{\varepsilon^2}{k} \tag{11}$$

where Gk is the production term of the turbulent kinetic energy caused by the average velocity gradient. xi and ui represent the coordinate directions and the velocity components, respectively. C1ε, C2ε, Cμ, αk and αε are the turbulence model constants.

#### 3.2 Grid meshing

Before the numerical solution of the governing equations, it is important to determine the computational domain and mesh the domain. In order to improve mesh quality and reduce the computer consumption, the computational domain should be simplified and reasonably divided before meshing. Figure 3 shows the relevant grid schematic diagram of the computational domain, which contains a fluid domain and a solid domain. The fluid domain comprises the internal area of the nozzle, the bearing, and the outlets as shown in Figure 3(a). The flow field

Flow and Heat Transfer in Jet Cooling Rolling Bearing DOI: http://dx.doi.org/10.5772/intechopen.84702

Figure 3.

Three-dimensional bearing heat transfer grid system: (a) mesh of the fluid domain and (b) mesh of the solid domain.

inside the bearing is the space enclosed by the inner surface of the bearing and the outer surface of the raceway, which is responsible for the most part of the interactions between the fluid flow and the solid elements.

Figure 3(b) is the solid domain, which includes the shaft, the rolling elements, the inner ring, the outer ring, the bearing seat, and the cage. The structured hexahedral mesh is used in the areas with regular shapes, such as the inner ring, the outer ring, the bearing seat, and the flow area inside the nozzle, and both of the outlets, etc., in contrast, for areas with relatively complex shapes, such as the flow field inside the bearing, was divided by a tetrahedral unstructured mesh.

The rotation of air-oil flow around the bearing rings is imposed by the rolling elements and the cage, which is rotating at a constant speed, which can be calculated by

$$m\_{\rm b} = \frac{1}{2}n\left(1 - \frac{D\_{\rm b}\cos a}{d}\right) \tag{12}$$

where nb is the rotary speed of the rolling elements, n is the rotary speed of the inner ring, Db is the ball diameter, α is the bearing contact angle, and d is the pitch diameter of the bearing.

When setting boundary conditions, the nozzle inlet is initialized with a constant mass flow rate and an initial flow temperature. Flow outlet is set at the end faces of the two outlets and is set to be a pressure outlet boundary condition. The ambient environment is set as 0 Pa gauge pressure and 298 K, respectively. The operating pressure is 101,325 Pa. The viscosity of the oil phase changes with the oil temperature, as shown in Table 3. The multiple reference frame (MRF) method is used to describe the rotation of the rolling elements and the flow field inside the bearing. The sliding mesh planes are defined to deal with the interferences between the stationary and rotating computational domains. The heat source was applied to the contact area between the rolling elements and the raceway. Based on the experiment condition, the heat source power was calculated according to Harris's method [13]. Regarding the heat transfer between the fluid and solid structures, both the air and oil heat transfer properties are considered. Coupled heat transfer wall condition

Table 3. Variation of the oil viscosity with the temperature.

was set at the solid-fluid interface. The convection coefficients were calculated by following the energy conservation equation in the computation.

### 3.3 Solution methods

The ANSYS FLUENT software platform [17] is used to perform the simulations. The solution format is set as a high-order solution mode. For the VOF air-oil twophase model, the air phase is set to be the main phase. All the governing equations are discretized by finite volume (FV) method with the second-order upwind scheme and solved by the SIMPLEC method.

The residuals and the flux conservation on boundaries, for example, the mass flow rate on inlet and outlet boundaries, are monitored to detect the convergence of the governing equations. The conservation standard is set to be 0.01; that is to say, the computation is considered as convergence, whenever the net mass flow rate between the inlet and outlet boundaries drops to 1% of the mass flow rate on the inlets. Other convergence criteria of residual, such as the volume of fluid function and each velocity component, are all set to be 10�5 , except for that of the turbulent kinetic energy and the turbulent kinetic energy dissipation rate which is 10�3 .

The criteria are given as follows:

$$\frac{|m\_{\text{inlet}} - m\_{\text{outlet}}|}{|m\_{\text{inlet}}|} < \varepsilon\_m \tag{13}$$

$$\frac{\left|T\_{\text{oj}+5000} - T\_{\text{oj}}\right|}{T\_{\text{oj}+5000}} < \varepsilon\_T \tag{14}$$

where minlet is the oil mass flow at the inlet, moutlet is the oil mass flow at the outlet, TO is the outflow temperature, and εm and εT are the tolerance of oil mass flow and temperature, respectively. The subscript j is the iteration number.

In numerical simulation, the mesh density has a great influence on the accuracy and correctness of the calculation results. Choosing the appropriate number of meshes not only save the workload of the computer but also increase the reliability of the calculation results. Therefore, grid independence verification is an indispensable task in the process of numerical computation. To perform the grid independence verification, a set of numerical calculation is carried out on a computer platform with the flowing configuration: Processor-Intel E5540 �<EMAIL_ADDRESS>GHz CPU, RAM-16 GB (4GB � 4), Hard Disk-2 TB, Graphic Card e AMD RADEON HD 6670–2 GB, and Operating system-Window 7 Ultimate 64-bit.

To determine the appropriate number of grids, three different sets of meshes with 135,929, 287,117, and 554,992 cell faces have been tested, and the outlet oil mass flow rate and the average oil volume fraction of the two-phase flow are obtained, as shown in Table 4. The numerical calculations show that with the increase of the number of grids, the variations of the calculated outlet oil mass flow rate and the average oil volume fraction are less than 2%. Considering both

Table 4. Technical data of the test apparatus.

calculation time and accuracy, the mesh with 135,929 cell faces is selected as a suitable number of grids.


5. An integration matrix

Since the determinant of the derivative matrix DN is not always zero, we expect that there exist an inverse of it. At a local level, the inverse of the finite differences derivation is the summation as was found in Eq. (46). In this section, we determine the inverse of the derivative matrix, and we find that it is a global finite difference integration operation.

Once we know the eigenvalues and eigenvectors of the derivative matrix DN, it turns out that we also know the eigenvectors and eigenvalues of the inverse matrix, when it exists. In fact, the equality DNem ¼ λmem, with λm 6¼ 0, imply that

$$\mathbf{D}\_N^{-1} \mathbf{e}\_m = \lambda\_m^{-1} \mathbf{e}\_m. \tag{58}$$

The inverse matrix SN ¼ D�1 N is

#### Matrices Which are Discrete Versions of Linear Operations http://dx.doi.org/10.5772/intechopen.74356 33

$$\mathbf{S}\_{N} = \frac{1}{z - \frac{1}{z}} \begin{pmatrix} 1 & -z & 1 & -z & 1 & \dots & -z & 1 \\ z & -1 & 1/z & -1 & 1/z & \dots & -1 & 1/z \\ 1 & -1/z & 1 & -z & 1 & \dots & -z & 1 \\ z & -1 & z & -1 & 1/z & \dots & -1 & 1/z \\ \vdots \\ 1 & -1/z & 1 & -1/z & 1 & \dots & -z & 1 \\ z & -1 & z & -1 & z & \dots & -1 & 1/z \\ 1 & -1/z & 1 & -1/z & 1 & \dots & -1/z & 1 \\ z & -1 & z & -1 & z & \dots & -1 & 1/z \\ 1 & -1/z & 1 & -1/z & 1 & \dots & -1/z & 1 \\ \end{pmatrix} \tag{59}$$

Its determinant is

4.1. The commutator between the derivative and coordinate matrices

[QN] which will represent the coordinate partition

32 Matrix Theory-Applications and Theorems

½ �¼ DN; QN

just

5. An integration matrix

The inverse matrix SN ¼ D�1

The commutator between the partition and the finite differences derivative can also be calculated from a global point of view using the corresponding matrices. Let the diagonal matrix

QN≔diag q1; q2;…; qN

⋮

This is a kind of nearest neighbors' average operator, inside the interval. The small Δ limit is

where I is the identity matrix, with the first and last elements replace with 1/2. Thus, coordi-

Since the determinant of the derivative matrix DN is not always zero, we expect that there exist an inverse of it. At a local level, the inverse of the finite differences derivation is the summation as was found in Eq. (46). In this section, we determine the inverse of the derivative matrix, and

Once we know the eigenvalues and eigenvectors of the derivative matrix DN, it turns out that we also know the eigenvectors and eigenvalues of the inverse matrix, when it exists. In fact, the

N em ¼ λ�1

D�1

BBBBBBBBBBBBBBBB@

0100 … 000 1010 … 000 0101 … 000

0000 … 010 0000 … 101 0000 … 010

Then, the commutator between the derivative matrix and the coordinate matrix is

0

Δ 2χð Þ v;Δ

nate and derivative matrices are finite differences conjugate of each other.

we find that it is a global finite difference integration operation.

N is

equality DNem ¼ λmem, with λm 6¼ 0, imply that

� �: (55)

1

CCCCCCCCCCCCCCCCA

½ � DN, QN ≈ I, (57)

m em: (58)

: (56)

$$|\mathbf{S}\_N| = \sinh^{N-1}(v\Delta). \tag{60}$$

This matrix represents an integration on the partition, with an exact value when it is applied to the exponential function evq on the partition. When applied to an arbitrary vector g ¼ g1; g2;…; gN � �T , we obtain formulas for the finite differences integration, including the edge points

$$(\mathbf{S}\_{\rm N}\mathbf{g})\_1 = \frac{1}{z - 1/z} \left[ \mathbf{g}\_1 + \sum\_{i=1}^{M} (\mathbf{g}\_{2i+1} - z\mathbf{g}\_{2i}) \right] \tag{61}$$

$$(\mathbf{S}\_{\mathbf{N}}\mathbf{g})\_{2j} = \frac{1}{z - 1/z} \left[ z\,\mathbf{g}\_1 + \sum\_{k=1}^{j-1} \left( z\,\mathbf{g}\_{2k+1} - \mathbf{g}\_{2k} \right) + \sum\_{k=j}^{M} \left( \frac{\mathbf{g}\_{2k+1}}{z} - \mathbf{g}\_{2k} \right) \right],\tag{62}$$

$$(\mathbf{S}\_{\mathbf{N}}\mathbf{g})\_{2j+1} = \frac{1}{z - 1/z} \left[ g\_1 + \sum\_{k=1}^{j} \left( g\_{2k+1} - \frac{g\_{2k}}{z} \right) + \sum\_{k=j+1}^{M} \left( g\_{2k+1} - z g\_{2k} \right) \right],\tag{63}$$

$$(\mathbf{S}\_N \mathbf{g})\_N = \frac{1}{z - 1/z} \left[ \mathbf{g}\_1 + \sum\_{i=1}^M \left( \mathbf{g}\_{2i+1} - \frac{\mathbf{g}\_{2i}}{z} \right) \right] \tag{64}$$

where N ¼ 2M þ 1. These are new formulas for discrete integration for the exponential function on a partition of equally separated points with the characteristic that it is exact for the exponential function evq.


**2.5 Inheritance for resistance to diseases**

Several diseases infect cucumber which results in huge yield losses in production. The common disease infecting cucumber is powdery mildew, downy mildew, anthracnose, scab, angular leaf spot and virus diseases (cucumber mosaic virus (CMV), papaya ring spot virus, (PRSV), zucchini yellows mosaic virus). The management of these diseases increase the cost of production because of increasing use of chemicals for control of diseases which also has adverse implication on environment and ecology. The development of resistant sources and breeding of resistant varieties are economical, healthier and eco-friendly approach. There are different approaches for breeding resistance against different kinds of stresses which involve both conventional and modern tools. Achieving the goal of development of a resistant variety also needs attention on the durability of resistance for which the knowledge of resistance on the inheritance, expression and interaction with related genes and environment aspects are required.


**4.1 Vascular changes**

In the mid-1960s, within a military setting, the immediate exposure to 10–60 Hz, at 118–140 dB, for 2 minutes, induced disturbances of the visual field as reported by all five human subjects [12]. In 1985, laboratorial animal studies exposed rats to tonal 8 Hz at 100–140 dB, 3 hours daily, for 5, 10, 15, or 25 days, and examined the blood and lymph networks of the palpebral (eyelid) and bulbar (eye globe) conjunctiva. *Day 5*: narrowing of all parts of the conjunctiva blood network was observed, with decreased blood capillary lumens. Capillaries, precapillaries, and arterioles were twisted, and blood component agglomerations were identified in venous vessels. *Day 10*: conjunctiva capillaries were twisted and large vessel diameters were decreased. *Day 15:* blood and lymph vessel tonus had changed, and stagnation was present. *Day 25:* failure of tissue homeostasis was aggravated. Capillary penetration was increased, as seen through tissue enlargement, and significant agglutination was observed in the large vessels [13].

In a similar study, animals were exposed to 8 Hz at 100 dB, or to 16 Hz at 100 dB, 3 hours daily, for 1 month. Clinical and morphological evaluations were conducted at days 3, 7, 15, 30, and also post-exposure at days 30, 60, and 90. *Day 3:* clinical changes were not observed, but morphological changes were present: edema in the upper and middle areas of the eyelid derma and heterogeneous blood filling of vessels with extra-vascular erythrocytes were also observed. Fine focal hemorrhages were identified under the corneous layer of the eyelid. Sclera exhibited edema, and blood vessels were filled heterogeneously with stasis and extra-vascular intraconjunctive hemorrhages. In the 8-Hz group, moderate edema was present near the optical nerve, and the 16-Hz group exhibited perineural hemorrhages in the optical nerve. *Day 7:* in both groups, conjunctiva blood vessels had expanded and arteries in the oculus fundus were narrower and twisted. Eyelid edema of the derma was identified in both groups. The most pronounced vascular changes were found in the eyelid conjunctiva: stasis, edema, and pericapillary hemorrhages. Sclera capillaries were overfilled with blood and extra-vascular hemorrhages were observed. *Day 15:* in both groups, conjunctiva vessels were narrower and twisted, and ocular globe conjunctiva exhibited nonvascularized

**105**

**Table 1.**

*Acoustics and Biological Structures*

*DOI: http://dx.doi.org/10.5772/intechopen.82761*

were observed in either group [14].

were divided into two groups:

Palpebral and bulbar arteries (%)

Retinal arteries (%)

Retinal veins (%)

*occupationally exposed workers [14].*

areas. Vascular changes as seen previously were more expressed: edema, paresis state in capillaries (erythrocyte stasis), and extra-vascular erythrocytes. The iris exhibited narrower vessels. *Day 30:* narrowed and twisted vessels were clinically detected, with ocular fundus arteries and veins significantly narrowed and twisted, more pronounced in the 16-Hz group. In the eyelid conjunctiva, derma exhibited the same vascular changes seen before: edema and erythrocyte stasis. Sclera arteries and veins were larger, overfilled with blood, and with the presence of extra-vascular focal and diffuse hemorrhages with conjunctiva involvement. At all time points, the 16-Hz group disclosed more destruction than the 8-Hz group. *Day 60 (30 days post-exposure)*: clinical evaluations revealed less twisted and narrow arteries and veins, but morphological recovery was slower. In the 8-Hz group, moderate regeneration was observed in the eyelid conjunctiva epithelium. In the 16-Hz group, predominant retinal damage persisted. *Day 90:* no clinical changes

Within an occupational setting (reinforced concrete factory), vessel changes in the palpebral and bulbar conjunctiva, and in the retina, were investigated among 214 workers (age range: 20–58 years), with 1–30 years of employment. Workers

• *Control group* (n = 54): not occupationally exposed to significant levels of infra-

• *Exposed group* (n = 160): tonal 8 and 16 Hz at 96–100 dB, simultaneously with

The exposed group was divided into subgroups as per years of professional activity. **Table 1** describes each subgroup and the vessel abnormalities found. No

Within a different occupational setting (aircraft industry), ocular changes were studied in 23 male workers (average age: 42, range: 32–58 years). Lesions

**Occupational exposure time 1–2 yrs 3–10 yrs 11–20 yrs 20–30 yrs** Number of workers 21 84 36 19

*Enlarged* 0 82 8 0 *Narrow* 0 17 91 100 *Twisted* 0 80 100 100

*Enlarged* 0 0 0 0 *Narrow* 0 91 100 100 *Twisted* 0 90 100 100

*Enlarged* 0 87 11 0 *Narrow* 0 13 88 100 *Twisted* 0 75 97 100

*Percentage of abnormal vessel changes seen in the palpebral and bulbar conjunctiva and retina among*

sonic and lower frequency airborne pressure waves.

such abnormalities were found in the control population [14].

non-tonal 20–500 Hz at 91–93 dBA.


**3. Pathogenesis**

This is a multisystem condition, of unknown etiology, which affects the lungs in most patients (90%) and usually involves the nodes and mediastinum. Cardiac involvement varies according to the population studied and can reach up to 25% [3]. The typical histological feature is the presence of non-necrotizing granuloma (see **Figure 1**) [6] with a central area rich in macrophages, epithelial cells, giant multinucleated cells, and T CD4-positive lymphocytes. In the periphery, there is an abundant population of T CD8 and CD4 lymphocytes, mast cells, and fibroblasts [7]. The origin of this condition is unknown, but one of the theories proposed is antigenic stimulation due to occupational and environmental exposure and infectious agents such as mycobacteria [8].

#### **Figure 1.**

*Cardiac tissue biopsy. Fragments of myocardium can be observed with compromise due to multiple epithelial, non-necrotizing, focal, and coalesced granules, which involve about 30% of the tissue analyzed. The granules contain numerous multinucleated giant cells and, in the confluent areas, are associated with interstitial fibrosis. Stains were negative for mycobacteria and fungi.*


**Author details**

Nuray Misir1\* and Mehmet Misir2

\*Address all correspondence to<EMAIL_ADDRESS>
1 Karadeniz Technical University, Faculty of Forestry, Turkey

2 Department of Forest Management, Turkey

#### **References**

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Modeling of Soil Erosion and Its Implication to Forest Management

http://dx.doi.org/10.5772/ 53741

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[16] Kangas, A., & Kangas, J. (1999). Optimization bias in forest management planning

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[19] Leskinen, P., & Kangas, J. (1998). Analysing uncertainties of interval judgment data

[20] Mabvurira, D., & Miina, J. (2002). Individual-tree growth and mortality models for Eucalyptus grandis (Hill) maiden plantations in Zimbabwe. *Forest Ecology and Man‐*

[21] Megahan, W. F. (1990). Erosion and site productivity in Western-Montane foresteco‐ systems. Symposium on Management and Productivity of Western-Montane. *Boise,*

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[23] Mısır, M. (2001). Developing a Multi objective model forest management plan using GIS and Goal Programming (A case study of Ormanüstü Planning Unit). *Karadeniz*

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[26] Ojansuu, R., Hynynene, J. , Koivunen, J., & Luoma, P. Luonnonprosessit metsalaskel‐

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Umea, Sweden

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2 Department of Forest Management, Turkey

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*woodland ecology, University of Göttingen*.

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[2] Asan, Ü. (1992). letme sınıfı ayrımında fonksiyonel yaklaşım. *Orman Mühendisliği*

[3] Burgman, M., Incoll, W., Ades, P., Ferguson, I., Fletcher, T., & Wholers, A. (1994). Mortality models for mountain and Alpine Ash. *Forest Ecology and Management*, 67,

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[8] De Bano, L. F., & Wood, M. K. (1990). Soil loss tolerance as related to rangeland pro‐ ductivity. Proceedings of the Soil Quality Standards Symposium. U.S. Department of

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[10] Drew, T. J., & Flewelling, J. W. (1977). Stand density management: an alternative ap‐ proach and its application to Douglas-Fir plantations. *Forest Science*, 25, 518-532. [11] Gadow, K., & Hui, G. (1998). Modelling forest development. *Faculty of forest and*

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**Chapter 6**

**Change of Soil Surface Roughness of Splash Erosion**

Soil erosion is a common global environmental problem and undermines sustainable devel‐ opment in various economies and societies. Detailed information about changes in surface roughness during the whole soil erosion process remains limited, however, due to practical difficulties in obtaining direct soil microrelief measurements (Huang, 1998) and a lack in systematic research. The Chinese Loess Plateau is one of the most severely eroded regions in the world, which has created many environmental problems along the lower reaches of the Yellow River. Despite this, however, very little erosion-based research has been conducted on the Loess Plateau. Erosion and runoff processes are influenced mainly by soil surface characteristics such as soil surface roughness, cohesion, and granular stability. Among these characteristics, soil surface roughness is a key parameter (Gómez, and Nearing, 2005; Mir‐ zaei et al., 2008), and is used to describe the variation in surface elevation across a field. The soil surface micro-topography or roughness is strongly influenced by agricultural activities, together with soil properties and climate. The term soil roughness was used to describe dis‐ turbances or irregularities in the soil surface at a scale which was generally too small to be captured by a conventional topographic map or survey. Soil surface roughness is an impor‐ tant parameter in understanding the mechanisms of soil erosion by water and wind. Many erosion related surface processes, such as depression water storage, raindrop or wind shear detachment, and sediment transport have characteristic lengths in millimeter scales. Thus, soil surface roughness resulting from small scale elements is important in understanding these processes and their spatial variation (Huang and Bradford, 1990). Soil surface rough‐ ness determines the storage of water on the soil surface and may indirectly influence its in‐ filtration capacity. The velocity of overland flow is controlled by the hydraulic resistance of the soil surface. Soil surface roughness affects the organization of the drainage pattern on

> © 2012 Zheng and He; licensee InTech. This is an open access article 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.

© 2012 Zheng and He; licensee InTech. This is a paper 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.

**Process**

Zicheng Zheng and Shuqin He

http://dx.doi.org/10.5772/51278

**1. Introduction**

Additional information is available at the end of the chapter


**Author details**

Yanni Sudiyani\*, Muhammad Eka Prastya, Roni Maryana, Eka Triwahyuni and Muryanto Research Center for Chemistry, Indonesian Institute of Sciences, Serpong Tangerang Selatan, Banten, Indonesia

\*Address all correspondence to<EMAIL_ADDRESS>
© 2021 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.


*3.2. Coal Decommissioning Potential*

Figure 11 shows the minimum coal capacity that could satisfy the demand for each of the 30 scenarios. The impact of yearly variations can be observed through the range of minimum coal capacity for each LNG quota scenario. As the LNG quota increases, the coal capacity could gradually be decommissioned without adding additional LNG capacity.

About 3.5 GW of the 7 GW coal capacity is older than 40 years old and should be decommissioned in the near future. However, based on the simulation results, this will be challenging if the LNG quota is not met. In the near term, where 10 GW of solar energy is already installed, the LNG quota must be at least 16 TWh. In the long term, where 16 GW of solar energy is already installed, the LNG quota must be at least 12 TWh. In both cases, as highlighted in Figure 12, around 400 to 600 MW of standby coal capacity is necessary to account for the yearly variations. As noted in the analysis of the demand duration curve, this standby capacity will be needed during the winter and summer periods, particularly in January, February, August, and September (Figure 10). Nonetheless, Figure 12 clearly shows the limitation for solar power in regard to decommissioning coal power plants beyond 12 GW installed capacity, since the minimum coal capacity no longer decreases despite additional solar generation.

**Figure 11.** Minimum required coal capacity as installed solar capacity increases, and various LNG quotas.

**Figure 12.** Standby coal capacity needed to ensure that the electricity grid can still handle weather-driven demand variations.


**Author details**

Hans-Rudolf Weiss1 \* and Deborah Turnbull2,3

1 Schroth Best Practice Academy, Abtweiler, Germany

2 The London Orthotic Consultancy, Kingston upon Thames, UK

3 School of Health and Social Care, University of Teesside, Middlesbrough, UK

\*Address all correspondence to<EMAIL_ADDRESS>
© 2020 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.

*Brace Treatment for Adults with Spinal Deformities DOI: http://dx.doi.org/10.5772/intechopen.92321*


*3.2. Functional Classification of Putative Warming Genes*

As shown in Table 2 and Tables S12–S14, most genes belonging to the GO categories "heat acclimation", "response to heat", and "chromosome organization" were upregulated in both inbred lines, but their levels were higher in Kenshin than in Chiifu. These results suggest that the minor differences in expression of these genes in *B. rapa* could result from long-term adaptation to HS or that the genes identified in *Arabidopsis* could be associated with short-term HS adaptation. *BrCYP71B2* (involved in "heat acclimation") was upregulated in Kenshin under both minor-warming and warming conditions; its homolog is also upregulated upon HS in *Arabidopsis* [35], indicating its possible involvement in the HSR in *B. rapa*. Some putative HT adaptation-related genes have well-known functions in *Arabidopsis*. For example, *Mge1* is induced by heat (under the control of HsfA1) and confers thermotolerance under priming conditions [36]. *Arabidopsis* SMP1 and SWC6 are associated with splicing [37] and chromatin remodeling [38], respectively. These findings suggest that these genes might play a role in HT adaptation in Kenshin. Kenshin-specific genes were classified into four categories ("lipid biosynthetic process", "response to hormone stimulus", "intracellular membrane bound organelle", and "signal transduction") (Table 2; Table S12), but none were found to be involved in HT adaptation, except for auxin-responsive genes. Further studies are needed to investigate the roles of these genes in *B. rapa*.